Contents

Introduction

Chapter 1: How the Minerals Drive the Body’s Essential Processes

Chapter 2: Minerals Needed by the Body

Chapter 3: Superoxide Anions Drive Chronic Diseases and Minerals Are the Antidote

Chapter 4: Calcium, Magnesium, Hard Water and Your Heart

Chapter 5: Taking the Waters: Mineral Waters with Magnesium and Calcium

Chapter 6: Magnesium, Calcium, and Phosphorus: Softening Up the Arteries and Hardening the Bones

Chapter 7: The History and Importance of Copper in the Diet

Chapter 8: Getting the Right Amount of Copper, Zinc, and Iron

Chapter 9: Zinc for the Immune and Endocrine System

Chapter 10: Hypothyroidism and Hyperthyroidism: The Sodium-Selenium-Iodine Connection

Chapter 11: Potassium, Sodium, and Hypertension

Chapter 12: Boron and Other Possibly Essential Trace Minerals

Chapter 13: Sulfur, Glutathione, and Organosulfur Compounds

Chapter 14: Chromium and Blood Sugar Management

Chapter 15: Manganese and Molybdenum: Hidden Players of the Body’s Antioxidant Defense

Chapter 16: Eating for the Minerals and Preventing Deficiencies

Introduction

The criteria for essential nutrients were established in the 1960s and 1970s. It included the following requirements:

1. The element must be able to react with biological materials or form chelates.
2. The element must be ubiquitous in sea waters and the earth’s crust. In other words, it had to be present during the evolution of many organisms and the development of their essential functions.
3. The element must be present in a significant amount in living animals.
4. The element should be toxic only at extremely high intakes compared to regular nutritional intakes.
5. The body should have homeostatic mechanisms for regulating the element’s levels consistently.
6. Deficiencies in the element must have consistent and adverse effects on the body’s biological functions and this change is reversible or preventable with physiological intakes of the element.

There are two kinds of minerals: macrominerals, which you need rather large amounts of, typically more than 100 milligrams (mg) per day, and trace minerals, which are typically consumed in amounts less than 100 mg per day.

There are 17 essential minerals, although there is considerable debate on this number. However, in general, there are 7 essential macrominerals and 10 essential trace minerals. These essential minerals cannot be produced by the body and are considered essential to get in the diet in order for us to live. There are at least 5 minerals that could be considered essential but have yet to be deemed as such.

7 Macrominerals (in general you need more than 100 mg of each per day):

Macromineral: Dietary Sources: RDA/AI in adults

• Calcium: Spinach, nuts, dairy & mineral waters: 1,000- 1,200 mg
• Chloride: Salt, seaweed, celery: Upper limit is typically set at 3,600 mg or 1 tsp of salt. However, intake depends on salt needs.
• Magnesium: Spinach, nuts, seeds, meat, whole grains & mineral waters: 400-420 mg
• Phosphorus: Meat: 700 mg
• Potassium: Potatoes, beans, greens, tomatoes and fish: 2,600-3,400 mg
• Sodium: Salt: Upper limit is usually set at 2,300 mg but this will change based on salt loss.
• Sulfur: Garlic, onions, eggs, Brussel sprouts & mineral water: No RDA set

10 Trace Minerals (in general you need less than 100 mg of each per day)

• Chromium: Brewer’s yeast, lobster mushrooms, chicken, shrimp, black pepper & broccoli: 25-35 mcg
• Cobalt: Liver, fish & beef (comes from food sources of B12 or cobalamin): No RDA but 10-20 mcg has been suggested
• Copper: Liver, oysters, potatoes, mushrooms, shellfish, nuts, seeds and whole grains: 0.9 mg
• Fluoride: Black tea, coffee, shrimp, raisins and grapes: 3-4 mg
• Iodine: Seaweed or nori, oysters, milk, eggs, pink salt, iodized salt, liver, cheese, shrimp & tuna: 150 mcg (220 to 290 mcg for pregnancy and lactation, respectively)
• Iron: Oysters, white beans, dark chocolate, liver, lentils, red meat, sardines & spinach: 8 mg for men and 18 mg for women (19- 50), 8 mg for men and women 51 years and older.
• Manganese: Mussels, whole grains, hazelnuts, pecans, brown rice, oysters, clams, chickpeas, spinach, pineapple and almonds: 1.8-2.3 mg
• Molybdenum: Black-eyed peas, beef liver, lima beans, yogurt, milk, potatoes, and bananas: 45 mcg
• Selenium: Brewer’s yeast, selenium from yeast, Brazil nuts, tuna, halibut, sardines, ham, shrimp & beef: 55 mcg
• Zinc: Oysters, beef, crab, lobster, pork, baked beans, chicken, pumpkin seeds, yogurt, cashews, and cheese: 8-11 mg

5 Possibly Essential Trace Minerals

• Boron: Prunes, raisins, almonds, peanuts, hazelnuts, dates and apples: No RDA/AI established but a diet high in boron is considered to contain 3.25 mg/2,000 calories
• Lithium: Mineral water, grains, vegetables, mustard, kelp, pistachios, dairy, fish and meat: No RDA/AI
• Nickel: Black tea, nuts and seeds, cacao, chocolate, meat, fish, and grains: No RDA/AI
• Silicon: Whole grains, fruits & vegetables: No RDA/AI
• Vanadium: Mushrooms, shellfish, black pepper, beer, wine, grains and certain unrefined salts: No RDA/AI

Rheumatoid arthritis and other inflammatory disorders, can cause levels of iron, zinc and selenium to drop in the blood and hence in the hair. High amounts of inflammation can increase copper levels in the blood and in the hair even when there is copper deficiency.

The % of the U.S. population not meeting the RDA or AI for minerals is as follows:

1. Boron (no RDA established, > 75% are likely deficient based on our estimate)
2. Manganese (~75%, our estimate)
3. Magnesium (52.2-68%)
4. Potassium (~ 50-60%)
5. Calcium (44.1-73%)
6. Zinc (42%)
7. Iron (34%)
8. Copper (31%)
9. Selenium (15%)

Here are the Main Reasons for Widespread Mineral and Nutrient Deficiencies

The Overconsumption of Highly Refined Foods:

• The inflammation that occurs in the body when we overconsume these processed foods also increases mineral demand as more minerals get shunted towards antioxidant enzymes to handle increased oxidative stress rather than being utilized for other essential purposes. Many of these processed foods also induce high insulin levels, which cause us to lose calcium and magnesium out the urine and insulin resistance reduces the entry of magnesium and potassium into the cell.

Soil Erosion, Fertilizers, Pesticides, Herbicides and Insecticides:

• The food that we now eat is about 30% less nutritious than the same food from 1940. That means you literally need to eat 30% more food to get the same level of minerals that someone used to get who lived just 80 years ago. And who knows how less nutritious our food was back in 1940 compared to what we evolved eating tens of thousands of years ago.
• The problem lies in not getting enough calories and macronutrients but missing out on the key micronutrients, especially minerals.
• The reduction of minerals in our food is the result of using pesticides and fertilizers that kill off beneficial bacteria, earthworms, and bugs in the soil that create many of the essential nutrients in the first place and inhibit the uptake of nutrients into the plant. Fertilizing crops with nitrogen, phosphorus and potassium has led to declines in magnesium, zinc, iron and iodine.
• There has been on average about a 30% decline in the magnesium content of wheat. This is partly due to potassium being an antagonist for magnesium absorption by plants. Lower magnesium levels in soil also occur with acidic soils and around 70% of the arable land on earth is now acidic.
• Even the seeds of today are lower in nutrients than before. For example, wheat seed micronutrient contents in Kansas from 1920 to 2000 showed decreases in numerous minerals including zinc (-11 to -31%), iron (-24%) and selenium (-16%). The way we grow broccoli has also led to reductions in the manganese content by around 27% compared to 1950.
• Other issues that damage the soil’s nutrient content include possible mineral binding due to the herbicide glyphosate making minerals less available to plants. Indeed, glyphosate drift has been found to reduce the concentrations of calcium, manganese, and magnesium in young leaves of non-glyphosate resistant soybean plants and the seed concentrations of calcium, magnesium, iron and manganese.

Heavy Metals Competing with Absorption:

• Heavy metals like aluminum, lead, cadmium, arsenic, and mercury can accumulate in the food supply from industrial pollution. These heavy metals can compete for mineral absorption as well as mineral binding sites on enzymes. Thus, heavy metals deplete and reduce the functions of minerals in the body.
• The selenium to mercury ratio of seafood matters more than the overall mercury content as selenium reduces mercury toxicity and in many instances foods that are highest in mercury, such as tuna, are also very high in selenium.
• The 5 most common heavy metal toxins in the body are:

1. Aluminum (9.4%)
2. Lead (3.0%)
3. Cadmium (0.8%)
4. Arsenic (0.1%)
5. Mercury (0.1%)

• Heavy metals also increase inflammation in the body, which can increase the body’s mineral requirements, as there is a greater need for antioxidant enzymes to counteract heavy metal-induced inflammation.
  • There is copper,zinc-superoxide dismutase (Cu,ZnSOD). There is another superoxide dismutase in the mitochondria that needs manganese to function (MnSOD). Glutathione peroxidase and peroxiredoxin, both of which helps handle hydrogen peroxide, requires selenium. Selenium is needed to reduce thioredoxin, which donates an electron to peroxiredoxin to help it reduce and take care of hydrogen peroxide. Peroxiredoxin is also needed to reduce the toxic oxidant peroxynitrite, which is formed when superoxide combines with nitric oxide. Hence, selenium is needed to also handle peroxynitrite. Thioredoxin reductase and methionine sulfoxide reductase also require selenium and both are needed to protect methionine residues on proteins from oxidizing and to recycle them once they get oxidized.
  • Magnesium deficiency can reduce glutathione levels and increase the susceptibility of our tissues to oxidative stress.

Chapter 1: How the Minerals Drive the Body’s Essential Processes

Minerals Driving Energy Production

In total, there are up to 22 vitamins and minerals that support mitochondrial enzymes and are needed for energy production. Minerals also help to activate antioxidant enzymes that protect the mitochondria from oxidative stress. Deficiencies in these minerals can lead to a reduction in ATP production, mitochondrial degradation and can accelerate mitochondrial aging.

Importantly, magnesium is needed as a cofactor in several electron transport chain complex subunits, including methylenetetra-hydrofolate dehydrogenase 2 and pyruvate dehydrogenase phosphatase, and controls GLUT4 translocation to the cell membrane surface. GLUT4 is a glucose transporter that helps bring glucose into the cell for energy production. Thus, magnesium deficiency can contribute to a lack of ATP production in the mitochondria. 

The inner mitochondrial membrane contains the electron transport chain (ETC), which is a series of 5 complexes that transfers electrons and protons across the membrane. This drives the creation of ATP by complex V (otherwise known as ATP synthase). Energy containing cofactors like NADH and coenzymes like FADH are used to deliver electrons to the electron transport chain for ATP production.

In the electron transport chain, NAD+ functions as an electron transfer molecule. NAD has two forms: NAD+ and NADH which both govern electron transfer reactions:

• NAD+ is an oxidizing agent that picks up electrons from other molecules and thus becomes reduced.
• NADH is a reducing agent that forms from reduced NAD+ and it can then be used to donate electrons to other molecules, thus becoming NAD+ again.

There are 5 membrane-bound complexes in the mitochondrial electron transport chain – complex I, II, III, IV and V. They are all embedded inside the inner mitochondrial membrane. Here is an overview of their role and function:

• Complex I – In complex I, NADH gets stripped of two electrons that get transported to a lipid-soluble carrier called ubiquinone (Q). Every electron passes through an iron-sulfur cluster. As electrons become oxidized and reduced, an electron current gets formed, which powers the transport of 4 protons per 2 electrons of NADH into the intermembrane space.
• Complex II – In complex II, additional electrons are delivered to Q by succinate dehydrogenase (SDHA), fatty acids, glycerol 3-phosphate, and other electron donors. Complex II doesn’t carry any protons into the intermembrane space, thus contributing less total energy to the electron transport chain.
• Complex III – In complex III, electrons are carried to cytochrome c within the intermembrane space through a proton movement system called the Q-cycle. It works by sequential oxidation and reduction of coenzyme Q10 (CoQ10).
• Complex IV – In complex IV, 4 electrons are removed from the 4 molecules of cytochrome c and transported to molecular oxygen (O 2). This creates 2 water molecules.
• Complex IV contains copper ions and multiple heme groups.
• Complex V (ATP synthase) – Complex V is also called ATP synthase because it generates ATP from ADP and inorganic phosphate created by the proton electrochemical gradient. ATP synthase consists of two sub-units FO and F1, which work as a rotational motor. Calcium stimulates ATP synthase.

Carbohydrates, proteins, fatty acids and ketones will ultimately be broken down into acetyl-CoA, which then delivers the acetyl group into the citric acid cycle (TCA or Krebs cycle). Acetyl-CoA created from carbohydrates happens via glycolysis and via beta-oxidation from fatty acids. These pathways require zinc, magnesium and chromium, which ensure the capacity for energy expenditure and muscle performance.

• Zinc is required to form pyruvic acid from lactic acid – the metabolic product of glucose metabolism.
• Selenium deficiency causes defects in mitochondrial structure, integrity, and electron transport chain function.
• Removal of extracellular magnesium ion inhibits glycolysis and limits glucose transport by red blood cells.
• The availability of zinc, iron and chromium are necessary for the synthesis of insulin and glucose utilization, which contributes to ATP production by the mitochondria.
• Mitochondrial fat oxidation, which also contributes to ATP production, is initiated by calcium. Calcium is a key regulator of mitochondrial function because it is involved in many mitochondrial enzymes, such as pyruvate dehydrogenase and α-ketoglutarate dehydrogenase as a cofactor.

The entry of acetyl-CoA into the TCA cycle needs magnesium and manganese, which creates NADH and FADH2 to then feed into the electron transport chain (which needs iron and copper) to produce adenosine triphosphate (ATP) the energy currency of cells. All reactions where ATP is involved require magnesium ions. The magnesium ion is an integral part of the last enzyme in the respiratory chain, which initiates reduction of molecular oxygen. As a component of membranes and nucleic acids, magnesium is present in the mitochondria.

• Magnesium and copper are the star minerals for making ATP and without enough ATP or energy this can lead to fatigue. By binding to ATP and releasing the terminal phosphate, magnesium activates ATP and liberates its energy.
• A deficiency in magnesium can lead to mitochondrial damage and decreased ATP formation through potassium depletion and sodium and calcium overload. Administrating magnesium can improve symptoms of chronic fatigue and these benefits are associated with increasing low magnesium levels in red blood cells in these patients. Patients treated with magnesium report improved energy levels, better emotional state and less pain. Thus, it might be that people with chronic fatigue or burnout are actually deficient in magnesium or other minerals involved with energy production.

Zinc, selenium, iron, copper, manganese, magnesium and iodine are all needed for proper thyroid functioning.

Magnesium:

• Essential for nerves and muscle function
• Co-factor in over 600 enzymatic reactions
• Required for ATP production and transportation

Calcium:

• Essential for nerves and muscle function
• Initiates fat oxidation
• Carries ATP with magnesium

Phosphorus:

• Structural component of ATP and creatine phosphate
• Part of energy metabolism as it makes up ATP

Copper:

• Essential co-factor of cytochrome c oxidase – the last part of the mitochondrial electron transport chain
• Involved in iron metabolism and balance

Chromium:

• Potentiates the actions of insulin and thus glucose uptake
• Needed for glycolysis and ATP production

Iron:

• Essential part of hemoglobin for oxygen transport
• Facilitates transfer of electrons in the respiratory chain
• Necessary for red blood cell function

Manganese:

• Co-factor of enzymes involved in carbohydrate metabolism and gluconeogenesis

Zinc:

• Essential for glycolysis and beta-oxidation
• Part of over 100 enzymes involved in energy metabolism
• Needed for producing thyroid hormones

Selenium:

• Needed for producing thyroid hormones
• Needed for glutathione and antioxidant production

Iodine:

• Needed for producing thyroid hormones
• Affects metabolic rate and energy metabolism

Electrolytes and Minerals

The main electrolytes are sodium, potassium, magnesium, phosphate, calcium, chloride and bicarbonate. There are others like zinc, copper, iron, manganese, molybdenum and chromium. You obtain these minerals from food, water and supplements.

Electrolytes, especially sodium, help your body maintain normal fluid levels in the blood, within cells and outside of cells. How much fluid each of these compartments hold depends on the amount and concentration of electrolytes in it.

• If the electrolyte concentration is too low, fluid will leave that particular compartment (blood or intra-, extracellular space)
• If the electrolyte concentration is too high, fluid will move into that particular compartment (osmosis).

The Sodium-Potassium Pump moves sodium ions out and potassium ions into the cell. This is powered by magnesium and ATP. For every ATP that gets broken down, 3 sodium ions move out and 2 potassium ions move in.

Electrolyte imbalances can have many negative health consequences such as heart failure, arrythmias, oxidative stress or even death.

• Fluid and electrolyte imbalances are most often caused by dehydration, excessive sweating, vomiting, diarrhea and nutrient deficiencies. Certain conditions like kidney disease, anorexia nervosa, and medical burns can also cause this.
• Symptoms of electrolyte imbalances include chronic fatigue, irregular heartbeat, high blood pressure, brain fog, sleeping problems, muscle weakness, cramping, headaches and numbness.

Here are the reference ranges for electrolytes measured through blood:

• Calcium: 5–5.5 mEq/L
• Chloride: 97–107 mEq/L
• Potassium: 5–5.3 mEq/L
• Magnesium: 1.5-2.5 mEq/L
• Sodium: 136–145 mEq/L

To avoid electrolyte imbalances, you have to be obtaining enough minerals from food and liquids. You also need to avoid damage to your organs like your intestines, liver and kidneys so you don’t lose the ability to absorb, reabsorb and/or utilize these minerals.

Magnesium is what primarily regulates the sodium potassium pump. However, a lack of sodium can lead to magnesium deficiency, as can a lack of vitamin B6 or selenium. Thus, salt, vitamin B6 and selenium also control the sodium potassium pump indirectly because they control magnesium status in the body. When in a magnesium deficient state, calcium and sodium accumulate in the cell, promoting hypertension and cardiomyopathy. Magnesium protects against potassium loss and muscle potassium levels won’t normalize unless magnesium status is restored even when serum potassium rises.

Chapter 2: Minerals Needed by the Body

Minerals Needed by the Brain

Serotonin (5HT) regulates cognition, mood, and sleep in the central nervous system. Serotonin is both an inhibitory and excitatory neurotransmitter. In the enteric (intestinal) nervous system, serotonin affects digestion, motility and sensation. A serotonin deficiency in the brain causes symptoms of depression and decreased social exploration. Serotonin also gets converted into melatonin, which is called the main sleep hormone, but it also governs central antioxidant and repair processes during nocturnal sleep.

To make serotonin and melatonin, you need magnesium, calcium, iron, copper, cobalt and zinc. About 2% of the circulating amino acid tryptophan is converted into 5-hydroxytryptophan (5HTP) by tryptophan hydroxylase, which is an enzyme that uses 5-MTHF (the active form of folate), iron, calcium, and vitamin B3 as cofactors. 5HTP is further converted into serotonin by an enzyme called dopa decarboxylase, which uses magnesium, zinc, vitamin B6 and vitamin C as co-factors.

• Melatonin is also synthesized in local tissues outside of the brain, such as the retina, bone marrow, gastrointestinal tract and the innate immune system, which takes place in the mitochondria. Besides the retina, melatonin production outside of the pineal gland in the brain does not follow circadian rhythms and functions primarily as an antioxidant. Melatonin is primarily a mitochondrial-targeted antioxidant that protects the mitochondria against oxidative stress and damage.

The magnesium ion is required for activating vitamin B6, which helps the conversion of serotonin into melatonin. Supplemental magnesium improves subjective measures of insomnia such as sleep onset latency and efficiency in the elderly. In patients with primary insomnia, administration of melatonin, zinc and magnesium improves the quality of sleep and quality of life.

Calcium helps tryptophan to be converted into 5-HTP by tryptophan hydroxylase, thus enabling melatonin production. A study found that fixing a calcium deficiency helped to regain normal REM sleep.

Potassium supplementation has a positive effect on sleep quality and slow-wave-sleep. Since magnesium controls the levels of potassium in the body this further highlights the importance of both magnesium and potassium for sleep.

Dopamine is both a hormone and a neurotransmitter that regulates mood, motivation, well-being and the feeling of reward. Imbalances in dopamine affect fatigue in multiple sclerosis and other neurological disorders. With aging, dopamine levels decrease, causing cognitive inflexibility and rigidity. Not producing enough dopamine may cause symptoms of depression, anxiety, apathy and promote pleasure seeking from harmful activities like drugs or alcohol.

• Dopamine is created from the amino acid L-tyrosine. Tyrosine hydroxylase converts L-tyrosine to L-dopa, which gets converted into dopamine. Both tyrosine hydroxylase and tryptophan hydroxylase contain iron. Iron deficiency is associated with anxiety, depression, social problems, and behavioral abnormalities. Magnesium and zinc also help with potentiating dopamine production. During protein turnover, the active form of vitamin B6, pyridoxal 5-phosphate, requires Mg-ATP and potassium for its reformation in the salvage pathway. Thus, both magnesium and potassium help to keep active vitamin B6 levels at sufficient levels. Additionally, magnesium is used with active vitamin B6 to convert L-dopa to dopamine, which then requires copper to be converted into norepinephrine. Norepinephrine is the third primary neurotransmitter in the brain and its levels are typically decreased in those with major depressive disorder. Medications that treat depression block the reuptake of serotonin and norepinephrine increasing their levels in the brain, whereas minerals help to boost their levels naturally.

Magnesium, as noted previously, is needed for creating neurotransmitters and hormones like serotonin, dopamine, norepinephrine and melatonin. Low magnesium intake is associated with depression in a near linear fashion. Magnesium supplementation of 450 mg per day was found to improve symptoms of depression and was comparable to the antidepressant drug imipramine. Magnesium can also be helpful in treating anxiety symptoms. Magnesium deficiency induces anxiety and HPA axis dysfunction. In bipolar disorder and mania, magnesium can stabilize mood. There is a clearly established link between the development of migraines and magnesium. 

Iron is an essential cofactor for the synthesis of neurotransmitters and myelin. Deficient iron levels are associated with cognitive decline in the elderly. In toddlers, a deficiency in iron causes poor cognitive development, which impairs brain morphology and cognition. However, high iron levels in the brain are associated with Alzheimer’s disease. That is because iron is a major source of reactive oxygen species and oxidation. In reality, the loss in the ability to utilize iron, which can occur with copper deficiency for example, may be driving many of these iron ‘overload’ issues.

Zinc is the most concentrated metal in the brain next to iron. It has an important role in synaptic transmission, nucleic acid metabolism and axonal transmission. There is an association between higher zinc levels during aging and healthy brain aging. In the elderly, zinc concentrations are higher in those with unimpaired cognitive function compared to those with memory impairment. Children with ADHD have reduced ADHD symptoms when given a zinc supplement for 12 weeks. And zinc imbalances may cause neuronal death, neurological disorders, stroke, epilepsy and Alzheimer’s disease.

Here are the most important organs and tissues that need various minerals

Heart – related to cardiac function, cardiovascular disease risk, atherosclerosis, hypertension and stroke.

• Magnesium has a central role in protecting against cardiovascular disease and regulating the function of the heart. In addition to activating ATP, magnesium also runs the sodium potassium pump, thus controlling blood pressure. Magnesium deficiency promotes hypertension via cellular accumulation of calcium and sodium. Magnesium is also a cofactor for the enzymes involved in cardiac mitochondria. Self-reported magnesium intake is inversely associated with arterial calcification, stroke and fatal coronary heart disease and its supplementation has been found to reduce the incidence of cardiac arrhythmias.
• Potassium intake is inversely related to overall mortality, stroke, hypertension and heart disease. It controls the heartbeat and muscle function. Potassium deficiency contributes to cardiovascular disease by promoting atherosclerosis and hypertension. Because of its relationship with sodium, potassium affects intracellular fluid concentration and plasma volume. The primary role of potassium is that it allows the body to effectively use and handle sodium. Hence, many people who cannot tolerate normal sodium intakes simply need more dietary potassium and/or magnesium.
• Zinc status affects heart health by regulating heart muscle and cardiac function. Low zinc is associated with diabetic cardiomyopathy and animal studies have found that zinc supplementation protects against this. Heart failure is also found to be connected to lower selenium and zinc and higher copper concentration. In overweight type-2 diabetic subjects, zinc supplementation reduces inflammation and oxidative stress, which are risk factors for cardiovascular disease. Zinc supplementation (40 mg plus 1 mg of copper twice daily) in those 50-80 years old significantly reduced mortality by 27% in the AREDS study.

Gut, intestines, intestinal lining and the microbiome.

• It is estimated that 80-90% of the serotonin in the body is made in the gut with the help of microbes. That process requires magnesium, zinc and iron. In magnesium-deficient mice, intestinal bifidobacteria levels (the bacteria considered to be beneficial) are associated with inflammation induced by magnesium deficiency. Low magnesium signals the intestinal colonization of Escherichia coli, which is a pathogen responsible for hemorrhage of the intestines. Magnesium deficiency alters the gut microbiota and causes depressive-like behavior.
• Melatonin is also produced by the enterochromaffin (EC) cells in the gastrointestinal (GI) tract. EC cells take up tryptophan from the bloodstream and converts it into 5-HTP by tryptophan-5- hydroxylase. 5-HTP then gets decarboxylated into serotonin or 5-HT. The melatonin synthesis rate-limiting enzyme AANAT acetylates serotonin into N-acetyl serotonin (NAS), which gets further methylated by HIOMT into melatonin. Zinc and magnesium enhance melatonin production by binding to AANAT, thus increasing serotonin’s affinity for binding to AANAT. There is a direct correlation between serum zinc and melatonin levels in human patients. In rodents, omega-3 fatty acid deficiency reduces nighttime melatonin, which is normalized by DHA supplementation.
• Malabsorption, intestinal permeability and lack of digestive enzymes can cause low magnesium levels due to lack of intestinal absorption. Dietary magnesium also helps to decrease the intestinal absorption of lead. Zinc supplementation has been shown to improve intestinal barrier function and resolve permeability in patients with Crohn’s disease.
• Daily consumption of magnesium-rich mineral water improves bowel movement frequency and stool consistency in subjects with constipation. Even magnesium oxide, which tends to have low solubility but very high elemental magnesium levels, has been shown to improve bowel movements in chronic constipation.

Liver – everything related to liver function and energy metabolism is controlled by the liver.

• In both alcoholic- and nonalcoholic fatty liver disease, low magnesium levels have been found and a magnesium deficiency may be a risk factor for these conditions. Higher magnesium levels are associated with a reduced risk of mortality from liver disease. Excess iron can also cause liver damage because of its high oxidative capacity.
• Liver detoxification pathways require zinc, selenium, magnesium and molybdenum. The liver also produces bile, which is a substance that helps to break down fat from food and removing toxins from the body. 

Eyes – everything related to vision, eye health, and preventing macular degeneration.

• Blurry vision might be caused by a magnesium deficiency. Oral magnesium supplementation in normotensive glaucoma patients improves visual fields and vision. Magnesium may even protect against glaucoma and retinal neuropathy.
• Selenium has been shown to slow down the development of Graves’ eye disease and orbitopathy. And a selenium deficiency promotes Graves’ eye disease.
• Zinc supplementation with vitamin C and E reduces the risk of developing age-related macular degeneration. However, high levels of zinc are found in age-related macular degeneration suggesting a loss in zinc utilization.

Collagen – everything related to the skin, tendons, ligaments and soft tissue.

• Copper is essential for collagen and elastin synthesis. In young women, copper supplementation increased collagen formation. Zinc deficiency slows down tissue regenerative processes and administrating zinc normalizes this. Additionally, zinc may promote bone formation by stimulating cell proliferation similarly to the way it does with collagen synthesis.

Minerals for Managing Stress and Steroid Hormones

All nutrients and minerals follow a hormetic U-shaped curve.

• Magnesium is one of the most relevant minerals for the nervous system and stress management. Stress depletes magnesium by activating the sympathetic nervous system and supplementation helps to reduce this effect. Although not conclusive, studies on humans as well as animals show that magnesium supplementation can alleviate many of the negative side-effects of stress like anxiety, depression and sleeping problems.
• Potassium is important for cardiovascular function, nerve firing, muscles and endurance. Deficiencies in potassium can weaken muscle contraction, cause arrhythmias and impair insulin production.
• Sodium is important for energy production, digestion, and electrolyte balance. Deficiencies in sodium can cause muscle cramping, brain fog, fatigue, water retention and even insulin resistance. Low-salt diets also raise triglycerides, LDL cholesterol and lower HDL. Although reducing salt intake can lower blood pressure in hypertensive subjects, there is no evidence that salt restriction reduces the risk of heart attacks or mortality. In fact, several reports show that less than 3,000 mg of sodium per day is linked to a significantly higher chance of dying overall or from heart disease. Thus, the real problem isn’t salt, which is composed of two essential minerals sodium and chloride, it’s insulin resistance and metabolic syndrome that doubles the risk of cardiovascular disease and increases all-cause mortality.
• Iron is essential for hemoglobin transportation, which helps to transfer oxygen to muscles and cells. Iron deficiency anemia is one of the most common nutrient deficiencies in the world and it causes chronic fatigue and lethargy (although some of these cases may actually be due to copper deficiency). Excess iron is a risk factor for cardiovascular disease and can be toxic. Consult your doctor first before supplementation or increasing dietary iron intake.
• Zinc plays an important role as a structural agent of proteins and cell membranes preventing oxidative stress. Low zinc status can cause gastrointestinal problems and increase the risk of pneumonia.

Corticosteroids are a class of steroid hormones that are synthesized in the adrenal cortex from cholesterol. The most common steroid hormones are aldosterone, testosterone, cortisol, cortisone, pregnenolone, progesterone, DHEA and others. Steroid hormones regulate metabolism, inflammation, body composition, immunity, stress adaptation, and recovery from injuries.

In order to make steroid hormones, vitamin D and DHEA, you need complex II, III, and IV, which are dependent on selenium, copper, magnesium, and iron. You also need ferredoxin and ferredoxin reductase for producing steroid hormones, which are iron-sulfur proteins (thus we need iron and sulfur). Anytime iron is needed in a reaction that automatically means copper is needed because copper is needed to oxidize ferrous iron (Fe2+) to ferric iron (Fe3+) so iron can move and be transported around the body. Thus, you need adequate levels of numerous minerals to produce sex hormones, corticosteroids and other steroid hormones.

Steroid hormone synthesis is regulated by trophic hormones like adrenocorticotropin hormone (ACTH) and luteinizing hormone (LH). They activate G protein-coupled receptors, promoting intracellular cyclic AMP (cAMP) levels, which supports cAMP-dependent protein kinase (PKA), protein synthesis, and protein phosphorylation. All of these processes assist in delivering cholesterol from the outer mitochondrial membrane to the inner one, which overcomes the rate-limiting step in producing steroid hormones.

Zinc deficiency is associated with lower testosterone in men and supplementation can improve testosterone levels. Magnesium also affects free and total testosterone levels.

Magnesium sulphate helps with the formation of cyclic AMP and governs its antiplatelet effects, thus affecting steroidogenesis. ATP is also required for steroid synthesis, which requires iron, copper, manganese and magnesium.

Malnourished individuals are more vulnerable to infections and illness because their immune system lacks the nutrients to function properly.

• Selenium is an essential mineral that helps increase glutathione levels. It’s also important for hormonal balance, antioxidant defense and balancing oxidative stress in the body.
• Magnesium is important for all bodily processes, including immunity. Magnesium deficiency elevates proinflammatory cytokines like TNF-alpha and reduces CD8+ T cells. Magnesium deficiency in immune cells can reduce their ability to kill viruses and increase Epstein-Barr activation.
• Zinc is important for synthesizing hormones and for a strong immune system. Studies on children show that regular use of zinc can prevent the incidence of the flu. Zinc acetate and zinc gluconate lozenges have been shown to inhibit cold viruses from latching onto cells and shorten flu duration. Lozenges are beneficial only if used in the early stages of infection. The optimal total daily dose is above 75 mg/day divided into multiple doses taken 2–3 hours apart. The best results are achieved when starting within 24 hours of first symptoms.

One of the most impactful forms of oxidative stress is DNA damage that results in mutations and genomic instability. This may lead to cancer, chronic diseases and accelerated aging because the DNA replication mechanism stops working properly. Unrepaired DNA damage leads to the accumulation of misfolded proteins, inflammatory cytokines, and dysfunctional cells, which can spread inflammation and lead to accelerated aging. Cellular senescence occurs in response to DNA damage that results from exposure to reactive oxygen species (ROS) and free radicals. Deficiencies in DNA repair mechanisms increase the frequency of mutations and leaves cells more vulnerable to malignancies. Reduced DNA repair protein activity are seen in early stages of cancer and are thought to contribute to the genetic instability of cancer.

• Magnesium deficiency increases the risk of oxidative damage to DNA. Importantly, magnesium is needed to activate the enzymes involved with DNA repair, DNA replication and transcription.
• Zinc can antagonize the toxic heavy metal cadmium, an inducer of oxidative stress that plays a role in DNA damage and premature cellular aging. Zinc is important in maintaining DNA integrity and zinc deficiency increases DNA damage. Moreover, a 12-week clinical study in elderly subjects with low serum zinc levels showed that supplemental zinc (20 mg/day of zinc from zinc carnosine) reduced DNA damage and improved the antioxidant profile. Zinc deficiency in human cells causes the release of more oxidants, resulting in oxidative damage to DNA.

Autophagy has a protective role against many metabolic and age-related diseases such as insulin resistance, heart disease, atherosclerosis, inflammation, Crohn’s, bacterial infections, neurodegeneration, gut health, fatty liver and aging in general.

• In vitro studies have shown that zinc is critical for basal autophagy. In yeast, zinc depletion induces non-selective autophagy by inhibiting mTORC1, which leads to the recycling of zinc from degraded proteins.
• Calcium has been shown to control various stages of autophagic flux by triggering autophagy but also inhibiting it. Low potassium activates calcium signaling, which results in chronically excessive autophagy, leading to calcification. So, activating autophagy with calcium isn’t a good thing.
• Magnesium is needed for calcium absorption and without enough magnesium calcium will begin to accumulate in soft tissue. Elevated levels of magnesium inhibit extracellular matrix calcification and protects articular cartilage via Erk/autophagy pathway.

Nutrient: Synergistic Relationship (SR): Varies Based on Nutrient Levels (VBNL): Antagonistic Relationship (AR)

• Vitamin A: SR: Iodine, Iron, Zinc: VBNL: Vitamin E: AR: Vitamin K, Vitamin D
• Vitamin B1 (Thiamine): SR Magnesium: AR: Vitamin B6
• Vitamin B2 (Riboflavin): AR: Calcium
• Vitamin B3 (Niacin): SR: Zinc
• Vitamin B5 (Pantothenic Acid): AR: Copper
• Vitamin B6 (Pyridoxine): AR: Vitamin B1, Vitamin B9, Zinc
• Vitamin B7 (Biotin): VBNL: Vitamin B5
• Vitamin B9 (Folic Acid): AR: Vitamin B6, Vitamin B12, Zinc
• Vitamin B12 (Cobalamin): AR: Vitamin B9, Vitamin C
• Vitamin C: SR: Vitamin E: VBNL: Copper, Iron, Selenium: AR: Vitamin B12
• Vitamin D: SR Vitamin K, Calcium, Magnesium, Selenium: AR: Vitamin A, Vitamin E
• Vitamin E: SR: Vitamin C, Selenium, Zinc: VBNL: Vitamin A: AR: Vitamin D, Vitamin K
• Vitamin K: SR: Calcium: VBNL: Vitamin D: AR Vitamin A, Vitamin E
• Calcium: SR: Vitamin D, Potassium: AR: Magnesium, Phosphorus, Sodium, Iron, Manganese, Zinc
• Magnesium: SR: Vitamin B1, Vitamin B6, Vitamin D, Potassium: AR: Calcium, Phosphorus, Zinc
• Phosphorus: AR: Calcium, Magnesium
• Potassium: SR: Calcium, Manganese, Sodium
• Sodium: SR: Potassium: AR: Calcium
• Copper: VBNL: Vitamin C: AR: Iron, Molybdenum, Selenium, Zinc
• Iodine: SR: Vitamin A, Selenium
• Iron: SR: Vitamin A, Vitamin C: AR: Vitamin E, Calcium, Copper, Manganese, Zinc
• Manganese: AR: Calcium, Iron
• Molybdenum: AR: Copper
• Selenium: SR: Vitamin D, Vitamin E, Iodine: VBNL: Vitamin C: AR: Copper
• Zinc: SR: Vitamin A, Vitamin B3: AR: Calcium, Magnesium, Copper, Iron
• Sulfur: SR: Molybdenum

Low micronutrient intakes can even accelerate the so-called degenerative diseases of aging. This is known as the triage theory invented by Bruce Ames. The idea is that if you are deficient in a particular micronutrient, it gets triaged where it is needed most for survival while non-vital functions suffer causing insidious diseases such as cancer, metabolic disease and vascular calcifications. Although virtually impossible to prove with long-term randomized controlled trials, this logic is consistent with evolutionary theory, wherein natural selection favors short-term survival and reproduction over long-term health and nutritional status.

Chromium, vanadium and magnesium are some of the most common deficiencies associated with diabetes.

Chapter 3: Superoxide Anions Drive Chronic Diseases and Minerals Are the Antidote

Most free radicals are very reactive and they can cause oxidative damage. However, free radicals are also important for inducing hormesis, whereby a small exposure to free radicals makes our body more resilient to them in the future.

A reducing agent is a compound that can donate an electron to a free radical to neutralize it. For example, NADPH is the universal electron donor in the body and it helps to recycle or “reduce” oxidized glutathione back to its reduced or unoxidized form.

Age-related impairments in the mitochondrial respiratory chain decrease ATP synthesis, damage DNA, and make the cells more susceptible to oxidative stress.

Superoxide and Peroxynitrite – Worst of the Free Radicals

Oxidative stress results from an imbalance in the proinflammatory molecules compared to the anti-inflammatory enzymes and antioxidants in the cell – more pro-oxidants than antioxidants mean chronic inflammation and mitochondrial/tissue damage. Free radicals are implicated in serious health conditions like atherosclerosis, diabetes, cancer and neurodegeneration.

Harmful free radicals include superoxide anion radical (O 2 *), reactive oxygen species (ROS), superoxide anion (O 2 *), hydrogen peroxide (H 2 O 2), singlet oxygen, hydroxyl radical (OH •), peroxy radical, as well as the second messenger nitric oxide (NO •), which can react with O 2 * to form peroxynitrite (ONOO −). They can be created from internal sources during mitochondrial energy production or through exposure to external stimuli like pollution or poor diet.

The body has an entire grid of antioxidant systems that consists of multiple lines of defense:

• The first line of defense includes antioxidant enzymes called superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) that suppress or prevent the formation of free radicals. They are quick to neutralize any molecule that has the potential to turn into a free radical.
• The second line of defense refers to antioxidants that scavenge active free radicals and thus inhibit a chain reaction of oxidative stress. Antioxidants belonging to this group include ascorbic acid, vitamin E, glutathione and ubiquinol. By donating one of their electrons to the free radical they neutralize it. In the process these antioxidants become free radicals themselves (but much fewer damaging ones) and will get neutralized by other antioxidants.
• The third line of defense is utilized once free radical damage has already occurred. It includes DNA damage repair proteins, enzymes, and lipids, such as the DNA repair enzyme systems (polymerases, glycosylases, and nucleases) and proteolytic enzymes (proteinases, proteases, and peptidases). They are important for repairing damage including post-insult damage as is seen in COVID-19 long haulers or radiation exposure.
• The fourth line of defense involves forming and transporting antioxidants to the site of injury for adaptation and to prevent additional free radicals from being created there. They react to the signals created by free radicals.

Unrepaired DNA damage leads to the accumulation of misfolded proteins, inflammatory cytokines and dysfunctional cells, which can spread inflammation and induce accelerated aging.

To deal with environmental stress and oxidative damage, organisms have evolved systems of DNA damage response (DDR). This includes DNA repair mechanisms, damage tolerance and adaptation. The rate of DNA repair depends on many factors, such as cell type, age of cell and the surrounding environment. A cell that has accumulated too much DNA damage, or no longer repairs itself, can go into one of three states:

• Senescence – zombie cell in irreversible dormancy and disease. These cells can also secrete proinflammatory molecules damaging healthy surrounding tissues.
• Apoptosis – programmed cell death or suicide (which is a good thing).
• Tumorigenesis – unregulated cell division into cancer or tumors.

Having enough DHA in the cardiolipin of the mitochondria is extremely important for a cell’s ability to induce apoptosis and controlled cell and/or cancer cell death.

Cells with deletion of the essential autophagy gene Atg7 exhibit degradation and attenuated activation of checkpoint kinase 1 (Chk1) and diminished repair of DNA double-strand breaks by homologous recombination.

SIRT7 depletion causes impaired DNA repair and genome instability. One of the best activators of sirtuins is melatonin. Thus, maintaining good levels of melatonin production throughout the day, with things like morning light exposure, avoiding light at night and consuming an optimal amount of nutrients (so the body can synthesize melatonin) can help with sirtuin activation and DNA repair.

There are at least 169 enzymes involved in DNA repair pathways, including superoxide dismutase, glutathione, Nrf2 and others. They all require minerals to work, such as copper, zinc, selenium and magnesium.

• Selenium is involved in repairing oxidized methionine residues, thus playing a role in oxidized protein repair systems. Cooking protein-rich food like meat at high temperatures creates carcinogenic compounds called heterocyclic amines and polycyclic aromatic hydrocarbons, which might be mitigated in the presence of adequate selenium.
• Magnesium is essential for base excision repair enzymes, which is a type of DNA damage response. In large quantities, magnesium can suppress N-Methylpurine-DNA glycosylase (MPG) that initiates base excision repair in DNA. However, magnesium is required for all the downstream actions of base excision repair proteins like apurinic/apyrimidinic endonuclease, DNA polymerase β and ligases. Thus, magnesium regulates repair processes to ensure a balanced repair of damaged DNA bases.
• Zinc deficiency promotes oxidative stress, DNA damage and undermines antioxidant defenses in rats. In humans, zinc deficiency causes DNA damage. Zinc is involved in hundreds of proteins, including DNA-binding proteins, copper/zinc superoxide dismutase (CuZnSOD), and DNA damage repair proteins like p53. Zinc is also needed for activating poly (ADP-ribose) polymerase that are involved in DNA repair at DNA damage sites.
• Iron is a cofactor to many DNA repair and replication proteins like Pol #, Rad 3/XPD and Dna2. Mutations of iron-requiring proteins are associated with diseases of DNA repair defects in mammals. Base excision repair glycosylases that remove damaged bases contain the iron-sulfur cluster protein cofactor. Hence, good iron (and thus by default copper) and sulfur status are important for DNA repair.

Superoxide can combine with nitric oxide to form the highly reactive nitrogen species peroxynitrite (ONOO −). Even though there are other oxidants that are formed in the body like hydroxyl radicals, for example, peroxynitrite has a much longer half-life, it can penetrate into multiple cells and it causes significant and relevant damage to the body. Peroxynitrite creates a burst of oxidative stress, mitochondrial dysfunction, inflammation, DNA damage, lipid peroxidation, necrosis and shuts down many enzymes. It also modifies tyrosine into nitrotyrosines, which are associated with atherosclerosis, myocardial ischemia, and inflammatory bowel disease. In fact, peroxynitrite is implicated in nearly every pathology, starting with hypertension, heart failure and ending with diabetes and vascular aging. Thus, the production of superoxide anions and the subsequent formation of peroxynitrite can be viewed as one of the most harmful and relevant oxidative stressors that occurs within our bodies.

• The main way your body deals with oxidative stress and DNA damage is by activating sirtuins and a group of enzymes called PARPs (poly ADP ribose polymerases). Both of them consume NAD+ and can lead to energy depletion. When that happens, you’re left with chronic fatigue, getting sick easily, lackluster performance, brain fog and decelerated healing. NAD deficiency causes tissue damage in response to ionizing radiation, which also increases peroxynitrite and administrating NAD protects against these effects. NADPH is also essential for lowering oxidative stress and inflammation.
• Superoxide is generated by two main pathways in the body, NADPH oxidase and in the electron transport chain of mitochondria. This is important because in almost all chronic diseases NADPH-oxidase is activated, which increases the production of superoxide anions. In fact, the damage that comes from high glucose levels and free fatty acids in the body are actually due to the activation of NADPH oxidase. Additionally, in the mitochondria, there is an approximate 3-4% loss of electrons that spill from the electron transport chain, leading to the formation of superoxide, which can damage and degrade our mitochondria.
• Thus, chronic diseases can be thought of as a state of superoxide and peroxynitrite excess and nitric oxide deficiency. This is primarily driven by the activation of NADPH oxidase, which is caused by many factors such as acute and chronic infections, nutrient deficiencies, heavy metals and the overconsumption of refined foods.
• However, the body has a natural antidote to superoxide, and that is an antioxidant enzyme called superoxide dismutase (SOD). This enzyme dismutases or ‘declaws’ superoxide to hydrogen peroxide and oxygen, which are less damaging molecules. To be more precise, the superoxide dismutase enzymes that do this are called copper,zinc -superoxide dismutase (Cu,Zn-SOD) and manganese – superoxide dismutase (Mn-SOD). In other words, if you want to remove superoxide anions in the body you need to have the minerals copper, zinc and manganese as they are cofactors for superoxide dismutase enzymes in your body. If you are lacking in these minerals, then the function of your antioxidant enzyme superoxide dismutase goes down and more superoxide will bind to nitric oxide, thereby depleting nitric oxide levels and forming the toxic peroxynitrite.
• There is a total of three superoxide dismutases in humans: superoxide dismutase (SOD)-1 and superoxide dismutase (SOD)-3 contain copper and zinc and are found in the cytoplasm and extracellular space, respectively, superoxide dismutase (SOD)-2, which is found in the mitochondria, contains manganese. Thus, the minerals copper, zinc, and manganese help to protect your body from some of the most harmful oxidants that get produced. Additionally, other molecules and enzymes such as catalase, glutathione, glutathione peroxidase and peroxiredoxin help to eliminate the toxic hydrogen peroxide that gets created after superoxide dismutase does its job eliminating superoxide anions. Glutathione, glutathione peroxidase and peroxiredoxin depend on iron, selenium, magnesium and copper. Additionally, catalase levels are decreased with selenium deficiency and the peroxynitrite that is formed from the combination of nitric oxide and superoxide requires peroxiredoxin and thioredoxin for its elimination, which depend on manganese, iron and selenium.

Nitric Oxide (NO) is an important signaling molecule that’s known for its benefits on the cardiovascular system and its antiviral effects. Nitric oxide (NO) suppresses platelet aggregation, lowers blood pressure, reduces blood clot formation, prevents blood vessel inflammation and improves the transport of lipids and cholesterol. It promotes blood flow through vasodilation and reduces the time these particles stay in your bloodstream. Reduced availability of nitric oxide has been implicated in the pathogenesis of hypertension and atherosclerosis.

• Signs of sexual dysfunction and erectile dysfunction can indicate low nitric oxide levels and cardiovascular problems or even atherosclerosis. Endothelial nitric oxide synthase (eNOS) also regulates female genital tract structures and has an important role in female sexual arousal.
• Nitric oxide has even been shown to fight against certain viruses and bacterial infections. Supplementation with nitric oxide boosters (such as L-arginine, but more importantly L-citrulline, as well as foods rich in nitrates like beets and leafy greens) has potential to reduce viral replication of severe acute respiratory syndrome (SARS) coronavirus and others. Indeed, nitric oxide inhibits SARS-CoV replication in two ways. First, nitric oxide and its derivatives reduce the palmitoylation of nascently expressed spike (S) protein, which affects the fusion between the S protein and its cognate receptor, angiotensin converting enzyme (ACE). Secondly, nitric oxide and its derivatives reduce viral RNA production during the early stages of viral replication.
• Enzymatic nitric oxide creation is initiated by nitric oxide synthase (NOS) by degrading L-arginine, L-citrulline, and nitric oxide in the presence of oxygen and NADPH. L-arginine is an amino acid that can be derived from dietary sources or the body’s own protein, is converted into citrulline and nitric oxide in the presence of NADPH and oxygen. Importantly, exogenous intake of citrulline is better at increasing arginine and nitric oxide levels in the body compared to arginine intake because citrulline has better bioavailability and gets converted to arginine in the body.
• NADPH protects against the oxidative stress from excessive reactive oxygen species (ROS) because it is the universal electron donor. It also allows for the regeneration of glutathione (GSH), which is our body’s master antioxidant. NADPH is important because it will reduce and neutralize oxidized antioxidants and free radicals by donating electrons. The enzymatic nitric oxide synthase (NOS) and NADPH pathways are dependent of essential co-factors that require iron and calcium to work properly.

Here are the nutrients needed for nitric oxide production and cardiovascular health:

• Citrulline/arginine – Arginine and citrulline are substrates needed to form nitric oxide. They are one of the main amino acids in the urea cycle. Short-term L-citrulline supplementation has been shown to improve arterial stiffness, independent of blood pressure, in middle-aged men. It also increases blood flow during exercise and improves erectile dysfunction. Citrulline is more readily absorbed than arginine, having shown twice the potency of arginine in relation to raising arginine levels in the blood.
• Supplementing extra glutathione with citrulline may promote NO synthesis and stabilize it. Some cells can’t make NO without glutathione.
• Calcium – Endothelial NOS (eNOS) and neuronal NOS (nNOS) are controlled by intracellular calcium. Increasing intracellular calcium with glutamate stimulates nNOS to promote nitric oxide. Calcium also initiates the electron flow in the NOS reaction from NADPH to heme and oxygen. The long-chain omega-3 fatty acid EPA has been shown to increase nitric oxide synthesis by increasing intracellular calcium.
• Iron – Heme, which is an iron containing and oxygen carrying substance, is an essential part of NOS. An iron deficiency has been shown to reduce nNOS and ileal NOS in rats.
• Copper – is required for the movement and utilization of iron in the body as well as the formation of ATP.
• Zinc – Zinc is bound to all isoforms of NOS, thereby it is necessary for NOS activity. In high concentrations, zinc inhibits eNOS and nNOS. Thus, a loss in the control of zinc levels may reduce nitric oxide production.
• Manganese – Increasing extracellular manganese stimulates nitric oxide synthesis in murine astrocytes. High amounts of administered manganese or lead in the brain of rats interferes with calcium-mediated nitric oxide synthesis and causes neuronal dysfunction. Thus, when the body loses the ability to regulate minerals, especially copper, iron and manganese this can lead to negative consequences.
• Magnesium – Activates vitamin D, which increases eNOS gene expression. Magnesium ions also seem to directly enhance endothelial nitric oxide production in healthy humans in a dose-dependent manner. Thus, magnesium deficiency reduces nitric oxide synthesis and magnesium supplementation can restore endothelium-dependent vasorelaxation.
• Carbohydrates – Glucose metabolism is the major source of NADPH for nitric oxide synthesis. Thus, nitric oxide synthesis is very much glucose-dependent and a deficiency in the utilization of glucose molecules can reduce nitric oxide synthesis. On the flip side, hyperglycemia (elevated blood sugar) impairs nitric oxide-mediated endothelial function and causes vascular dysfunction in diabetic patients. Thus, maintaining a normal blood sugar is beneficial because you don’t need a high amount of carbohydrates to facilitate NADPH. We also know that a deficiency in copper, magnesium and chromium leads to hyperglycemia, which lowers nitric oxide further.

Glutathione (GSH) is another internal antioxidant in the body. It protects against reactive oxygen species and free radicals like peroxides, lipid peroxides and heavy metals. Glutathione promotes the regulation of nitric oxide by enhancing citrulline function. Without enough NADPH, your body can’t recharge glutathione after it becomes oxidized. This will put breaks on all the detoxification systems. Glutathione is extremely important for protecting red blood cells from oxidative stress and its levels are highly dependent on magnesium.

• Additionally, magnesium helps to provide the ATP required for glutathione synthesis and two ATP molecules are used for the biosynthesis of one glutathione molecule.
• Selenium is a cofactor for the antioxidant glutathione peroxidase, boosting its expression and activity, this is important for reducing inflammation during viral infections. Supplementing selenium replete humans with 200 mcg/day of selenium can improve T-lymphocyte mediated immune responses, increase cytotoxic lymphocyte-mediated tumor cytotoxicity and natural killer cell activity compared to baseline.
• Furthermore, taking 297 mcg/day vs. 13 mcg/day of selenium improves the activation and proliferation of B lymphocytes, enhances cytotoxic T lymphocytes and improves activated T cell function.
• Another antioxidant defense mechanism against free radicals are metallothioneins (MTs), which are small, cysteine-rich, heavy metal-binding proteins. They are mostly known for detoxifying heavy metals, in particular cadmium and maintaining metal ion homeostasis. Human cells with excessive MTs are resistant to cadmium poisoning. In mammals, MTs bind zinc but if there’s excess cadmium, MTs will bind cadmium instead of zinc. During stress, MTs release zinc when nitric oxide and ROS levels increase. Although zinc itself raises the zinc-binding activity of metallothionein, zinc is needed to upregulate MTs through metal regulatory transcription factor 1 (MTF-1). Thus, the antioxidant effects of MTs are dependent on zinc. Zinc is also needed for glutathione production, as revealed by studies wherein zinc deficiency is accompanied by a deficiency of glutathione and increased oxidative stress. Zinc also protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis.

Minerals for Preventing Premature Aging and Promoting Longevity

Premature aging is primarily caused by damage to tissues from numerous factors and reduced cellular repair. This leads to an accumulation of dysfunctional enzymes, proteins, and cellular membranes and if it reaches a certain threshold, it can present as disease and ultimately death. As you’ve just learned, the major cause of this damage in the body is from the activation of NADPH oxidase, which produces the harmful superoxide anion and the reactive nitrogen species peroxynitrite.

Inflammasomes Drive a Vast Range of Acute and Chronic Inflammatory Diseases

Inflammation is considered one of the main contributing factors to many chronic diseases like cardiovascular disease, cancer, autoimmunity and brain aging.

Inflammasomes, which are protein complexes that assemble in response to certain pro-inflammatory signals exert pro-inflammatory and pro-apoptotic effects. They have been shown to have a pathogenic role in diabetes, neurodegenerative diseases, autoimmune disorders like rheumatoid arthritis, psoriasis, asthma, allergies and acne.

Inflammasomes mediate acute inflammatory conditions such as gout and the acute respiratory distress syndrome (ARDS) seen in COVID-19. Inflammasomes can also trigger a type of cell death called pyroptosis, which essentially spills the cells’ guts releasing its inflammatory materials driving many chronic inflammatory conditions.

• The most known inflammasome is the NLRP3/ASC/caspase-1 complex, which is initiated by NF-kB-mediated oxidative stress. NLRP3 regulates aging-associated chronic inflammation and insulin resistance. NLRP3 can also be triggered by low intracellular potassium.
• Potassium depletion is needed for NLRP3 to be bound by NEK7, which is an accessory protein of the NLRP3/ASC/caspase-1 complex.
• A lack of salt can lead to magnesium deficiency, which causes a loss of potassium in the cell.
• During inflammation and oxidative stress, ATP is pushed out of the cell where it can connect with P2X7R. This activation creates a pore in the plasma membrane, allowing potassium to leach out and calcium to move in. Furthermore, activated P2X7R also promotes NADPH oxidase activation and oxidative stress. Fortunately, magnesium can bind to ATP, forming Mg-ATP, releasing the terminal phosphate to release energy. Thus, this binding with magnesium might help to prevent and reduce inflammasome activation.
• Additionally, magnesium is needed to activate vitamin D into calcitriol and calcitriol, through its binding to vitamin D receptors, can inhibit NF-kB activation, which is the main driver of NLRP3 inflammasomes.
• The assembly of inflammasomes requires NLRP3 connecting with thioredoxin interacting protein (TXNIP). When TXNIP is tied up with thioredoxin it cannot merge with and activate NLRP3. However, when oxidation increases, thioredoxin is summoned to reduce oxidized proteins. This can leave TXNIP open to bind to NLRP3 and trigger inflammation. Reconverting thioredoxin back into its reduced, unoxidized form is done by thioredoxin reductase, which uses NADPH as a reductant and selenium as a cofactor. Thus, oxidative damage to thioredoxin will liberate TXNIP so it can begin to interact with NLRP3, whereas adequate thioredoxin reductase helps to keep thioredoxin reduced or unoxidized so it can remain attached to TXNIP, thereby preventing inflammasome activation. Boosting NADPH and selenium intake is important for forming reduced thioredoxin through their required action on thioredoxin reductase. In other words, if you have low NADPH or selenium levels, this will increase the activation of NLRP3 inflammasomes and increase the risk of acute or chronic inflammatory diseases.

One of the primary regulators of our body’s antioxidant systems is Nuclear Factor Erythroid 2-Related Factor 2 (Nfr2), which is a transcription factor that binds to DNA to express various genes. Nrf2 works by activating the antioxidant response element (ARE), which increases antioxidants like glutathione, NADPH, bilirubin, thioredoxin and cell protection, producing major anti-inflammatory changes and lowering oxidative stress.

• Compounds that activate NRF2/ARE include broccoli sprouts (sulforaphane), curcumin, coffee (chlorogenic/caffeic/ferulic acid and diterpenes such as cafestol), red wine (quercetin and resveratrol), whole grains (ferulic acid), olive oil, green tea (EGCG), garlic, onions, cinnamon, hops plant (xanthohumol), spirulina (heme-oxygenase 1, phycocyanin), astaxanthin, berberine, berries (especially blueberries), nuts (pterostilbene), grapes, passion fruit, white tea, Japanese knotweed (piceatannol), buckwheat and asparagus (rutin).
• Ferulic acid appears to have anti-inflammatory actions that suppress NFkB activity, thus being able to curb the activation and formation of inflammasomes.
  • Ferulic acid can be obtained from the ingestion of pycnogenol and many other plant anthocyanins (like black elderberry for example), coffee and unrefined whole grains.

How to Suppress NLRP3 Inflammasome Activation:

• Optimal selenium levels
• Maintain optimal NADPH levels
  • Periodic ketosis, intermittent fasting, regular exercise, improve insulin resistance (restrict refined carbohydrates, sugars and omega-6 seed oils), glycine intake, optimal mineral intake, sunlight and exercise.
• Activate Nrf2
  • Plant polyphenols, alpha lipoic acid, melatonin, ferulic acid (includes coffee and unrefined whole grains), pycnogenol, broccoli sprout powder (sulforaphane), quercetin (found in onions and leeks), EGCG (from green tea), regular exercise, intermittent fasting.
• EPA/DHA from whole food seafood and fatty fish. Avoid overcooking to prevent oxidation of the fats.
• Zinc and glucosamine
• Inhibit NF-kB
  • Turmeric, magnesium, intermittent fasting, optimal omega-6/3 balance, avoid oxidized vegetable and seed oils, sulforaphane, ketosis and quercetin.
• Increase hydrogen sulfide (H2S)
  • NAC, taurine and methyl donors (folate, B12 and betaine)
• Activate AMPK
  • Intermittent fasting, exercise, heat exposure, ketosis, berberine, curcumin, plant polyphenols, coffee, green tea, quercetin.
• Inhibit NOX (NADPH oxidase)
  • Spirulina, glycine, bilirubin, exercise, fasting and improve insulin resistance.

The active form of vitamin D, known as calcitriol, can also suppress MAP kinase, which is a major driver of inflammation during infections and sepsis but vitamin D requires magnesium for its activation. It has been found that 15 ng/ml of vitamin D which is considered an insufficient serum vitamin D level in humans, does not suppress lipopolysaccharide (LPS)-induced inflammation. Whereas, inhibition of LPS (i.e., endotoxin) inflammation was significantly reduced with vitamin D levels at 30 ng/ml but maximal inhibition occurred at a vitamin D level of 50 ng/ml.

NADPH oxidase or NOX is a complex of enzymes bound to the cellular membrane. It senses the presence of oxygen and nutrients to balance the body’s ROS. Inhibiting NOX increases NADPH and combats oxidative stress. NOX proteins are involved in the inflammation of the vasculature. However, NOX also generates free radicals that destroy pathogens through a process called the respiratory burst.

Here are several ways to increase NADPH to promote the regeneration of antioxidant defenses in the body such as glutathione and thioredoxin:

• Increase NAD – NAD+ or Nicotinamide adenine dinucleotide is a key co-enzyme involved with virtually all cellular processes and energy production. NAD+ deficiencies are linked to aging and disease. The extra phosphate group of NADP+ is added by NAD+ kinase.
  • NAD can be synthesized from tryptophan or aspartic acid and vitamin B3 or niacin. Fermented foods like sauerkraut and kimchi have B vitamins and increase NAD+. The fermentation process produces NADH and lactate, which regenerates NAD+.
  • Fasting and calorie restriction increase NAD+ and SIRT1 levels, which has many antiaging benefits. Fasting promotes the recycling of NAD by activating NAMPT, which governs the NAD resalvage pathway by promoting AMPK.
  • Exercise also increases NAD+ and sirtuins as does heat exposure and sauna sessions. They also help to recycle NAD.
• Ketosis – Ketone bodies lower the production of reactive oxygen species in the mitochondria by increasing NADH oxidation into NAD+. However, hyperketonemia (excessively high ketones in the blood) upregulates NOX4 and oxidative stress. Such hyperketonemia or ketoacidosis usually occurs in states of insulin deficiency like type-1 diabetes, type-2 diabetes or alcohol poisoning.
  • Refined carbohydrate restriction can be an effective strategy for lowering inflammation, hyperglycemia and raising NAD+. Both inflammation and hyperglycemia deplete NAD and NADPH. At the same time, glucose is a major source of NADPH but you don’t need high amounts of glucose to facilitate that response. Furthermore, the body can create glucose itself through endogenous means. 
• Glycine – The amino acid glycine, as well as collagen, inhibit NOX and raise NADPH. This occurs by increasing chloride in cells that would generate oxidative stress. Glycine is one of the main amino acids that comprises glutathione as does glutamine and cysteine. McCarty and DiNicolantonio (2019): “Supplemental glycine may be useful for the prevention and control of atherosclerosis, heart failure, angiogenesis associated with cancer or retinal disorders and a range of inflammation-driven syndromes, including metabolic syndrome.”
• Bilirubin – Bilirubin is a yellow compound that gets created during heme breakdown. It’s needed for clearing waste products from the death of red blood cells. Elevated levels of bilirubin might be indicative of some disease but physiological intracellular levels have been shown to inhibit NOX. Oral administration of bilirubin is not feasible because of its very low water solubility, however, biliverdin, which is a more water-soluble precursor to bilirubin, can be taken orally.
  • Spirulina or Blue-Green Algae – Biliverdin’s metabolite phycocyanobilin (PhyCB) can be converted by biliverdin reductase to phycocyanorubin, which is analogous to bilirubin in the body and can inhibit NOX complexes. This might explain why spirulina (specifically phycocyanobilin, which is the light harvester in spirulina) has been shown to have antioxidant and anti-inflammatory effects in numerous clinical studies.
• Improve Insulin Resistance – NOX appears to have a role in inducing insulin resistance and cytokines in hypertrophied fat cells. Bilirubin works in many ways to reduce obesity and its health complications, primarily by lowering NOX. It’s been found that plasma levels of bilirubin are inversely correlated with the risk of metabolic syndrome and diabetes. In cross-sectional and prospective studies, higher bilirubin levels are associated with improved insulin sensitivity and reduced risk of metabolic syndrome and type-2 diabetes independent of BMI.
• Don’t Overeat Calories – One of the biggest consumers of NADPH is fat storage and de novo lipogenesis. In essence, if your body has to store fat, it depletes NADPH and reduces its antioxidant capacity thus making you more vulnerable to oxidative stress and free radicals. When given the option to either get fat for the coming winter or preserve antioxidant defenses, the body will prioritize the storage of calories because they are scarcer.

Chapter 4: Calcium, Magnesium, Hard Water and Your Heart

Hard Water vs. Soft Water

Around 20% of your daily fluid intake comes from food while the rest is provided by what you drink. Water hardness simply means the mineral content of the water. The softer the water the higher rate of cardiovascular disease.

• Soft Water – water low in calcium and magnesium. Calcium and magnesium concentration is less than 100 mg/L.
• Hard Water – water with moderate calcium and magnesium. Calcium and magnesium concentration of 100-200 mg/L.
• Very Hard Water – water high in calcium and magnesium. Calcium and magnesium concentration exceeding 200 mg/L.

Sodium, potassium and lithium are considered monovalent cations (or single positively charged molecules) and do not contribute to the hardness of water, only divalent cations (such as calcium or magnesium) contribute.

Most of the people in industrialized societies consume soft water or water that lacks minerals. The reason is because soft water is cheaper and easier to use. Soft water requires less soap, both for personal hygiene and when washing clothes or dishes and it causes less scaling of pipes and leaves fewer stains in pots and pans and enamel sinks. There is a counterpoint to that however: over time, soft water does the opposite of depositing limescale, as it is more corrosive and it can dissolve some of the metals found in the water distribution pipes, which can include copper, zinc and cadmium.

Masironi and Shaper noted that, “Soft waters could be carrying trace levels of toxic elements from pipes or soil into supply; hard waters could be protective due to their content in calcium and magnesium or in beneficial trace elements.”

Many researchers cite the lack of magnesium in the water supply as a significant factor. Magnesium deficiency is considered a principal driver of cardiovascular disease that increases the risk of heart disease substantially. This problem is magnified by the fact that about 50-75% of the population isn’t meeting the 350-420 mg RDA for magnesium. Magnesium regulates vascular smooth muscle cells, affecting blood pressure, calcification, atherosclerosis, kidney disease, arrhythmias and thrombosis (clots).

Challenging the Food-Mineral Hypothesis

Given that the majority of the population is already consuming too many calories, optimizing the water mineral content should be a matter of high priority.

A lower intake of minerals increases the absorption and the toxic effect of heavy metals, so in this way, by not consuming mineral rich water, we may increase the risk of certain diseases and enhance the harmful effects of toxic heavy metals found in the environment such as aluminum, cadmium, lead, mercury, and arsenic. We should bear in mind that, calcium, which is contained in substantially greater amounts in hard water, may help protect us against lead and cadmium absorption.

To maximize the potential benefits from water that is rich in minerals, it should be used when cooking and preparing your foods too. Boiling pasta, rice and vegetables in the right water endows those foods with a higher mineral content, the proportion of water in your food being higher than you may at first imagine.

The Ratio of Minerals to Toxic Heavy Metals in Water is Just as Important as Absolute Values

High-calcium water may well have a double protective effect, containing decreased amounts of toxic heavy metals as well as reducing their degree of absorption into the body. Put simply, although from a practical point of view, you may be frustrated by the calcium rich ‘hard’ water furring-up the pipes and kitchen equipment such as coffee makers and kettles, it is precisely that calcium lining of those water pipes which blocks any leaching effect giving you double protection.

However, just getting more calcium, especially if it’s being provided in high amounts from supplements or food fortification, is not always beneficial and could even be harmful. Although this does not appear to be the case from naturally high calcium waters as the intake of calcium is slower and doesn’t spike blood levels like higher amounts of calcium can do from supplements and food fortifications. Indeed, a high intake of supplemental calcium is associated with increased risk of cardiovascular disease death in both men and women. Calcium supplementation without co-administered vitamin D increases the risk of having a heart attack (which also requires vitamin K and magnesium).

Extra calcium intake through supplementation results in higher circulating calcium, leading to calcification and calcium deposition in the coronary arteries and extra-skeletal muscle tissue.

• To promote calcium absorption and to keep calcium out of the arteries and into the bones, you need sufficient vitamin D and vitamin K2. Vitamin D regulates calcium levels in the blood and vitamin K2 directs it into the right place such as the bones and teeth.
• Vitamin D toxicity and vitamin K deficiency are associated with soft tissue calcification. Low levels of vitamin K are also linked to cardiovascular disease.
• Supplementing with vitamin K has been shown to reduce coronary artery calcification. Unfortunately, the majority of people are also deficient in vitamin D and K, which might explain the susceptibility to calcification with calcium supplementation.
• On top of that, magnesium is needed to activate vitamin D and move it around the body. Deficient magnesium can reduce the active form of vitamin D, also known as calcitriol, and impair the parathyroid hormonal response. This can lead to magnesium-dependent vitamin-D resistant rickets. Thus, optimizing vitamin D levels requires an optimal magnesium status.
• Importantly, active vitamin D is needed to produce vitamin K-dependent proteins and helps to activate them, which requires magnesium.

It is estimated that less than 30% of the calcium ingested through food is absorbed, but if you consider the factors that affect your body’s absorption, the importance of water as a source of calcium may be greater than most of us appreciate. Consider the fact that the more calcium you take in at one time, the harder it is for your body to process it, which speaks for the steady ‘supplementation’ provided by your hard water supply, rather than occasionally swallowing calcium-rich pills.

Magnesium in Mineral Waters Provide Optimal Heart Health

The magnesium concentration in the hearts of subjects dying of heart disease is 24% lower than that of those subjects dying from accidents. There is also a link between magnesium deficiency and sudden death, suggesting that (1) sudden death is common in areas where community water supplies are magnesium deficient, (2) Myocardial magnesium content is low in people who die of sudden death, (3) Cardiac arrhythmias and coronary artery vasospasm can be caused by magnesium deficiency and (4) Intravenous magnesium reduces the risk of arrhythmia and death immediately after a heart attack. Thus, sufficient magnesium levels are strongly and negatively correlated with rates of sudden cardiac death even after adjusting for other risk factors.

In the body, magnesium has antithrombotic effects and reduces mortality in pulmonary thromboembolism. This suggests that magnesium has anticoagulant properties. Magnesium deficiency has been implicated in insulin resistance, type-2 diabetes, hyperglycemia, and hyperinsulinemia, all of which are considered risk factors of heart disease.

Just because your water is classified as hard that does not mean there is necessarily ample magnesium in it, it may simply be high in calcium.

Other Relevant Minerals in Your Water Supply

Chromium has been shown to play an important role in glucose metabolism, which influences glucose tolerance. Chromium picolinate, specifically, has been shown to reduce insulin resistance and may even reduce the risk of cardiovascular disease and type-2 diabetes. A report on four meta-analyses of human studies saw a significant reduction in fasting plasma glucose levels from chromium supplementation. A 2016 review covering six meta-analyses concluded that chromium decreases fasting blood glucose and HbA1C. Thus, you do not want to be deficient in chromium because that is associated with diabetes and hyperglycemia.

• A reported benefit of chromium is that it has also been found to be protective against atherosclerotic lesions (so it protects blood vessels), but to date, this has only been observed in experimental animals. Chromium picolinate has been shown to significantly decrease triglycerides, insulin, HOMA-IR, inflammation, and insulin resistance in patients with nonalcoholic fatty liver disease.
• Although a number of researchers have demonstrated this inverse association between cardiovascular disease and the chromium content of drinking water, it is important to add that the causal relationship is not proven. It remains an area worthy of further investigation, but certainly suggests that chromium can be significant as a nutritional source when it is present in your drinking water.

Lithium is the lightest solid element in the periodic table, and it is an essential trace mineral with many recommending an intake of 1 mg/day to meet requirements. In miniscule doses, lithium has been shown to have a number of health-related benefits. Observational studies in Japan have noted that low-dose lithium in drinking water is associated with better longevity.

• Lithium has been associated with the low prevalence of both coronary heart disease and of gastroduodenal ulcers among the Pima Indians of Arizona, where levels in their water supplies can exceed 100 ug/l. That’s over fifty times the U.S. average. Other teams of researchers found a negative correlation between lithium levels in drinking water and cardiovascular death rates in the U.S. and given that lithium has for years been prescribed as a mood stabilizer, associations with less aggressive behavior among the populations using the water could lie behind a lower incidence of mental disorders, violence and also of heart attacks.
• More recently in Denmark, higher levels of lithium in the local water supply have been linked to lower levels of dementia. Higher lithium levels in drinking water have also been shown to have a protective effect on the risk of suicide in countries across the entire world. Therapeutic doses of lithium (600-1800 mg/day) are commonly used to treat mania and depression in patients of bipolar disorder.
• Lithium administration has been shown to protect against hyponatremia or low sodium levels in the blood. The mechanisms for that are proposed to be lithium’s ability to reduce water retention in diabetes insipidus. Lithium toxicity, however, can cause hypotension and cardiovascular complications, which is why its serum levels have to be monitored carefully. Maternal use of lithium during the first trimester has been found to increase the risk of cardiac malformations.

Iodine – The regular consumption of iodine is important because it allows our bodies to make the all-important thyroid hormones. Low thyroid function leads to hypothyroidism, which can raise cholesterol, promote weight gain, and predispose you to metabolic syndrome. A telltale goiter (neck swelling) is one of the most visible signs of iodine deficiency.

• We find iodine often added to salt. In Canada for example, all salt sold to consumers for table and household use must be iodized with 0.01% potassium iodide, but there are exceptions for the more specialized and exotic salts or those used for pickling vegetables. If you are lucky enough to receive iodine naturally from your tap water, you may be among the best protected.
• There is also evidence linking the iodine content in water to other health benefits: “Water may contribute significantly to the daily requirement of iodine, perhaps up to 20%. The iodine content in water is negatively correlated to cardiovascular disease (CVD) rates in Finland. The susceptibility of the Finnish population to CVD apparently increases when there is less than 2-3 ug of iodine per liter of drinking water.”

Fluoride – The mineral fluorine presents us with a somewhat different situation, since many authorities around the world add fluoride to the water supply, usually citing studies which have shown how this measure can reduce the prevalence of tooth decay. Untreated dental caries can lead to weight gain, impair growth, increase the risk of infections, affect school performance and possibly lead to death. Adequate fluoride intake inhibits demineralization and bacterial activity in dental plaque.

• Fluoride is the ionic form of fluorine, which promotes bone formation and fights tooth decay. Teeth and bones store 99% of the fluoride in the human body. In adults, 50% of absorbed fluoride gets retained and 50% is excreted through urine. In children the absorption rate is up to 80% because their bones and teeth are in the growth stage.
• A 2015 review of 20 observational studies discovered that water fluoridation reduces the risk of tooth decay and fillings by 35% and permanent loss of adult teeth by 26% in children receiving fluoridated water compared to children receiving unfluoridated water. A 2018 cross-sectional study in the U.S. found that living in a county where 75% or more of the drinking water is fluoridated with at least 0.7 mg/L of fluoride was associated with a 30% reduction in the rate of primary teeth caries and a 12% reduction in the rate of caries in primary teeth. In Australian adults, exposure to fluoridated municipal water for at least 14 years associates with an 11-12% lower rate of decayed, missing or filled teeth than those whose water had negligible amounts of fluoride. The average rate of decayed, missing or filled teeth in Australian Defense Force members aged 17-56 is 24% lower in those whose water that contained 0.5- 1.0 mg/L of fluoride for at least half of their lifetime compared to those exposed for less than 10% of their lifetime. However, the benefit of fluoride is from its topical use, not its oral ingestion, and there are potential side effects from consuming fluoridated water. One group of authors concluded, “Fluoride has modest benefit in terms of reduction of dental caries but significant costs in relation to cognitive impairment, hypothyroidism, dental and skeletal fluorosis, enzyme and electrolyte derangement, and uterine cancer. Given that most of the toxic effects of fluoride are due to ingestion, whereas its predominant beneficial effect is obtained via topical application, ingestion or inhalation of fluoride predominantly in any form constitutes an unacceptable risk with virtually no proven benefit.”
• The daily adequate intake (AI) for fluoride in adults is 3-4 mg, 3 mg in teens aged 14-18, 1-2 mg in children aged 4-13, 0.7 mg in 1-3-year-olds, 0.5 mg in 7-12- month-olds and 0.01 mg in newborns less than 6 months of age. The U.S. Public Health Service recommends a fluoride concentration of 0.7 mg/L in drinking water for prevention of dental caries. The maximum allowable concentration established by the EPA is 4.0 mg/L and maximum recommended concentration is 2.0 mg/L. Average fluoride intakes in the U.S. from both foods and fluorinated drinking water is 1.2-1.6 mg for infants less than 4 years old, 2.0-2.2 mg for 4-11-year-olds, 2.4 mg for 11- 14-year-olds and 2.9 mg for adults.
• Most toothpaste in the U.S. contains sodium fluoride or monofluorophosphate, usually at a concentration of 1,000-1,100 mg/L (about 1.3 mg per quarter of a teaspoon used for one brushing). How much fluoride is absorbed from toothpaste depends on the amount used and how much a person swallows it. It is estimated that adults ingest 0.1 mg/d from toothpaste, children aged 6-12 ingest 0.2-0.3 mg/d and children less than 5 years old 0.1-0.25 mg/d. Other dental products that contain fluoride are mouth washes, orthodontic bracket adhesives and cavity liners. Oral antifungal medicine like voriconazole provides 65 mg/d of fluoride, which in the long-term can cause high serum fluoride levels.
• Serious systemic fluoride toxicity can be caused by doses of 5 mg/kg (about 375 mg for a 165 lb. person). That threshold is almost impossible to reach by being exposed to drinking water or dental care products. Excess fluoride intake causes gastrointestinal distress, nausea, abdominal pain and diarrhea. Ingestion of large doses of sodium fluoride (60 mg) can promote skeletal fluorosis, causing osteoporosis and bone fractures.
• Excess fluoride intake above the recommended intake, especially in childhood, can lead to dental fluorosis, characterized by white or brown lines or flecks on the teeth. NHANES data has discovered that the rates of dental fluorosis have increased from 29.7% in 2001-2002 to 61.3% in 2011-2012. High fluoride intake in children may also be associated with lower IQ and impaired cognition.
• A meta-analysis of all available studies on the topic from 2018 indicated that exposure to high levels of fluoride in water were strongly associated with reduced levels of intelligence in children. This was further endorsed by research published in 2019, focused on mother-child pairs from six Canadian cities which found that high fluoride exposure during pregnancy was correlated with lower IQ scores among young children, especially boys. It led to the author’s recommendation for pregnant mothers to reduce their fluoride intake during pregnancy, but the topic is controversial. It even led to the editor of the JAMA Pediatrics who published the findings, writing something of a disclaimer and reminding us that “scientific inquiry is an iterative process”. With the benefit of hindsight however, on the topic of fluoride and its various compounds, the jump to mandatory addition to the water supply in certain areas may have been taken too hastily.
• Brewed tea is one of the highest sources of dietary fluoride because the tea plants absorb fluoride from the soil. Fluoride levels in tea brewed with distilled water can range from 0.3 to 6.5 mg/L (0.07 to 1.5 mg/cup). One cup of coffee contains 0.22 mg of fluoride. Other foods like shrimp, pork, beef and tuna have 0.02-0.17 mg of fluoride per 3 oz. serving, while a medium baked potato has 0.08 mg. The amount of fluoride in breast milk and cow’s milk is almost undetectable. Thus, most food sources are relatively low in fluoride and unless you are regularly drinking tea, it would be difficult to reach the adequate intake of 3-4 mg/d. Fluorinated municipal drinking water accounts for 60% of the fluoride intake in the U.S.
• Overall, drinking only tap water might be problematic for infants and children in developing years but complete avoidance may lead to fluoride deficiencies. Even supplementing fluoride 0.25-1 mg/d for 24-55 months in children living in communities without fluorinated drinking water has resulted in a 24% reduced rate of decayed, missing and filled tooth surfaces. In areas where water fluoridation rates are lower than 0.6 mg/L, fluoride supplementation of 0.25-1 mg/d may reduce the rate of caries in primary teeth by 48-72% in children aged 6-10. Thus, a moderate consumption of fluorinated water (1-1.5 liters a day) should be acceptable and may even be beneficial. Cooking your food and vegetables with fluorinated water may also be recommended if you have a low intake of fluoride.

Silicon is best known to most of us as the base material for semiconductor manufacturing and the creation of the computer chip beginning with silica sand, which is made up of silicon dioxide. As the eighth most common element in the universe, making up more than 90% of the earth’s crust, it should be no surprise that trace elements (mostly silicon dioxides) are found in our drinking water. 

• We have already read that hard water is associated with lower death rates from coronary heart disease, but across the U.S., where the water contains above average levels of silicon – 15mg per liter vs. 8 mg per liter – that association becomes even more positive. This can be related to the silica content in natural water supplies which is commonly in the 5 to 25 mg/L range. The association is further supported by the situation in Eastern Finland, where lower silicon concentration levels in the water are associated with more heart disease than found in the west of the country.
• There are further benefits associated with silicon. Researchers at UK’s Keele University found that drinking around a liter of silicon-rich mineral water every day can speed up the removal of toxic aluminum from the body via the kidneys and ultimately urine. They even recommend selecting your bottled water according to its silicon content.

Cadmium – In its natural state, cadmium is a lustrous and silver-white, malleable metal, often used together with chromium in the electro-plating of steel, but you can also find it in hard and soft drinking water, albeit in miniscule quantities.

Working in the late 1950s, Dr. Henry Schroeder was also among those carrying out research which indicated that soft water was linked to higher levels of heart disease. He suggested that the action of soft water increased hypertension and pointed his finger particularly at higher cadmium levels. His four considerations were namely that:

• 1. Cadmium induced hypertension in rats
• 2. Cadmium levels were higher in humans who died of hypertension
• 3. The higher cadmium concentration in human subjects who died of hypertension was due to the leaching of cadmium from pipes through the corrosive action of soft water and
• 4. The relationship between soft water and cardiovascular mortality is linked to hypertension

This theory is supported by both experimental and clinical evidence, making cadmium something to watch out for, avoiding higher levels where you can. The wide use of cadmium in nickel-cadmium batteries, the coloration of plastics and in various discarded electronic products has led to cadmium getting into water supplies in certain areas. A potential environmental hazard to be aware of.

A Geographical Advantage? Tap Water from the Western United States and from Southern Europe May Provide Greater Health Benefits

To the north of Europe, vast and incredibly old geological substrata underlie surface rocks and topsoil meaning that the underground water flows are soft by nature. This represents a North-South direction, but a similar divisive feature can also be found in North America, albeit this time running in an East-West direction. In both continents, associations with cardiovascular disease are consistent with the softness of the water, which led the team to deduce (by elimination) that your latitude – that being how far North or South of the equator you are – plays little if any role in the matter. However, where you live in terms of your relationship to the underlying local geology consistently showed similar relationships concerning water hardness and cardiovascular disease.

As well as the many heart related correlations, it appears that the rates of stones formed in the bladder or urinary tract are also higher in areas that drink soft water (rabbit study).

Water is just slightly acidic and that’s down to the carbon dioxide content. Over time, this is what gives the water a cumulative, corrosive nature which can allow the water to strip cadmium, lead and other harmful elements from your piping, depending of course on what that piping is made of. This over time leads to adverse effects on your personal cardiovascular condition and represents a biologically plausible mechanism for how soft water supplies are associated with cardiovascular disease. That is in contrast to supplies of harder water which contain calcium and importantly, other beneficial minerals for your heart and health such as magnesium.

The Vital Role Played by Magnesium

Chalkiness in the form of calcium carbonate will be what you most often identify when looking at the limescale build-up in your household water pipes, kettle or coffee machine. Yet it is the magnesium content of that scale which may be having the biggest influence on your heart and surprisingly, on your taste buds too.

“While high bicarbonate levels are bad,” Hendon explains, “high magnesium ion levels increase the extraction of coffee into water and improve the taste.” His research showed that sodium rich waters produced by water softeners didn’t help the taste but that using magnesium-rich water was best.

Magnesium is essential for heart muscle contraction and for oxidative phosphorylation in heart mitochondria. It is important because oxidative phosphorylation is the process by which adenosine triphosphate (ATP) is formed. It is the high energy molecule which stores the energy we need to do just about everything we do, and it has been suggested that a magnesium-ATP complex is the true substrate for all reactions involving ATP.

Water Hardness and Magnesium – Their Role in Heart Muscle

Admittedly, it was not a large study but in all, 64 Canadian males had died as the result of accidents and thus were considered representative of the general population when compared with victims who die from “natural causes”. Of those 64 men, 20 were residents of three different hard-water areas while 44 of them were residents of five soft-water areas. The mean magnesium concentrations in wet heart tissue for the hard and soft water residents were 222.3 ug/gran and 206.7 ug/gram, respectively (the difference being statistically significant at the 0.01 level). Another way of interpreting these results would suggest that although the very fact of suffering heart disease per se may lead to a reduction in magnesium levels in the heart, drinking from a soft water supply that is lower in magnesium seems also to lead to a reduction in magnesium content.

After calcium, sodium and potassium, magnesium is the fourth most commonly found mineral in the human body. Of the 25 grams of magnesium present in an average 70-kilogram human (155 pounds), you will find half of it in your bones, around a quarter in your muscle tissue and the rest distributed among soft tissue and blood. A lack of magnesium is to be taken seriously, as it contributes not only to heart problems but to numerous health conditions, the mineral being necessary for the efficient biochemical functioning of numerous metabolic pathways.

Higher sodium levels in the resident’s tap water were also found to play their part in lowering the rates of cardiovascular, kidney and ischemic heart disease mortality.

Chapter 5: Taking the Waters: Mineral Waters with Magnesium and Calcium

The most common minerals found in spring water are calcium, sodium and magnesium. Older man-made water systems used copper for plumbing. Copper is important for energy production and it has antimicrobial properties, but it can also corrode easily and contribute to excess copper.

Historians nowadays think that lead poisoning because of lead water pipes played a major role in the downfall of the Roman Empire.

Water is by far a more bioavailable source of minerals because they are dissolved and charged in the liquid, rather than bound to food particles. Different foods also have ingredients and compounds, such as phytates, fiber or phytonutrients, that will decrease the amount of minerals you will absorb.

History of Spa and Mineral Water Therapy

The Romans began ‘taking the waters’ in spa towns over 2,000 years ago, and ‘the right kind of water’ has been reputed to cure all sorts of ailments, whether you are bathing in it or drinking copious amounts. Galen, the Roman surgeon, promoted the effects of mineral water on various diseases. Romans also built spas across Europe in newly conquered lands to treat wounded soldiers and recover from physical exertion. During the Renaissance, Italian doctors began to associate the health benefits of spas with the waters high in minerals. By the 17th century, many spa treatment resorts and centers were built in many regions of Europe, such as France, England, Italy, Germany, Austria and Eastern Europe.

Epsom’s salty springs possessed highly concentrated mineral rich waters, and that intensity of taste was due to the local rocks being richly endowed in magnesium and sulfate. While supplies lasted, these, sometimes cloudy waters, were used for bathing as well as consumption, sometimes in quantities of ‘several pints after another’ according to anecdotal tales.

• Other than its famous laxative properties, a dose of Epsom salts was said to be something of a cure-all, promising relief from bodily aches and pains as well as healing colds and congestion. 
• Still to this day, there is much debate as to whether a soothing bath in water infused with Epsom salts provides genuine benefits.

Paracelsus believed all diseases are the poisoning of a combustible element (sulphur), a fluid element (mercury) and a solid element (salt). According to him, these three substances are at the root of all physiological processes in the body – metabolism (sulphur), genetics (mercury) and enzymatic reactions (salt/minerals). Salt controls the body’s liquids so that materials could be moved around. If there’s excessive mineralization, arthritis and kidney stone formation occurs. Paracelsus figured out that some compounds that are poisonous in large amounts can be beneficial in smaller quantities, laying the foundation to future science about hormesis.

NASA scientists deduced that as water pressure increases with depth, the legs and abdomen are lightly compressed, expelling blood and some interstitial fluid, the thin liquid layer which surrounds the body’s cells. The fluid is pushed up into blood vessels in the chest, producing a marked increase in available central blood volume, which leads to an increase of about 50% in cardiac output. There being no associated rise in blood pressure, the resistance of the rest of the body’s veins and arteries has to go down – a factor that could be of great significance when treating conditions of poor blood circulation or early stages of paralysis.

Why Drink Water with Minerals?

There are many benefits to drinking water with minerals compared to regular plain water:

Improved Digestion and Gut Health – Stomach acid and digestion require salt and other minerals. Gastric juice is composed of hydrochloric acid, potassium and sodium chloride, which help to break down food and assimilate the nutrients. Other stomach cells produce bicarbonate that buffers against the acidity and regulates the pH.

• Lack of stomach acid can promote digestive problems, indigestion, heartburn, small intestinal bacterial overgrowth and an increased risk of infections. Low stomach acid may also reduce the absorption of other minerals. Acid-suppressing drugs decrease how much iron and zinc get absorbed. Aging also lowers stomach acid production, which is why the elderly commonly have a zinc deficiency. Drinking plain water without salt dilutes the stomach acid, making it less acidic. It shouldn’t matter much in between meals, but if you drink plain water right before, during or after meals you will have less digestive power to break down your food, making it more likely you’ll have bloating or other similar problems. At the same time, chloride-sulphate, calcium-sodium mineral water improves chronic gastritis with increased acid formation. So, minerals regulate both low acidity as well as high acidity. Mineral water can improve dyspepsia, which is a condition of indigestion.
• Constipation may also result from insufficient electrolytes. Electrolytes can improve bowel function in constipation. Mineral water supplementation in patients with functional dyspepsia has been shown improve gastric emptying of solids. Magnesium and sulphate-rich natural mineral water have been found to improve stool consistency and regularity compared to low-mineral natural water. Drinking 1 liter/day of sulfate-rich mineral water for 3 weeks increased the frequency of bowel movements in patients with functional constipation compared to regular tap water. However, the difference became less significant after 6 weeks.
• Mineral water consumption and baths help to treat patients with irritable bowel syndrome and improve their psycho-emotional status. Thermal mineral spring bathing improves mood and mental state. Mineral waters also have positive effects on the psychological status in children.
• Dietary calcium may reduce the risk of colon cancer by accelerating cytotoxic surfactants like bile acids in the colonic lumen. This prevents the formation and proliferation of harmful species and inflammation in the gut. Calcium-sulfate mineral water is equally as bioavailable as cow’s milk for calcium and retains as much of it. Bicarbonate-calcium mineral water improves inflammation of the stomach lining.

May Help Chronic Diseases – A higher intake of calcium and magnesium, aligned with the RDA, may be protective against many chronic diseases, such as osteoporosis, hypertension, sudden cardiac death and cardiovascular disease.

• Drinking 1 L/day of mineral water reduces cardiometabolic risk factors, such as blood lipids, lipid oxidation, glucose, insulin and cholesterol. Sodium-bicarbonate mineral water with a meal reduces postprandial lipemia compared to a low mineral water. High bicarbonate mineral water lowers triglycerides and VLDL cholesterol compared to low mineral water. Bathing in mineral-rich mud has been shown to improve lipidemia and flow mediated dilation in peripheral arterial occlusive disease.
• A low salt intake induces insulin resistance, even in healthy subjects. By only drinking plain water and not salting your food, you may be excreting more salt through the urine and becoming deficient.
• Although meta-analyses and observational studies suggest that magnesium supplements improve glycemic control, more evidence is needed to convincingly show that mineral water has a similar benefit. Drinking sodium-rich bicarbonate mineral waters with a meal does lower postprandial insulin compared to low mineral water in postmenopausal women. Sodium is required for insulin to do its job and thus more salt in the diet can improve insulin sensitivity. High amounts of sodium (4,600 mg per day), if given to individuals with a poor diet, however, may impair insulin sensitivity. Thus, sodium must always be balanced with potassium, magnesium and other base-forming substances in the diet.
• Spa therapy can improve plasma levels of adiponectin and leptin, which are important hormones for appetite regulation, satiety, weight loss as well as cartilage metabolism.
• Carbonated water can lower hunger, which is important for not overeating calories during the day. The effects appear to be mediated by enhanced postprandial gastric and cardiac activity. Mineral waters are a calorie-free source of essential minerals that can prevent certain nutrient deficiencies.
• Drinking 500 ml/day of bicarbonate-rich Água Vitalis® for 7 weeks caused blood pressure lowering effects. Sodium bicarbonate water consumption appears to decrease blood pressure in normal as well as hypertensive men, whereas regular sodium chloride water does not. Mineral water intake lowers blood pressure especially in subjects with low urinary magnesium and calcium levels. Head-out immersion in natural mineral water also appears to have positive effects on hypertensive patients, as assessed by 12 randomized controlled trials, involving 1,122 participants.
• Spa mineral water treatment has been shown to reduce markers of stress. After 2 weeks of geothermic water therapy, symptoms of stress declined 60%, intensity of stress reduced 41% and control of stress improved 32%. As a result, the health risks caused by stress decreased 26%, health resources increased by 11%, and the probability of general health risk dropped by 18%. Functional water infused with herbs and minerals can reduce heart rate and restore parasympathetic activity. Sodium restriction with a low salt diet does not lower glucocorticoid activity or its induced acidity. It has been found that anxiety or fear-induced sweating can make you lose trace minerals similar to exercise, although the two types of sweat have a slightly different composition. Thus, you need more minerals if you are constantly stressed. At the same time, the loss of minerals will cause additional stress and sympathetic nervous system activity.
• Among 192 patients with chronic venous insufficiency receiving spa mineral therapy, 66% saw improvements compared to the 28% in the control group. Highly mineralized baths with a salt concentration of 20 g/L have been shown to reduce peripheral vascular resistance and hypertension.
• Drinking Sulfurous mineral water protects against lipid and protein oxidation. Oxidation of these molecules increases the risk of cardiovascular disease, cancer and aging.

Improve Lung and Respiratory Conditions. Aerosol therapy using “Dovolenskaya” mineral water, improves bronchial drainage and inflammation in patients with occupational bronchopulmonary diseases. Inhaling aerosolized sulphurous mineral water has been shown to improve inflammation in 65% of the studied subjects who suffer from chronic inflammation of the upper respiratory airway. A meta-analysis of 13 clinical studies utilizing thermal water inhalations and irrigations concluded, “Thermal water applications with radon or sulphur can be recommended as additional nonpharmacological treatment in upper airway diseases.”

• Sanatorium and spa treatment have been shown to improve cystic fibrosis of the lungs and pancreatic lesions in children.
• Thermal water nasal spray improves chronic rhinosinusitis pathologies better than just saline water spray. Nasal irritation with sulfurous, salty, bromic, iodic (SSBI) thermal water improves non-allergic chronic rhinosinusitis. Sulphurous thermal water inhalations have been shown to be effective in the treatment of chronic rhinosinusitis. Thermal water nasal aerosol has also been shown to help with seasonal allergic rhinitis.
• It is important to note than any nasal inhalation or irrigation using mineral waters should only be performed after the water has been sterilized (boiled for 5 minutes) and then allowed to cool off.

Natural mineral water intake improves skin hydration and dryness. Purified thermal water can reduce skin irritation and reduce transepidermal water loss. Spraying thermal spring water to the face after dermatological surgery, laser therapy or chemical peelings reduces local inflammatory symptoms and adverse effects associated with the procedure.

• A 10-minute hot bath at 42°C has been shown to improve symptoms of atopic dermatitis in 76% of studied subjects. Application of deep-sea mineral water inhibits the development of atopic dermatitis-like skin lesions in mice.
• Mineral water solutions enhance the benefits of phototherapy and light therapy. Dead Sea products have been shown to decrease skin and mucosal toxicity in head and neck cancer patients who are receiving radio-chemotherapy. A systematic review has concluded that Dead Sea treatments could be beneficial for rheumatoid arthritis and psoriasis.

Rheumatoid Arthritis and Osteoarthritis – Minerals, especially magnesium and calcium, have a crucial role in bone health and density. Your bones are made of calcium and they need minerals to maintain their integrity. Skeletal bone acts as a sodium-rich reservoir that can be depleted during sodium deficiency, which has adverse negative side-effects on bone quality and fracture risk.

• Spa therapy has been used to treat physical pains and diseases of physical degeneration for centuries. Long-term mud therapy also appears to be beneficial for bone mineral density.
• Consuming high calcium mineral water lowers bone remodeling in postmenopausal women on a low calcium intake. Drinking alkaline mineral water has also been shown to lower bone resorption even in those with a normal calcium intake. In the same study, calcium-rich acidic water had no effect on bone resorption, suggesting that the benefits are due to the alkalinity of the water. Another study found that consuming mineral water with a modest amount of calcium (172 mg) inhibited bone resorption and parathyroid activity.
• Drinking sodium-rich bicarbonate mineral water with a meal increases urinary sodium excretion without changing the excretion of potassium and bone minerals. This was due to a decrease in aldosterone, the hormone that regulates sodium retention, after 120 minutes of consumption.
• Bathing in mineral-rich bath waters has been found to improve fibromyalgia. The effects of balneotherapy (bathing in mineral waters) on fibromyalgia appear to last for up to 3 months, whereas mud-bath treatments give longer lasting results. Mud bathing in patients with fibromyalgia also lowers triglycerides and C-reactive protein.
• Magnesium citrate appears to be effective on pain and clinical parameters in people with fibromyalgia. Magnesium citrate is also more available and easily absorbable compared to magnesium oxide. Magnesium-rich mineral water can be as easily absorbed as magnesium supplements, perhaps slightly better. With age, magnesium absorption decreases, and magnesium mineral water might be able to compensate for that.
• Drinking magnesium-rich mineral water alone ensures that about 50% of the magnesium gets absorbed. Consuming high doses of magnesium all at once is not optimal for absorption. It turns out that you can get 40% better absorption and retention of magnesium from mineral water if consumed at a lower dose but higher frequency, as noted when drinking 7 oz. of mineral water seven times per day versus 25 oz. twice per day.
• Spa therapy improves pain, functionality and quality of life in patients with shoulder pain. Magnesium-Calcium-Sulfur spa therapy shows significant improvements of non-specific chronic lower back pain. Bathing in calcium-magnesium, bicarbonate thermal mineral water improves clinical parameters and quality of life in patients with chronic low back pain. Mineral water baths also improve clinical parameters of back pain more than tap water baths.
• Taking a 30-min thermal water bath at 34°C (93.2°F) five times a week for 3 weeks improves osteoarthritis. The same Szigetvár spa waters in Hungary have been seen to help with range of motion in osteoarthritis. Exercise combined with a sulfur bath therapy for 12 weeks has shown more sustained, significant benefits on joint function and decreased pain in hip osteoarthritis, compared to just exercise alone.
• Compared to a bath with regular tap water, taking a sulphurous water bath for 15 to 20-min sessions significantly improves hand osteoarthritis after 3 months. Bathing in mineral waters combined with drinking mineral water improves pain and function of hand osteoarthritis significantly more so than either treatment alone. However, there is not enough evidence to claim that bathing in mineral waters alone is better than other treatments. A meta-analysis of 122 studies on Hungarian thermal mineral waters concludes it is an effective therapy for lower back pain, as well as knee and hand osteoarthritis.
• Treatment with mud and mud baths with Sillene mineral water remarkably improves clinical conditions of patients with knee arthritis. Daily mud packs and mineral baths are superior to short-wave therapy in treating knee osteoarthritis although both show improvements. Mud therapy maintains benefits on hand osteoarthritis for up to 3 to 6 months and also improves lumbar spine osteoarthritis.
• Thermal balneotherapy may provide pain relief, improve joint function, and increase walking speed in patients with knee osteoarthritis. Sulfurous baths have more long-lasting effects than non-sulfurous baths although both are therapeutic. The benefits on pain relief appear to be increasingly better with up to 15 spa sessions. Spa therapy for just 2 weeks maintains the benefits on rheumatoid arthritis for up to 3 to 12 months. Studies between 1980 and 2014 show balneotherapy significantly improves clinical parameters of rheumatoid arthritis.
• A review of 27 double-blind randomized clinical trials, involving 1,118 patients, found that mineral balneology (bathing in mineral waters) improves pain, functionality and rheumatological diseases compared to baseline and non-mineral similar treatments. In rheumatoid arthritis, taking 12 thermal mineral spa baths at 36-37°C (96.8-98.6°C) for 20 min over the course of 2 weeks increased antioxidant levels like superoxide dismutase and decreased oxidative stress markers. Bathing in thermal mineral waters may lower free radicals. Bathing in sulfur-rich thermal water also increases the anti-inflammatory cytokine IL-10 and regulates antioxidant enzymes, which can help to lower inflammation.

Maintain Kidney Health – The body’s fluid balance and electrolyte status are governed by the kidneys. Electrolyte imbalances are commonly seen in kidney disease. Dehydration can cause elevated levels of blood sodium, which is often seen in diseases associated with kidney problems like diabetes. Edema, which is characteristic to nephrotic syndrome, can cause low sodium levels in the blood due to fluid retention.

• Drinking magnesium-calcium carbonate mineral water can benefit those with kidney disease. Consuming sulfate-bicarbonate, calcium-magnesium mineral water has also shown efficacy in patients with chronic pyelonephritis, which is renal disorders characterized by chronic inflammation. Drinking water rich in sodium-bicarbonate is also used to help with gastrointestinal issues, metabolism, kidneys and the urinary pathways.
• Drinking mineral water can help with kidney stones. Calcium can bind to oxalates, which are what the majority of kidney stones are made of. Indeed, about 80% of kidney stones are made of oxalates and 20% calcium phosphate. Oxalate, or oxalic acid, is an organic acid found in certain plants, such as leafy green vegetables, spinach, some fruit, nuts and seeds. Too many oxalates can prevent calcium from being absorbed into the body and they may also lead to kidney stones and chronic systemic pain. Eating calcium-rich foods like cheese, dairy, fish, and broccoli can actually reduce the oxalate load in your body by providing calcium that can bind with oxalates in the gut. Drinking calcium and magnesium rich mineral water can reduce calcium oxalate stone formation.

Cognition and Neurological Health – Drinking rosemary-infused water can improve cognition and cerebrovascular health. Mineral water consumption can increase the excretion of silicic acid and aluminum in Alzheimer’s disease.

Exercise Performance – Electrolytes, especially sodium and magnesium, are especially important for physical activities and muscle contraction. Sodium generates action potentials of nerves and muscle cells by entering the cell. Physical exertion and exercise burn through minerals and electrolytes, while increasing the demand for them. In professional sports, vitamin and mineral supplementation can provide a competitive advantage. Athletes should be well-hydrated with fluids and electrolytes before and after exercise for optimal results.

• Consuming only water or dilute solutions with little to no sodium during prolonged exercise, such as a marathon or a race, can lower plasma sodium levels and increase the risk of swelling in the brain. Especially during events that last hours or where intense sweating will occur, foods and fluids that contain sodium should be consumed. If you exercise 1 hour per day, you may need 68 mg/kg of body weight of sodium to maintain a positive calcium and magnesium balance. In other words, a 70 kg adult may need 4,760 mg of sodium/day just to prevent calcium and magnesium loss from the body.
• Mineral waters can help with post-exercise rehydration by replenishing the minerals lost through sweat versus low mineral waters. Deep sea minerals can also improve hydration recovery after dehydrating exercise, which benefits muscle strength and recovery.
• Not getting enough electrolytes and salt can cause negative health effects, especially when performing physical activity. Sweat loss during sports can cause heat cramps and decreased performance, which can be prevented with appropriate salt and fluid intake. Thus, obtaining enough salt keeps your body cooler during physical exertion, especially in the heat.
• High heat exposure caused by either exercise, sauna or exercising in a hot climate raises the demand for sodium and potassium. Exercise-induced sweating has been shown to promote the excretion of trace minerals. Additional sodium supplementation while exercising in 40°C does not result in potassium deficiency.
• Exposure to different temperatures and seasons has been shown to influence the amount of minerals being excreted through sweat. However, results may be contradicting, depending on whether sweat is collected with an arm-bag technique or with whole-body collection methods. There are reports that show decreased concentrations of magnesium and copper in people’s sweat during the summer versus the winter. In contrast, sweat calcium, copper and zinc does not appear to differ between individuals living in the tropics compared to those living in cooler regions. There is also a difference between how much individuals will excrete based on their level of heat adaptation. The amount of sodium or chloride lost through sweat can be as low as 292 mg/L or up to 8,650 mg/L.
• After 10 days of exercising on a treadmill in 39.5°C, sweat calcium reduced by about 29%, copper 50%, and magnesium 43%. Exercise-heat acclimatization has been shown to preserve some minerals lost through sweat. It takes about 5-10 days for the body to acclimatize to heat whereby the sweat glands achieve maximal capacity for sodium conservation. Regardless of heat adaptation, there can still be a significant loss of whole-body sodium levels because sweating rate increases independent of the temperature.
• There have been reported losses of 54% of sweat zinc concentrations over the first hour of exercise in a hot climate. The second hour of exercise produces up to 38% reduction in sweat zinc. Heat acclimatization also promotes the conservation of calcium and zinc.
• Numerous studies show that slowly consuming a salt solution that contains ~ 2,300-2,900 mg of sodium in 20 to 26 oz. of water over the course of 60 minutes, starting 90-105 minutes prior to competition, dramatically increases how long an individual can exercise (21 minutes longer), reduces core body temperature (-0.75 ° F), lowers heart rate (9-10 beats/min) and boosts plasma volume (up to +8%). Drinking 2,300 mg of sodium/liter of fluid, vs. 115 or 1,150 mg/L, reduces dehydration (0.75 L less fluid loss). Drinking salt solutions that contain 680 mg of sodium/liter reduces the decrease in plasma sodium levels and lowers the incidence of mild/severe hyponatremia.
• Oral consumption of deep-sea minerals increases high-intensity intermittent running capacity in soccer players in a double-blind, placebo-controlled crossover trial. Sodium helps to buffer lactic acid that gets produced during exercise. Sulfurous mineral water may protect against exercise-induced muscle damage and promote recovery. These benefits may have been due to the hydrogen sulfide contained in the water. Regardless, it is important to note that sulfate in mineral water needs to be balanced with bicarbonate, as sulfate is acidic and contributes to the dietary acid load.
• Potassium and magnesium have an important role in physical performance. Magnesium deficiency is associated with limited strength and power and athletes might be in more need of magnesium.
  • •  

A blood sodium level of less than 135 mEq/L is considered low. It is called hyponatremia, which can be characterized by headaches, cramps, arrhythmia, and increased risk of seizures. In certain cases, it is not a lack of sodium that is causing the problems but the excess water in relation to the amount of sodium, which dilutes the sodium concentration. That is why overhydration can easily cause hyponatremia, which has led to death and brain swelling.

Here are the most common causes of low sodium levels:

• Rapid loss of electrolytes from the body like during diarrhea, vomiting or excessive sweating
• Intestinal damage such as bariatric surgery, celiac’s, IBS, Crohn’s and ulcerative colitis
• Medications, particularly diuretics
• Prolonged exercise for several hours.
• Exercising in the heat or intense exercising causing significant sweating.
• Sauna sessions.
• Overhydration, i.e., drinking too much plain water without enough salt
• States of water retention such as congestive heart failure, cirrhosis and kidney failure
• Medications that cause water retention, such as selective serotonin reuptake inhibitors (SSRIs)
• Syndrome of inappropriate antidiuretic hormone production (SIADH). Anti-diuretic hormone is produced by the hypothalamus and it regulates water retention by the kidneys. When antidiuretic hormone is produced in excess, it causes a drop in blood sodium levels.
• Hormonal imbalances affecting levels of aldosterone, thyroid hormones and cortisol

Hypernatremia refers to a blood sodium level above 145 mEq/L. This most commonly happens because of water restriction that elevates the ratio of sodium to water. That is why hypernatremia is seen in diseases like diabetes and with excessive use of loop diuretics.

Here are the most common causes of high sodium levels:

• Lack of water intake
• Dehydration because of diarrhea or vomiting
• Diabetes
• Excess sodium consumption or supplementation

The body regulates and reduces the excretion of minerals out of urine when you are very deficient as a means of slowing down additional depletion. The absorption of minerals is also lowered when you reach excessive amounts of them in the body to prevent overload and toxicity. However, if you have a poor diet, metabolic syndrome, damaged kidneys or bad digestion, then your ability to absorb or reabsorb minerals is greatly diminished. There are additional things that can make you hold onto less minerals, like excess consumption of plain water without minerals or fasting (due to metabolic acidosis and mineral losses from bone). Bicarbonate has been shown to reduce acute acidosis and improve exercise performance.

Drink Mineral Spring Water: But Check the Label

Among commercial bottled waters, there is a large variation of minerals – magnesium ranging from 0-126 mg/L, sodium 0-1,200 mg/L and calcium 0-546 mg/L. Generally, European bottled waters have a higher mineral content than North American ones. In North America, the average concentration of magnesium is 2.5 mg/L, sodium 5 mg/L and calcium 8 mg/L. In Europe, it is 23.5 mg/L for magnesium, 20 mg/L for sodium and 115 mg/L for calcium.

There are some American brands like Adobe Springs and Mendocino that have magnesium levels comparable to European sparkling waters. According to the International Bottled Water Association, variation of minerals between individual bottles of the same brand are less than 5%.

Sulfates are the 8th most common mineral in our bodies with benefits on the antioxidant system. Getting the right amount of sulfate can help to support joints, the nervous system, the cardiovascular system and reduce inflammation. Unfortunately, nowadays our food contains less sulfur and sulfates because of soil depletion. However, sulfate is also acidic, and if you are looking to reduce metabolic acidosis or improve athletic performance, you need to be careful with overconsuming waters that are high in sulfate and low in bicarbonate.

Sulfites are inorganic salts used for food preservation and in medications. You can get sulfites mostly from processed foods, wine and processed meat. They can also inhibit the browning of fruit and vegetables. Some people, especially asthmatics, are overly sensitive to sulfites, which cause gastrointestinal, cardiovascular, pulmonary and dermatological problems. Nausea, abdominal cramps, diarrhea, and urticaria are commonly reported. Although carcinogenic in laboratory animals, the FDA considers sulfites generally recognized as safe…

Carbon dioxide in the blood will join with water to create carbonic acid. This lowers the blood pH and the nervous system responds by increasing your breathing rate, which is termed “respiratory compensation”. During exhalation, CO2 gets exhaled and pH normalizes. Thus, CO2 is important for keeping your metabolic rate elevated and active.

• Hypothyroidism results in lower carbon dioxide production. Lactic acidosis or metabolic acidosis is a medical condition caused by decreased tissue oxygenation (no Bohr Effect). It can cause inflammation, oxidative stress and growth of malignant cells, also known as The Warburg Effect.
• Naturally carbonated waters have more minerals because the carbonic acid allows the water to absorb the minerals from the rock better. Artificially flavored zero-calorie carbonated waters may have added sulfites, which you might have to be cautious of if sensitive.

When drinking bottled mineral water, it is better to have it in glass bottles to avoid the plastics and heavy metals in cans and plastic bottles. Most plastics leach hormone mimicking agents called ‘xenoestrogens’ that mimic the hormone estrogen in the body.

• Xenoestrogens can also disrupt natural hormone production, inhibiting testosterone. Too much estrogen increases the risk of blood clots, heart attack, stroke, breast cancer, ovarian cancer and depression. The observed decline in male testosterone levels might be explained by the increased use of plastics in our everyday life. You can get exposed to xenoestrogens through water, food, soil and air. Nearly 70% of 450 tested products release chemicals that act like estrogen. The most common xenoestrogens in plastics are bisphenol A (BPA), phthalates, parabens and dozens of others.

Here are the benefits of mineral waters:

• High bioavailability of minerals when consumed with food
• Lowers post-prandial lipids and insulin
• Fuels the body’s physiological processes
• Helps to lower inflammation and stress
• Can relieve constipation, bloating, and digestion issues
• Improves insulin sensitivity and exercise performance
• Provides a zero-calorie source of essential trace minerals
• Covers the body’s daily mineral demands for many elements
• Promotes skin hydration and health
• Decreases hunger levels
• Protects against lipid/protein oxidation

In essence, our bodies are walking bags of salt water that contain various electrolytes and minerals. Electrolytes are the ancient components of optimal cellular functioning used for centuries to improve health and treat certain conditions. The most frequent benefits of drinking mineral waters are better blood pressure and hydration. Spa therapy and thermal baths have more evidence for improving physical pains such as lower back pain, osteoarthritis and fibromyalgia. It requires almost no effort to implement mineral rich waters into your diet. Theoretically, you could get all the minerals you need from food, but as we’ve seen from research, adding mineral water and slowly consuming small amounts throughout the day provides a more bioavailable source of minerals. Thus, it is a prudent strategy for optimal results.

Chapter 6: Magnesium, Calcium, and Phosphorus: Softening Up the Arteries and Hardening the Bones

Magnesium and calcium are particularly relevant to cardiovascular health, bone health and blood pressure. It is known that calcium build-up in the arteries contributes to atherosclerosis and heart disease risk. Calcium supplementation has been associated with increased CVD mortality. High calcium intake from supplements can offset the balance with magnesium. Low magnesium is associated with an increased risk of cardiovascular disease, whereas high magnesium status is associated with a lower risk.

Magnesium intake is also inversely associated with the risk of metabolic syndrome and diabetes. Magnesium also antagonizes the inflammation caused by increased intracellular calcium, which is why it is often called ‘nature’s calcium blocker’.

However, increased dietary calcium intake has been found to be linked with a reduced incidence of atherosclerosis. High intakes of calcium from food does not appear to increase vascular calcification either. Whole foods that contain calcium also bring some magnesium, which keeps the two in balance. Vitamin K1, and especially K2, also helps keeps calcium in check by directing calcium into the bones instead of the arteries.

Very little calcium from supplements will end up in the bones and high doses of calcium can lead to calcium overload in the blood and arterial calcifications. In older adults, osteoporosis co-exists with higher rates of arterial calcification. Low bone mineral density is linked with vascular calcification. Hypercalcemia (high calcium in the blood) is associated with worse rheumatoid arthritis disease markers. However, vitamin K, magnesium and vitamin D are linked with better bone mineral density.

Magnesium Deficiency and Calcium Overload

Magnesium is the 4th most common cation (positively charged ion) in the human body, the 2nd most common intracellular cation and the most common intracellular divalent cation. It is required for over 300 enzymes in the human body. The main functions of magnesium include regulation of sodium, calcium and potassium levels, ATP generation, modulation of inflammation, DNA/RNA protein synthesis and neurotransmitter production.

Extracellular magnesium contributes only ∼ 1% of total body magnesium, which is concentrated primarily in the serum and red blood cells. The human body contains roughly 25 grams of magnesium with 50-60% of it being in bones and the remainder in soft tissue. Out of that amount, 90% is bound and 10% is free. In the blood, 32% of magnesium is bound to albumin and 55% is free.

Here is how magnesium affects the pathogenesis of cardiovascular disease:

• Magnesium activates ATP, which is essential for energy production and cell function. The sodium-potassium pump is magnesium-ATP-driven, and it affects blood pressure as well as sodium accumulation in the cell. ATP is required for heart muscle contraction and oxidative phosphorylation in heart mitochondria.
• Magnesium deficiency leads to intracellular sodium and calcium accumulation, which promotes arterial vasospasms, blood vessel constriction and hypercoagulability. Increased intracellular calcium can lead to hypertension and vasospasms. Coronary vasospasms are thought to be one of the causes of sudden cardiac death.
• Magnesium deficiency reduces membrane potential polarization through intracellular sodium accumulation, which can cause arrhythmias.
• Magnesium deficiency results in increased oxidative stress and low antioxidant defense, which leaves the heart vulnerable to myocardial injury.
• Magnesium supports glutathione synthesis and glutathione deficiency promotes the accumulation of calcium.
• Low magnesium status is associated with hypertension.
• Magnesium deficiency increases inflammatory cytokines and interleukins, which promotes metabolic syndrome, cardiovascular disease and endothelial dysfunction.
• Low magnesium promotes endothelial dysfunction, thrombosis and atherosclerosis.
• Magnesium lowers clotting factors and inhibits ADP-induced platelet aggregation.
• Magnesium deficiency causes myocardial lesions through calcium overload and catecholamine excess.
• Magnesium depletion increases vasoconstriction and worsens cardiac contractility.
• Vasoconstrictor hormones, such as angiotensin, serotonin and acetylcholine increase when extracellular magnesium is low.
• Low serum magnesium is associated with atrial fibrillation in people without cardiovascular disease by modulating the inflow of calcium into the cell.
• Magnesium reduces the inhibition of plasmin, which is an enzyme that degrades fibrin clots.
• Magnesium deficiency results in an increase in triglycerides and blood lipids. Three months of magnesium therapy in patients with ischemic heart disease decreases apolipoprotein B concentrations by 15% and VLDL concentrations by 27%.
• Hypomagnesemia is the result and cause of insulin resistance. Higher magnesium intake is associated with a reduced risk of diabetes.

Magnesium supplementation in patients of coronary heart disease has been found to decrease platelet-dependent thrombosis, improve flow-mediated vasodilation and increase VO2 max.

Women with osteoporosis have been found to have lower serum magnesium compared to those with osteopenia and healthy individuals. A short-term study on 20 postmenopausal women saw that 30 days of 290 mg/d of magnesium citrate suppressed bone turnover, indicating reduced bone loss.

Here are the magnesium-dependent enzymes, functions and consequences that may occur with a deficit:

Magnesium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• ATP Synthase: Produce and activate ATP: Energy shortage, not enough energy to carry out vital bodily processes
• Fatty Acid Oxidation: Burn triglycerides and lipids for fuel: Hyperlipidemia, hypercholesterolemia
• Pyruvate Dehydrogenase: Convert pyruvate into acetyl-CoA and enable the burning of glucose for fuel: Hyperglycemia, insulin resistance
• Glycolysis: Burn glucose for fuel: Hyperglycemia, glycation, insulin resistance
• TCA Cycle: Direct acetyl-CoA into ATP production, NAD/NADH: Energy shortage, mitochondrial dysfunction
• Insulin Production: Produce insulin to enable cells to pick up glucose from the blood: Insulin resistance, hyperglycemia
• GLUT4 Translocation: Enable cells to pick up glucose without insulin: Hyperglycemia
• Thyroid Hormones: Regulate metabolic rate and energy production: Hypothyroidism, chronic fatigue, brittle skin and hair, hypercholesterolemia
• Glutathione Synthesis: Protect against oxidative stress: Increased oxidative stress and weaker immunity
• Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
• Serotonin Production: Enable melatonin production, govern relaxation and docility: Chronic stress, anxiety and sleep problems
• Melatonin Production: Promote sleep, relaxation and antioxidant repair: Oxidative stress, sleep problems, chronic stress
• Dopamine Production: Regulate motivation, mood, attention and behavior: Depression, attention deficit disorders, procrastination
• Steroid Hormone Production: Physical repair, protect against stress, regulate sex hormones: Frailty, aging and muscle loss, chronic stress
• Testosterone Production: Affect bone density, muscle mass, fat burning, mood, and stress: Increased risk of obesity, cardiovascular disease, frailty, and chronic stress
• DNA Repair: Repair damaged DNA: Cell senescence, increased DNA mutations
• T-cell Regulation: Balance anti-inflammatory and proinflammatory immune responses: Autoimmunity, inflammation, infection

Some studies indicate that 180-320 mg/d is enough to maintain a positive magnesium balance, but 107 mg/d is not enough. A study on postmenopausal women showed they were able to maintain a positive magnesium balance by getting 399 mg of magnesium per day on a 2000 kcal diet whereas ~100mg of magnesium per 2000 kcal was inadequate. However, that would refer to an already homeostatic magnesium status, which most people are not at, as well as being without disease states that increase the demand for magnesium.

Postmenopausal women on a low magnesium intake of 100 mg/d develop atrial fibrillation and elevated glucose levels.

Many studies find that at least 300 mg of magnesium needs to be supplemented in addition to the diet to increase serum magnesium levels. Thus, the RDA of 350-420 mg/d may not be adequate to reach that effect.

About 20-40% of the dietary magnesium gets absorbed by the body. It is commonly thought that phytate-rich foods like beans, grains and legumes will lead to magnesium deficiency by binding to it and preventing its absorption. However, urinary magnesium excretion will reduce to compensate for a reduction in magnesium intake. Consuming 322 mg/d of magnesium on a high fiber diet has been noted to result in a negative magnesium balance, but that may be due to the inadequate magnesium intake itself.

A vitamin B6 deficiency will increase magnesium excretion and promote a negative magnesium balance. Combining vitamin B6 with magnesium increases its absorption rate and helps to drive magnesium into the cell. Increased protein and fructo-oligosaccharide consumption appear to improve magnesium absorption.

In physiological intracellular concentrations, magnesium competes with calcium for binding with calmodulin and other calcium-binding proteins, which is how magnesium downregulates nuclear factor kappa-beta activation and inflammation.

Magnesium absorption can also be inhibited by antibiotics, such as ciprofloxacin, levofloxacin and demeclocycline, thus, antibiotics should be taken at least 2 hours before or 4-6 hours after magnesium supplementation. Magnesium decreases the absorption of bisphosphonates, such as alendronate, used to treat osteoporosis. Thus, magnesium supplements and bisphosphonates should be separated by at least 2 hours.

Magnesium Excretion and Assessment

Magnesium excretion is mainly regulated by the kidneys, which excrete about 120 mg of magnesium every day through urine. Magnesium excretion increases during a surplus and falls down to ~12mg during deficits. When magnesium blood levels are low, magnesium will be pulled from muscles, organs and even bones.

Here are factors that contribute to magnesium deficiency and increase magnesium excretion:

• Kidney failure and kidney diseases
• Hemodialysis and peritoneal dialysis
• Alcohol consumption
• Acetaminophen toxicity
• Antacids and diuretics
• Proton pump inhibitors
• Aluminum exposure
• Metabolic syndrome
• Diabetes type 1 and 2
• Calcium supplementation by competing with intestinal absorption
• Excessive vitamin D supplementation by increasing calcium absorption
• Physical exercise and exertion
• Increased sweating and sauna use
• High aldosterone
• Reduced stomach acid and low salt intake
• Malabsorption conditions
• Bariatric surgery, colon removal
• Aging
• Celiac disease
• Liver disease
• Cisplatin
• Crohn’s disease
• High sugar consumption
• High phosphorus intake
• Hyperinsulinemia
• Insulin resistance
• Emotional and psychological stress
• Enzymatic dysfunction by impairing magnesium distribution
• Estrogen therapy by shifting magnesium to soft and hard tissues, lowering serum magnesium
• Excessive or prolonged lactation
• Excessive menstruation
• Prolonged fasting
• Foscarnet, gentamicin and tobramycin
• Heart failure
• Diarrhea and laxatives
• Low selenium intake
• Vitamin B6 deficiency
• Metabolic acidosis
• Pancreatitis (acute and chronic)

Normal serum magnesium is considered to be 0.7-1.0 mmol/L, but the optimal range has been proposed to be>0.80 mmol/L. About 10-30% of a given population experiences subclinical magnesium deficiency based on serum magnesium levels below 0.80 mmol/L.

Muscle magnesium stores are a more accurate reflection of whole-body content of magnesium than the plasma, however muscle biopsy is an invasive procedure.

Here are the signs and symptoms of magnesium deficiency:

• Hypokalemia and hypocalcemia
• Tremors and fascilations
• Arrhythmias
• Migraine headaches
  • Taking 300 mg of magnesium twice a day may prevent migraines.
• Spontaneous spasms and muscle cramps
• Seizures
• Twitching of the facial muscles upon touch
• Aggression and irritability
• Confusion and disorientation
• Pain or hyperalgesia
• Photosensitivity
• Tinnitus (ringing in the ears)
• Hearing loss
• Vitamin D resistance
• Parathyroid resistance and impaired function
• Cataracts
• Coronary artery disease
• Cardiovascular disease
• Hypertension
• Mitral valve prolapse
• Weakened immune response
• Depression

An elevated retention of an intravenous or oral magnesium load is likely the best way to test for magnesium deficiency. It suggests that the body is trying to hold onto more magnesium because the tissues are depleted. However, the tests assume a normal kidney function for the IV test and normal gastrointestinal/kidney function for the oral test. If you do not have normal kidney function for the IV load or gastrointestinal/kidney function for the oral test, then the measurements can be inaccurate. Measuring hair, bone, lymphocyte, urinary or fecal magnesium excretion may be easier and cheaper, but they are less reliable methods. For the most reliable assessment, multiple methods need to be used. The easiest way to identify magnesium deficiency is from a low-normal blood level (< 0.82 mmol/L), especially if the 24-hour urinary magnesium is low (< 80 mg/day). This is not 100% accurate but it is highly suggestive of magnesium deficiency.

Healthy magnesium-sufficient subjects have an IV magnesium load retention of just 2-8%. On average elderly people retain around 28% of an IV magnesium load, suggesting that many older individuals have marginal magnesium deficiency.

Supplement overview:

• Magnesium L-threonate is the best form of magnesium for increasing magnesium levels in the brain. It has been shown to improve cognition in those with cognitive impairment, ADHD symptoms and IQ score in those with ADHD and memory in people with Alzheimer’s disease and in mice with dementia. It has very good bioavailability and a low risk for diarrhea. Some people prefer taking magnesium L-threonate in the morning for focus and alertness, whereas others prefer to take it at night for relaxation and sleep. Different people experience different effects when taking magnesium L-threonate as the benefits will depend on a persons’ baseline magnesium level in the brain.
• Magnesium Glycinate is one of the safest forms of magnesium with some of the least side-effects such as diarrhea. The added glycine, at least in children, may help with relaxation, pain and sleep by lowering body temperature. To be fair, the amount of glycine provided from magnesium glycinate supplements for adults is likely too low to have any real benefit. Doses of 125-300 mg of magnesium glycinate have been shown to rapidly resolve major depression in less than 7 days. Magnesium diglycinate seems to be a good alternative to magnesium oxide in patients with intestinal resection.
• Magnesium Malate has been used for chronic fatigue syndrome and fibromyalgia. Malic acid boosts ATP levels, which is a magnesium-dependent molecule. In animal studies, magnesium malate is highly bioavailable and stays elevated in the serum for hours.
• Magnesium Chloride is the best magnesium for digestion issues because the extra chloride helps to produce stomach acid, which is why it is used to treat digestive disorders. Magnesium chloride has been shown to improve insulin sensitivity and metabolic control in type-2 diabetics. It has also been shown to improve symptoms of depression. Transdermal magnesium chloride may improve pain and quality of life in fibromyalgia.
• Magnesium Citrate has fairly good bioavailability. It can withstand the acidic environment of the gut and can thus be absorbed over a longer period of time. Magnesium citrate has also been seen to improve arterial stiffness. Too much magnesium citrate can cause loose stool.
• Magnesium Taurate is used for cardiovascular conditions as taurine helps the heart to work properly. Taurine can benefit congestive heart failure patients. Both magnesium and taurine have vascular-protective properties.
• Magnesium Sulfate is mostly found in Epsom salt. It contains sulfur, which is a potent antioxidant needed for making glutathione. In pregnant women at imminent risk for delivery, magnesium sulfate supplementation has been shown to reduce the rate of cerebral palsy by 45%.
• Magnesium Arginate helps with vasodilation and blood flow thanks to arginine.
• Magnesium Lysine contains the amino acid lysine, which has anti-viral effects. It can also support skin health.
• Magnesium Ascorbate contains vitamin C, which is why it can cause loose stool in large doses. It is a good bioavailable source of vitamin C and magnesium.
• Magnesium Gluconate is chelated with gluconic acid, which is the by-product of glucose fermentation. Together with potassium gluconate it has been shown to benefit myocardial function.
• Magnesium Orotate is a magnesium salt of orotic acid. In patients with coronary heart disease, magnesium orotate improves heart function and exercise tolerance. It might be the best one for cardiovascular conditions. Even 25-50 mg/d of magnesium orotate has benefits in adolescents with syndromes of cardiac connective tissue dysplasia. Magnesium orotate has even been shown to improve survival in heart failure patients.
• Magnesium Oxide has a fairly low bioavailability compared to other magnesium supplements. It is also one of the most commonly used forms of magnesium, but it can cause negative side-effects as it is not chelated and has poor water solubility. However, there is a case report of hypo-magnesaemia due to malabsorption wherein oral magnesium oxide supplementation elicited a response whereas magnesium glycerophosphate didn’t. This may be because magnesium oxide is high in elemental magnesium compared to most magnesium supplements and if it does not cause diarrhea then it can provide a fairly large amount of magnesium.

When taking magnesium supplements, it is better to take smaller doses more frequently rather than large doses at once because of improved total absorption.

How to Restore Your Magnesium Levels: A 4 Step Plan

1. Determine the factors that are causing you to become depleted in magnesium and fix them.
2. Eat a high magnesium diet.
3. Determine if you are still magnesium deficient (low-end of normal serum magnesium levels plus low 24-hour urine magnesium level).
4. Consider magnesium supplementation.

Calcium Overload and Calcification

Calcium is the most abundant mineral in the human body. It is required for muscle contraction, vasodilation and bone health. However, only 1% of total body calcium is needed for carrying out these roles. The remaining 99% is stored in bones and teeth for structural support. The skeleton and bones are a readily available source of calcium to meet this baseline requirement. When calcium intake is low or malabsorbed, the body will pull stored calcium from bones to maintain normal functioning, which can eventually lead to osteoporosis and fractures. Low calcium levels in the body can cause muscle cramps, convulsions, abnormal heartbeat and eventually death.

Calcium homeostasis is regulated by parathyroid hormone, calcitriol and calcitonin. When blood calcium levels drop, the parathyroid glands secrete parathyroid hormone (PTH), which stimulates the conversion of vitamin D in the kidneys into its active form calcitriol. This decreases urinary excretion of calcium but raises urinary excretion of phosphorus. Elevated PTH also promotes bone resorption or breakdown, which releases calcium and phosphorus into the serum from bones. Higher calcitriol concentrations increase intestinal absorption of calcium and phosphorus. As calcium levels normalize, PTH secretion stops and the thyroid gland secretes a peptide hormone called calcitonin. Calcitonin inhibits PTH, reduces bone resorption as well as calcium absorption and promotes urinary calcium excretion.

Osteoporosis occurs when bone resorption is chronically higher than formation, which promotes the risk of fractures.

• The risk of osteoporotic hip fracture is determined by one’s peak bone mass and the rate of bone loss after that peak has been reached. Low calcium and low protein diets, age, female gender, estrogen deficiency, smoking, hyperthyroidism and high alcohol consumption increase the risk of developing osteoporosis.
• Estrogen deficiency reduces the absorption of calcium, whereas estrogen therapy enhances calcium absorption.
• Excessive calcium intake (>1,500 mg/d) can decrease parathyroid hormone (PTH), which increases the risk of low bone turnover. Too much calcium also reduces the bone growth stimulating effects of PTH.
• However, for the elderly or for someone with impaired calcium absorption, optimal calcium intake may be around 2,400 mg/d due to impaired absorption.

Hyperparathyroidism is the most common cause of elevated calcium in the blood (hypercalcemia). Patients with kidney disease on high calcium intakes experience low bone turnover and PTH suppression. Parathyroid hormone suppression caused by high calcium intake is also thought to reduce magnesium absorption. Sweden is the highest dairy and calcium consuming countries, but it also has the highest rate of hip fractures among developed nations. Meta-analysis find calcium supplementation does increase bone mineral density modestly but does not result in reduced incidence of fractures. Ultimately, the optimal level of calcium intake will also depend on the background intake of magnesium, vitamin D and vitamin K.

Extracellular calcium is constantly maintained at 1.25 mM by parathyroid hormone and 1,25-dihydroxyvitamin D (calcitriol) activity, except after supplementation over a 3-4-hour period.

Intracellular calcium levels are maintained around 100 nM (nanomolar) and can rise up to 1 mcM (micromolar) upon activation, whereas extracellular calcium sits at 1.2 mM.

When intracellular calcium reaches 1 mcM it is taken up by the mitochondria and through a uniporter it is released once levels drop below 1 mcM. Concentrations >1 mcM may inhibit mitochondrial respiration and trigger pro-cell death signals. The mitochondria can accumulate a lot of calcium, exceeding 1000 nmol/mg of mitochondrial protein. This ability is an intrinsic component of ATP production.

Heart mitochondria have a sodium-calcium exchanger in addition to the calcium uniporter. Intracellular calcium is kept at a balance by the influx and efflux of calcium by voltage-operated channels or agonist binding (glutamate, ATP, acetylcholine) via receptor-operated channels. Calcium can also be released from internal stores such as the endoplasmic reticulum.

Increased calcium intake decreases the gastrointestinal absorption of lead and can prevent it from being mobilized from bone during bone demineralization. Average dietary calcium intake of 900 mg/day and supplementation of 1,200 mg/d during pregnancy can reduce maternal lead concentrations by 8-14%. Similar results were found in the blood and breast milk.

Most calcium supplements contain some lead as they are typically sourced from oysters, shellfish, bone meal or dolomite. The FDA’s provisional total tolerable intake (PTTI) level for lead is set at 7.5 mg/1,000 mg of elemental calcium. A review of 324 multivitamin/mineral supplements found lead exposure ranges from 1% to 4% of the PTTI.

Dairy, in particular, promotes insulin-like growth factor (IGF-1), which regulates cell proliferation and growth. Circulating IGF-1 levels are positively correlated with cancer risk, especially prostate cancer. Prostate cancer risk has been observed to be the highest in people who consume the most dairy and animal protein. However, it has also been found that individuals with a higher dairy/calcium consumption are more likely to engage in healthy lifestyle practices like exercise or seeking of medical help, which might mitigate the association with increased prostate cancer risk.

A recent meta-analysis estimated that a high calcium intake (1,300 mg/d) increases fat oxidation by 11% compared to a low intake of 488 mg/d. Dietary calcium may also bind to fat from food in the digestive tract and prevent its absorption. Vitamin D sufficiency could also help with lipolysis as vitamin D deficiency is associated with obesity.

It appears to be dairy foods that are associated with the greatest fat loss seen from increased calcium intake. Calcium may also regulate appetite and hunger levels, making the person eat fewer calories, and whole foods are superior to supplements.

It is thought that calcium supplements override the homeostatic regulation of serum calcium, causing hypercalcemia. Hypercalcemia promotes blood coagulation, vascular calcification and arterial stiffness, which all elevate the risk of CVD.

Phosphate has a role in the accumulation of calcium by activating the calcium uniporter and inhibiting calcium efflux. One of the contributing factors for arterial calcification is high serum phosphate, which has been shown to promote calcification in animal models and cell studies. In humans, high serum phosphate is associated with increased cardiovascular disease events. For every 1 mg/dL increase above normal in phosphorus levels, the risk of coronary artery calcification has been seen to increase by 21%. A low calcium to phosphorus ratio in diet has adverse health effects, starting with arterial calcification and ending with bone loss.

Excessive supplemental calcium can contribute to calcium overload, increasing urinary calcium excretion and possibly soft tissue calcification.

Excess calcium converts smooth muscle cells into bone-forming cells or osteoblasts that promote arterial calcification. High calcium intake also suppresses kidney synthesis of calcitriol, which raises cardiovascular risk.

Calcium supplementation during pregnancy may reduce the risk of preeclampsia, in which the pregnant woman develops hypertension and proteinuria after 20 weeks’ gestation. Supplementing 1,000 mg/d of calcium may reduce the incidence of preeclampsia by 55%. However, it may only be effective in women with a low calcium intake (~314 mg/d) but not in those with more sufficient intakes (1,100 mg/d). There is an inverse relationship between calcium intake during pregnancy and the incidence of preeclampsia.

Intracellular calcium homeostasis is regulated by the mitochondria’s tightly regulated calcium transport system. The mitochondria also produce ATP, which generates reactive oxygen species as an inevitable by-product. In healthy subjects, this basal oxidative stress should be dealt with by the body’s endogenous antioxidant systems. However, during pathophysiological states the balance is offset, causing calcium dysregulation, oxidative stress and eventually cell death. In vitro studies find that calcium in the brain inhibits mitochondrial respiration by inhibition of Complex I and thus reduces mitochondria-generated reactive oxygen species in a dose-dependent manner. Calcium can also inhibit free radical production in the presence of ATP and magnesium.

Calcium signaling also regulates autophagy, which is the recycling of cellular material that is beneficial in moderation but can also lead to cell death when in excess.

Activation of the NMDA-selective glutamate receptors causes a massive influx of calcium into neurons, leading to their death. This is the result of excess mitochondrial superoxide production that damages organelles. Beta-amyloid proteins involved in Alzheimer’s disease cause sporadic intracellular calcium signaling and calcium influx that results in neuronal death.

Here are the calcium-dependent enzymes, functions and consequences that may occur with a deficit:

Calcium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• ATP Synthase: Produce and activate ATP: Energy shortage, not enough energy to carry out vital bodily processes
• Fatty Acid Oxidation: Burn triglycerides and lipids for fuel: Hyperlipidemia, hypercholesterolemia
• Lipolysis: Breakdown of fat cells: Obesity, visceral adiposity
• Glycolysis: Burn glucose for fuel: Hyperglycemia, glycation, insulin resistance
• 5-HTP: Melatonin production, serotonin production, relaxation, REM sleep: Sleeping problems, insomnia, arousal, anxiety, poor memory consolidation
• Parathyroid Hormone (PTH): Bone turnover, bone mineral density: Osteoporosis, increased bone loss, decreased bone density
• Calcitriol: Active form of vitamin D, promote bone density, support immunity, govern hormone regulation: Osteoporosis, decreased bone density, increased risk of fractures, weaker immunity
• Calcitonin: Regulate calcium balance, reduce calcium absorption: Calcium overload, calcification, atherosclerosis

Calcium Food Sources

The current RDA for calcium in women is 1,200 mg/d and for men 1,000 mg/d. The tolerable upper limit is 3,000 mg/d for 9-18-year-olds, 2,500 mg/d for adults 19-50 years old and 2,000 mg/d for 51+ years of age.

Healthy non-growing adults require 550-1,200 mg of calcium a day to maintain balance. For growing boys, the minimal intake to achieve maximal retention is 1,140 mg/d and 1,300 mg/d for growing girls. Intakes greater than 1,400 mg/d achieve a positive calcium balance in people with both normal renal function as well as in those with end-stage renal disease.

An intake of 2,000 mg/d has demonstrated a positive calcium balance of 450 mg/d in normal subjects and 750 mg/d in patients with mild chronic kidney disease (CKD). Thus, calcium retention is higher in people with renal dysfunction and/or kidney disease. As a result, they may also need to aim for the lower end of the RDA and be more cautious with calcium supplementation to prevent soft tissue calcification.

Females, especially adolescent girls, are generally less likely to get adequate amounts of calcium from food. Dairy contributes to 75% of the calcium intake in the American diet. It is common for children to replace milk for sugary soft drinks during the most critical period of their peak bone mass development. Replacing milk with carbonated soft drinks high in phosphorus has been associated with a rise in bone mineral density loss and fracture risk. Soft drinks that contain phosphoric acid have been a major source of phosphorus over the past quarter century.

Calcium from food is not correlated with increased CVD risk, whereas supplemental calcium is. Among calcium supplement users, taking more than 1,400 mg/d of calcium total (from diet and supplements) is associated with higher all-cause mortality, including cardiovascular disease. Dietary calcium intake and the association with cardiovascular mortality follows a U-shaped pattern with intakes < 800 mg/d or > 1,200 mg/d sharply associated with an increased risk of cardiovascular mortality.

Supplemental calcium >1,000 mg/d with or without vitamin D increases the risk of myocardial infarction slightly. The same applies to kidney stones – calcium from food decreases the risk while calcium supplementation increases it. It is thought that acute large boluses of calcium from supplements elevate serum calcium in a way that leads to transient vascular calcification.

Eating calcium-rich foods should not contribute to cardiovascular disease, unless magnesium deficiency occurs, or high-dose calcium supplements are taken.

The recommended ratio of calcium to magnesium is ~2:1 both for daily dietary intake and supplementation. In Western countries, the ratio of calcium to magnesium is much higher than it is in China (3 vs 1.7).

A recent meta-analysis of prospective studies in Shanghai discovered that in people with a Ca/Mg ratio below 1.7, increased magnesium intake was associated with higher mortality, whereas in those with a ratio above 1.7, magnesium reduced mortality. Thus, high supplemental magnesium may not be advisable if calcium intake is low. Instead, it is better to aim for 500-600 mg/d of magnesium and 1,000-1,200 mg of calcium per day, which provides an optimal calcium to magnesium ratio of ~ 2:1. When calcium intake is 10 mg/kg/d, magnesium balance begins to decrease.

The rate of gastrointestinal calcium absorption is about 10- 30% for adults and as high as 60% for growing children. Antacids increase urinary calcium excretion and glucocorticoids promote calcium depletion.

Urinary calcium excretion is limited to 4 mg/kg of bodyweight per day. For an average-weighing person that would equate to a limit of 280-350 mg per day. Because of that, the kidneys are not able to lower hypercalcemia during excess calcium intake. In the elderly and people with renal dysfunction, the arteries become a calcium sink because the kidneys are not able to excrete extra calcium. Hypercalcemia also increases the risk of developing kidney stones.

Here are things that reduce calcium absorption and increase calcium demand:

• Certain plant foods, even those rich in calcium like spinach and kale, inhibit calcium absorption due to their oxalic acid or oxalate content. Oxalates are found the most in spinach, rhubarb leaves, bok choy, sweet potato, cassava and beans. According to research, eating spinach and milk at the same time reduces the absorption of calcium from the milk. Citric acid or lemon juice helps to break down oxalate crystals.
  • Supplemental calcium increases the risk of calcium oxalate kidney stones. Higher dietary calcium intake, however, does not appear to promote kidney stone formation and may even lower the risk. Adequate calcium intake reduces the absorption of dietary oxalate and reduces urinary oxalate by forming insoluble calcium oxalate salts. Consuming large amounts of oxalate does not increase the risk of calcium oxalate stones when dietary calcium in the recommended amounts is present.
• Phytates are weaker inhibitors of calcium absorption than oxalates. Wheat bran or dried beans can substantially reduce calcium absorption, whereas regular wheat does not appear to do so. To reduce the phytate and oxalate content of these foods, you can soak and sprout them beforehand. Yeast also contains a phytate-breaking enzyme called phytase that helps to break down phytate during fermentation.
• High sodium and protein intake can increase urinary calcium excretion but also calcium absorption. Sodium and calcium appear to compete in the kidneys for reabsorption. Every gram increment of sodium (2.5 g of sodium chloride) excretion by the kidneys has been found to draw 26.3 mg of calcium into the urine. However, higher sodium intakes are associated with fewer hip fractures. Thus, the increased absorption of calcium may offset any calcium loss out the urine. At the same time, high protein intake increases intestinal calcium absorption, nullifying the higher calcium excretion. Metabolic acidosis, which may result from excess animal protein or cereal consumption, also increases calcium excretion. Bicarbonate from fruits, vegetables or bicarbonate mineral water can help to offset that.
• Lactose intolerance increases the risk of calcium deficiency due to the avoidance of dairy. Some lactose intolerant people can tolerate small amounts of dairy, like an 8 oz glass of milk, without side-effects. Consuming dairy with other foods or spread throughout the day may improve tolerance. Low-lactose dairy products include aged cheeses, yogurt or lactose-free milk.
• Vegan diets may not provide adequate amounts of calcium due to the avoidance of dairy as well as the reduced bioavailability of calcium from the increased phytonutrient content of plants. Bone fracture risk is higher in vegans compared to omnivores or vegetarians. Lacto-ovo-vegetarians (eggs and dairy) and non-vegetarians have similar calcium intakes. So, having some dairy products in the diet appears to be enough to cover calcium needs. Not to mention the oxalic acid and oxalate content vegans consume in their spinach, rhubarb leaves, bok choy, sweet potato, cassava and beans.
• Caffeine from coffee, tea or soda can also raise urinary excretion while reducing the rate of absorption of calcium. However, one cup of coffee causes a loss of only 2-3 mg of calcium. Doses of 400 mg of caffeine do not change 24-hour urinary calcium excretion. Moderate coffee consumption (1-2 cups a day) is not associated with poor outcomes on bone but when no milk or other calcium foods are consumed it is. Thus, habitual coffee consumption requires compensation in the form of increased calcium consumption from food. The increased urinary calcium excretion seen from the consumption of carbonated beverages is attributed to their caffeine content, not the carbonation or phosphorus.
• Alcohol reduces calcium absorption directly and by inhibiting enzymes that convert vitamin D into its active form. However, moderate alcohol consumption (1-2 drinks or 30 grams per day) does not have a significant impact on bone health or vitamin D status.
• Menopause promotes bone loss due to lower estrogen levels increasing bone resorption and reducing calcium absorption. During the first year of menopause, bone mass may decrease 3-5% per year, but it drops down to 1% after the age of 65. Increasing calcium intake does not completely offset this loss. To restore premenopausal bone remodeling, estrogen or hormone replacement therapy (HRT) may be needed. HRT is often prescribed to women at an increased risk of osteoporosis, but it must be balanced with a potential increased risk of cardiovascular events.
  • Low calcium intake is associated with premenstrual syndrome (PMS) and supplemental calcium decreases the symptoms. Women in the highest quartile of dietary calcium (~1,283 mg/d) have a 30% reduced risk of developing PMS compared to those with the lowest intake (~529 mg/d). Among 466 women with moderate-to-severe PMS symptoms, supplemental calcium of 1,200 mg/d for three menstrual cycles was associated with a 48% decrease in total symptoms compared to the 30% reduction of the placebo group. Similar results have been found with supplemental calcium of 400-500 mg/d and 1,000 mg/d.
• Amenorrhea, which is a condition wherein menstruation stops or fails to begin, causes a drop in circulating estrogen, which has a negative effect on calcium balance. Usually, it is associated with the “female athlete triad” – disordered eating or anorexia, amenorrhea and osteoporosis. Menstrual irregularities and low bone mineral density are associated with the risk of future fractures. Calcium and vitamin D supplementation has been shown to reduce the incidence of stress fractures among female navy recruits.

Calcium itself decreases the absorption of some drugs, such as bisphosphonates (used for osteoporosis), fluoroquinolones and tetracycline antibiotics, levothyroxine, phenytoin (an anticonvulsant), and tiludronate disodium (for Paget’s disease). Consuming 600 mg of calcium with a meal cuts the absorption of zinc in half from that meal. Taking calcium supplements together with thiazide diuretics increases the risk of hypercalcemia because of increased calcium reabsorption by the kidneys. It can also promote abnormal heartbeat in people taking digoxin for heart failure.

Calcium supplementation is not recommended for those who do not need it as dietary calcium comes in safer amounts and with other nutrients. However, it might be necessary for those who are having difficulties consuming calcium foods, like in those who are lactose intolerant or for postmenopausal women. To avoid calcium overload and increased urinary excretion, it is better to take no more than 500 mg per meal and not exceed 1,500 mg/d. Supplementing calcium (600-2,000 mg/d for 2-5 years) has been associated with gastrointestinal disturbance, constipation, cramping, bloating and diarrhea. The most cost-effective calcium supplement is calcium carbonate. Calcium citrate is best for those who have poor stomach acid or are on histamine-2 blockers or protein-pump inhibitors.

Phosphorus and Health

Phosphorus is another essential mineral component of bones and teeth as well as DNA and RNA. Calcium and phosphorus make up hydroxyapatite, which is the main structural component of bones, the collagen matrix and tooth enamel. In humans, phosphorus makes up ~1-1.4% of fat-free mass (approximately 700 grams). Out of this amount, 85% is located in bones and teeth as hydroxyapatite, 14% exists in soft tissue and 1% is present extracellularly.

Inorganic phosphorus as phosphate (PO 4 3−) is required for all known life forms. Phosphorus is a part of cell membranes, ATP and phospholipids. Phosphorylation is the addition of a phosphoryl group to an organic molecule, which affects many proteins and sugars in the body. The phosphorylation of carbohydrates is involved with many steps in glycolysis. Glucose phosphorylation is needed for insulin-dependent mTOR activity in the heart, regulating cardiac growth. Thus, without phosphorus, or phosphorylation, glycogen resynthesis and glycolysis do not work as well. Phosphorylation also affects amino acids and proteins like histidine, lysine, arginine, aspartic acid and glutamic acid.

Phosphorus deficiency can cause anorexia, muscle wasting, rickets, hyperparathyroidism, kidney tubule defects, and diabetic ketoacidosis. Genetic phosphorus disorders include X-linked hypophosphatemic rickets, which promotes rickets, osteomalacia, pseudofractures, dental damage and enthesopathy (mineralization of ligaments and tendons). Hypophosphatemic rickets may also be accompanied with hypercalciuria.

• In preterm infants, phosphorus and calcium deficiency are one of the main causes of osteopenia. Most of the fetal bone mineralization occurs during the third trimester of pregnancy, which is why preterm babies are born with low calcium and phosphorus in their bones.
• Phosphorus deficiency occurs in 21.5% of chronic obstructive pulmonary disease patients, 30.4% chronic alcoholics, 33.9% of ICU patients, 75% of severe trauma or burn victims and up to 80% of people with sepsis.
• Prolonged starvation or malnutrition can cause refeeding syndrome, which is characterized by hypophosphatemia but can also include abnormal balances in sodium and fluids, changes in metabolism, thiamine deficiency, hypokalaemia, and hypomagnesaemia.

In early starvation, the body will shift from using carbs to using fat and protein for fuel, which can decrease metabolic rate by up to 20-25%. During refeeding, the increase in blood glucose increases insulin and decreases glucagon, which stimulates synthesis of glycogen, fat, and protein. This process requires phosphate, magnesium, and vitamin B1. Insulin stimulates the absorption of potassium, magnesium, and phosphate into the cells via the sodium-potassium ATPase pump, which also shuttles glucose into cells. This process decreases serum levels of these minerals because the body is already depleted of them.

• Refeeding syndrome can cause electrolyte deficiencies, fluid retention, cramps, heart palpitations, hypoventilation, respiratory failure, heart failure, impaired blood clotting, coma and even death. It is more likely to develop in patients who are underweight, anorexic, have a low-nutrient diet or with a history of drug/alcohol abuse.
• Administration of phosphorus and thiamine can help to prevent refeeding syndrome. However, electrolytes and sodium are also vital because an actual phosphorus deficiency is rare. For most people to become deficient in phosphorus, you would have to be ingesting close to zero phosphorus for a month or longer, which is why it most commonly occurs in third world malnutrition victims. Refeeding syndrome while fasting or calorie restriction occurs mostly because of dehydration, lack of potassium, sodium, and magnesium.

Normal serum phosphate in adults is 2.5-4.5 mg/dL or 0.81-1.45 mmol/L. Hypophosphatemia is defined when phosphate drops below the lower end of the normal range and hyperphosphatemia is when it is above the high end. However, serum or plasma phosphate does not necessarily reflect whole-body phosphorus content.

Here are the phosphorus-dependent enzymes, functions and consequences that may occur with a deficit:

Phosphorus-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• ATP Synthase: Produce and activate ATP: Energy shortage, not enough energy to carry out vital bodily processes
• Phosphorylation: Burn triglycerides and lipids for fuel: Hyperlipidemia, hypercholesterolemia
• Glycolysis: Burn glucose for fuel: Hyperglycemia, glycation, insulin resistance
• Glucokinase: Catalyze the phosphorylation of glucose: Risk of hyperglycemia and insulin resistance
• Hexokinase: Catalyze the phosphorylation of glucose: Risk of hyperglycemia and insulin resistance
• Glucose 6-Phosphate: Convert glucose into glycogen, glycogenolysis, glycolysis, gluconeogenesis: Risk of hyperglycemia and low glycogen storage
• Fructose-6-Phosphate: Store glucose in the cells, glycolysis, gluconeogenesis: Risk of hyperglycemia and insulin resistance
• Fructose-1-Phosphate: Store fructose in the cells, glycolysis, gluconeogenesis: Risk of hyperglycemia and insulin resistance
• Parathyroid Hormone (PTH): Bone turnover, bone mineral density: Osteoporosis, increased bone loss, decreased bone density
• Calcitriol: Active form of vitamin D, promote bone density, support immunity, govern hormone regulation: Osteoporosis, decreased bone loss, decreased bone density, increased risk of fractures, weaker immunity
• Calcitonin: Regulate calcium balance, reduce calcium absorption: Calcium overload, calcification, atherosclerosis

The RDA for phosphorus is 700 mg for adults, 1,250 mg for teens 9-18 years of age, 500 mg for 1-8-year-olds and < 275 mg for infants. Tolerable upper intake levels (Uls) are set at 3,000-4,000 mg/d. Estimated Average Requirement (EARs) for basal requirements are deemed to be 580 mg/d for ages above 19. The RDA for phosphorus is being exceeded greatly and it may be even higher than currently estimated. NHANES data from 2015-2016 shows that adults get on average 1,189 mg/d for women and 1,596 mg/d for men, while children and teens get 1,237 mg/d. In 2013-2014, NHANES showed the average phosphorus intake from both food and supplements was 1,744 mg/d for men and 1,301 mg/d for women. However, this may not be adequate as these surveys don’t take into account the phosphate additives in many foods.

High intake of phosphorus can contribute to calcium overload and magnesium deficiency. Cell studies find excess phosphorus can cause vascular calcification and endothelial dysfunction. A high intake of phosphorus (>1,400 mg/d) in relation to calcium keeps parathyroid hormone elevated constantly, which decreases bone mineral density. Over the long term, it can lead to an increased risk of skeletal fractures and cardiovascular disease mortality.

However, if calcium intake is adequate, high intake of phosphorus doesn’t seem to have a negative effect on bone mineral content. Excess phosphorus, however, may promote the formation of kidney stones and calcium oxalate.

The recommended ratio of Ca/P is 1-2:1. That ratio in the U.S. between 1932-1939 was 1.2-1 and has risen to 1/4 in those who replaced soda with milk. Increased phosphoric acid consumption from soft drinks may have a negative effect on bone health. Diets with a low Ca/P ratio (≤0.5) have an increase in parathyroid hormone and urinary calcium excretion.

High dietary calcium and phosphate intake inhibit the absorption of magnesium. People eating refined low magnesium diets also tend to get a lot of phosphorus from those same foods. Since the early 1900s, the P/Mg ratio has increased from 1.2:1 to 7:1. Dairy, especially cheese has a high phosphorus to magnesium ratio. For example, cheddar cheese has a P/Mg ratio of 18 and Ca/Mg ratio of 26. Pumpkin seeds, on the other hand, have a P/Mg ratio of 0.35 and a Ca/Mg ratio of 0.21.

Phosphorus is found in many different types of foods, such as dairy, meats, fish, eggs, legumes, vegetables, grains and seeds. Infants fed cow-milk formulas have a 3x higher phosphorus intake and higher serum phosphate levels compared to those fed human milk. These levels seem to normalize after 6 weeks but less than 1 month old infants may be at a risk of hypocalcemia when fed exclusively high phosphorus formulas.

Phosphate additives like phosphoric acid, sodium phosphate and sodium polyphosphate are added to processed foods for preservation and they have been shown to reduce bone mineral density in humans. These additives can provide 300-1,000 mg to the total daily phosphorus intake with an average of 67 mg of phosphorus per serving. That is about 10-50% of the phosphorus intake in Western countries.

Absorption of phosphorus from whole foods is anywhere from 40-70% with animal foods being more bioavailable than plants. The absorption rate of phosphate additives added to foods is anywhere from 70-100%. Unenriched meat and cottage cheese are better choices than hard cheeses or sausages that tend to have added phosphate additives. In seeds and grains, phosphorus is stored as phytic acid. Because humans lack the phytase enzyme, phytic acid is not absorbed and it actually inhibits the absorption of other nutrients.

Calcium from foods and supplements may bind to phosphorus and reduce its absorption. A high intake of calcium (2,500 mg/d) can bind 0.61–1.05 grams of phosphorus. Replacing high phosphorus foods like animal protein and phosphate additives with more calcium foods can reduce serum phosphate levels.

Phosphorus homeostasis is regulated by the kidneys, bones and intestines. In kidney failure, the body cannot excrete phosphate efficiently and its levels rise. Phosphorus resorption by the kidneys also increases. Patients with moderate kidney dysfunction have higher serum phosphate levels (4.12 ml/dL) compared to those with normal kidney function (3.74 mg/dL). Higher phosphorus retention promotes chronic kidney disease (CKD) and bone disorders. High as well as low bone turnover are common in CKD.

Reducing phosphorus containing foods, which are often high in protein, in CKD patients may not outweigh the benefit of controlling phosphorus levels and may lead to higher mortality because of protein restriction. Instead, getting higher calcium proteins foods like cottage cheese or whey protein might be a better approach.

Antacids can bind to phosphorus and over the long-term lead to hypophosphatemia. If the antacids contain calcium carbonate, they can also decrease the intestinal absorption of phosphorus. Laxatives that contain sodium phosphate can increase serum phosphate levels. When taken at high doses, laxatives that contain sodium phosphate may even lead to death, especially in those with kidney failure, heart disease or dehydration.

Conclusion on Magnesium, Calcium, and Phosphorus

• The optimal daily magnesium intake from food is around 400-600 mg/d. Pumpkin seeds, nuts, spinach, beans, seafood, fish and leafy greens are the most abundant sources of magnesium.
• Magnesium supplementation may be advisable, especially for people who suffer from kidney stones, diabetes, CVD or some other co-morbidity.
• Drinking mineral waters is the most bioavailable form of getting natural magnesium.
• The optimal daily intake of calcium is 1,000-1,200 mg/d from whole foods, preferably dairy and green vegetables.
• An optimal Ca/Mg ratio is ~ 2:1 and don’t consume excessive amounts of phosphorus, especially phosphate additives.
• Taking calcium supplementation is not recommended unless you are eating a calcium deficient diet or are at a higher risk of osteoporosis. When taking calcium supplements, don’t exceed 1,000 mg/d and 500 mg/d may be more optimal.
• The optimal phosphorus intake is ~ 700-1,250 mg/d. Don’t exceed 1,400 mg/d chronically. You can find plenty of phosphorus from most foods, especially animal protein, which is why you more than likely do not and should not supplement with phosphorus.
• To maintain the optimal Ca/P ratio of 1-2:1, consume mineral waters high in calcium, green vegetables and/or some pastured milk or cheese. At the same time, make sure you are getting optimal intakes of magnesium. If you are consuming soda or processed foods with phosphate additives, replace them natural mineral waters.
• In practice, you can find the optimal balance between these minerals by eating plenty of vegetables, some meat and dairy. Limit your consumption of soda and other phosphate additive-laden foods. Sardines and fish with the bones are an excellent source of all 3 of these nutrients.

Chapter 7: The History and Importance of Copper in the Diet

Copper is a component of numerous enzymes in the body including cytochrome c oxidase in the electron transport chain. Copper helps with electron transport, energy production and oxygen transportation. It is also a very versatile catalyst for oxidation/reduction (redox) reactions.

As the Earth went from being anaerobic to aerobic due to the formation of oxygen from photosynthetic blue-green algae, the increase in atmospheric oxygen forced organisms to figure out a way to handle the highly reactive oxygen species such as hydroxyl radicals, peroxynitrite, superoxide anions and hydrogen peroxide. Thus, enzymes evolved like superoxide dismutase, which require copper, zinc and manganese in humans. In plants, copper is also needed for growth.

The human body contains roughly 1.4-2.1 mg of copper per kilogram of bodyweight. Thus, an average adult who weighs 70-90 kg has only about 1/8th to 1/10th of a single gram of copper.

Low copper intake jeopardizes the immune response, which is not restored even after several weeks of high copper intake. A large part of the population is not meeting the RDA of 0.9 mg/day, not to mention the optimal intake for copper, which sits at around 2.6 mg/day.

The History and Ancient Utility of Copper

Copper vessels have been used for cooking food, which can be beneficial or harmful, depending on the dose. Excess copper can promote reactive oxygen species formation, whereas deficient copper promotes anemia, neutropenia and ischemic heart disease. However, even 10 mg per day of copper has been found to be safe for most individuals. Copper excess is typically due to a loss in the control of copper utilization in the body and not due to an excessive intake.

The antiseptic properties of copper are known to kill off bacteria and viruses like E. coli, Candida utilis, and poliovirus, thus improving wound healing and reducing the risk of sepsis. The Egyptians, Aztecs, and Romans used copper mixtures for many different wound healing and pathogen destroying purposes. Even China supposedly used copper coins, due to their antiseptic properties. Also, France used it to treat epileptic hysteria, anemia, neuralgia, hysteria, hypochondria and nervous paralysis of various sorts, such as hemiplegia, paraplegia, amaurosis, hysteria with amenorrhea, hysteria, beginning paralysis, complete hysteric paralysis with amenorrhea, neurosis of hysteric nature and hysterical shaking.

The Modern Utilization of Copper

During the cholera epidemic, copper industry workers in France were protected from dying. The 16 people who were said to have died were unemployed from the copper industry at the time. Workers in non-copper manufacturing were 10-40 times more likely to die.

In regions of India and Nepal, copper was used for treating a variety of disorders such as venereal diseases, fevers, diarrhea, skin diseases (such as ringworm, eczema and leprosy), colic, hemorrhoids, indigestion, spleen, liver and blood diseases and wound healing of ulcers and sores.

The ancient Persians also used copper for treating boils, eye diseases and “yellow bile”.

In Switzerland, a physician named Köchlin used copper to treat syphilis, rickets, tuberculosis, cholera, boils, skin eruptions, chorea, ulcers, epilepsy, hypochondria, hysteria, melancholy and other afflictions. Köchlin also noted that copper improved male fertility.

Rademacher noted that copper cured neuralgias of the head, apoplexy, paralysis, angina (chest pain) and scarlatina (scarlet fever), pleurisy, dropsy, hematuria, acute and chronic rheumatism and asthma. Rademacher also used copper to kill and expel intestinal worms and utilized copper for treating numerous skin diseases such as eczema, itching, herpes and removal of warts.

Research nowadays reports that different copper chelates have anti-convulsant activity in animal models of epilepsy.

In 1930, de Nabias told the French Cancer Association that intramuscular injections of a copper preparation helped to expel tumor tissue. He also noticed that during the repair, necrotic cells were replaced by healthy ones. In 1959, Voisin saw adequate results in mice with adenocarcinoma with intravenous injections of colloidal copper. The growth of adenocarcinoma was inhibited in all but two cases with daily injections.

Kobert, in 1895, published a review paper covering the benefits of copper compounds for treating acute and chronic diarrhea, dysentery, cholera, adenitis, eczema, impetigo, tuberculosis, lupus, syphilis, anemias, chorea (a neurological disorder hallmarked by jerky involuntary movements) and facial neuralgia. Heilmeyer and Stüwe, in 1938, were the first to suggest that copper levels increase as a defense mechanism to combat diseases such as scarlet fever, diphtheria, tuberculosis, arthritis, malignant tumors, and lymphogranulomas. Fenz, in 1941, noted that copper was effective for patients with polyarthritis, acute and chronic rheumatoid arthritis and ankylosing polyarthritis.

With the discovery of corticosteroids, which are now common day medications to treat inflammation, the interest in copper compounds for treating rheumatic and arthritic conditions died off.

Copper Deficiency Anemia: The Copper/Iron Connection

Anemia is defined as a decrease in the oxygen carrying capacity of the blood. Anemia is suggested when levels are slightly below a normal hemoglobin level of around 13.8-17.2 g/dL in adult men and 12.1-15.1 g/dL in adult women.

As a result, you can experience chronic fatigue, shortness of breath, weakness, pale skin, lightheadedness and other problems. Both too much, as well as too little iron, can make people more susceptible to infections. Some amounts of iron are needed for fighting harmful bacteria; however, excess iron also promotes the growth of these pathogens.

Copper improves the ability of red blood cells to transport oxygen and nutrients, creating a ‘hypernutritive state’. Clinicians nowadays acknowledge that copper sulfate can increase the number of red blood cells. Copper can also protect against the oxidation of red blood cells, making them more resilient.

In the mid-1800s in France, it was common knowledge that chlorosis/anemia could be treated with exposure to copper. The essential role of copper in health was first discovered in 1928 when it was shown that rats fed a copper-deficient diet were unable to produce enough red blood cells.

Although copper was not a major component of hemoglobin, it was considered a catalyst needed for hemoglobin synthesis. Fixing a copper deficiency also improves erythropoietin unresponsiveness (erythropoietin is needed to make red blood cells) in anemic hemodialysis patients. In 1931, Cook and Spilles discovered that copper stimulates the release of stored iron in tissues during the creation of red blood cells. Thus, copper mobilizes iron, helping to shift iron storage into hemoglobin.

Iron and copper are absorbed in the upper small intestine and hepcidin controls the absorption of iron, by inhibiting iron export in the intestine. Hepcidin expression is decreased on a copper deficient diet, potentially leading to iron deficiency. In other words, a low copper diet can lead to low iron absorption and iron deficiency anemia.

Hephaestin and its homologue ceruloplasmin, the latter being the major copper-carrying protein in blood, are required for efficient iron transformation into transferrin. Their synthesis and activity are positively correlated with copper levels in the cell. Thus, a copper deficiency can lead to a reduction in hepcidin, hephaestin and ceruloplasmin jeopardizing iron metabolism and restricting its movement out of the gut and liver to areas where it may be needed in the body. Additionally, copper is also needed for the synthesis of heme, which is a constituent of hemoglobin. Thus, in order to get iron where it needs to go in the body, it must be placed onto transferrin, which requires copper.

• To sum it up, the absorption, export and transport of iron requires copper. All things regarding iron require adequate amounts of copper and many issues that are thought to be caused by “iron deficiency” may actually be caused by copper deficiency.

In 1966, Osaki and colleagues suggested to rename ceruloplasmin ‘serum ferroxidase’ because of its importance in iron metabolism. They showed how ceruloplasmin, which is the main copper-carrying protein in our blood, allowed iron to get into bone marrow by promoting iron transfer onto transferrin. Thus, numerous iron proteins need ceruloplasmin to work.

• However, it wasn’t even formally accepted until around 1984 that ceruloplasmin was an enzyme needed for iron to bind to transferrin. This is partly why so few doctors, or the lay public, knows about the benefits of copper in the body.
• Iron metabolism is not substantially affected until ceruloplasmin levels hit about 5% of normal levels. This was confirmed by Osaki and Johnson (1971) as well – ceruloplasmin works and promotes the release of iron from the liver at 10% of normal levels.
• A copper deficiency can decrease iron levels and cause iron deficiency anemia in some tissues while resulting in iron overload in other tissues, such as the liver and intestine. An absence or dysfunction of ceruloplasmin leads to the accumulation of iron in the brain, liver, intestine, pancreas and retina. Tissue iron overload and very high serum ferritin levels have been seen in those with familial ceruloplasmin deficiency. Deficiencies in ceruloplasmin also cause iron to accumulate in the spleen, which leads to microcytic, hypochromic anemia, dementia, cerebellar ataxia and diabetes.
• Patients with an acquired copper deficiency and lack of ceruloplasmin can get liver iron overload, diabetes, neurological issues and retinal degeneration. People with non-alcoholic fatty liver disease (NAFLD) have significantly lower copper levels in the liver, which suggests that copper deficiency likely contributes to the iron accumulation in the liver of those with NAFLD. Iron overload is associated with many diseases like arthritis, cancer, tumor growth, diabetes, heart failure and liver damage. Studies link excess heme iron with colon cancer. By reducing iron overload, copper may slow down the aging process. Furthermore, iron overload can induce copper deficiency. It’s a vicious cycle.

The potential consequences of copper deficiency:

• Iron deficiency anemia – decreases absorption of iron by enterocytes, reduces iron release from storage sites, and reduces iron incorporation into transferrin reducing hemoglobin synthesis. Enterocytes are polarized epithelial cells lining the intestinal track that regulate the uptake of nutrients from the diet. Like all other cells, they have to balance copper metabolism to cover essential requirements without causing toxicity. Enterocytes actually need quite a lot of copper as a cofactor for hephaestin, which is essential for absorption of dietary iron.
• Iron overload – in the liver (fatty liver disease), pancreas (diabetes), spleen (hypochromic anemia), brain (neurological disorders) and retina (retinopathy).
• Lipofuscinogenesis – lipofuscin is an age-related pigment that accumulates in the cells, promoting oxidative stress, cellular senescence and aging. Excess iron is one of the contributors for lipofuscin accumulation.

Copper deficient diets can reduce cytochrome c oxidase activity and heme synthesis from iron and protoporphyrin. This reduction in cytochrome c oxidase limits the reduction of Fe3+ iron to Fe2+ iron to form heme. Thus, copper deficiency reduces iron utilization by the mitochondria.

Why You Need Copper

Cardiovascular Disease – Copper deficiencies are seen animals and humans with a wide range of heart disease outcomes, such as aortic rupture, fissures, cardiac enlargement, abnormal lipid metabolism, and ischemic heart disease. Copper deficiency is one of the few nutrient shortages that elevates cholesterol, blood pressure, homocysteine, adversely affect the arteries, impairs glucose tolerance, and promotes thrombosis. People with hypertension tend to have lower copper than those with normal blood pressure. In men, copper deficiency can cause irregular heartbeat.

• According to a 1965 autopsy study, people who died from a heart attack, known as a myocardial infarction, had lower amounts of copper in their myocardium. Pigs fed a copper deficient diet have scarred blood vessels but exhibit atherosclerosis. The decrease of copper in the arteries appears to be linearly associated with an increase in atherosclerosis. There are approximately 80 anatomical, chemical and physiological similarities between copper-deficient animals and humans and ischemic heart disease.
• Atherosclerotic arteries have been shown to have lower copper and reduced cytochrome c oxidase activity than those without atherosclerosis. Cytochrome c oxidase is a copper-dependent enzyme. A shutdown of the copper-dependent cytochrome c oxidase is how cyanide leads to death, by inhibiting the production of ATP. Decreased cytochrome c oxidase in heart muscle has been noted after myocardial infarction. There is an increase of copper levels in patients with myocardial infarction, which may lead to copper depletion due an increase in copper need.
• A decline in the copper content of the aorta has been seen alongside increased atherosclerosis. Among Nigerians, in both older men and women, significant reductions of arterial copper are observed. Similar observations have been made in African Americans and Minnesota Caucasians, although their copper levels are higher.
• Copper deficiency and low ceruloplasmin raises iron levels and can cause iron overload. High iron is a risk factor for heart disease and is associated with cardiovascular events. Elevated iron raises the demand for copper by inducing a mild copper deficiency. 
• Copper is needed to strengthen collagen, and hence, a lack of copper may reduce the health of the arteries and the heart. Copper is needed as a cofactor for lysyl oxidase which cross-links collagen and elastin giving it tensile strength. High homocysteine increases homocysteine thiolactone, which inhibits lysyl oxidase. As a result, your arteries can get damaged and become more susceptible to atherosclerosis. Aneurysms and blood vessels are more likely to rupture/tear with high blood pressure on a diet deficient in copper due to decreased collagen/elastin strength. Low lysyl oxidase, a marker of reduced copper status, is associated with ischemic heart disease. Homocysteine alone is a risk factor for cardiovascular disease, stroke, and ischemic heart disease. Homocysteine can bind copper and induce copper deficiency.
• Copper is important for neovascularization or angiogenesis (the process of growing new blood vessels). Thus, copper is also important in wound healing, whether that be ulcers, cuts, bruises or organ damage. The repair of collaterals, which are new blood vessels that supply the heart when larger arteries become blocked due to atherosclerosis, may not occur if the diet is low in copper. Copper ions also activate endothelial nitric oxide synthase (eNOS), which explains its importance in vasodilation and better endothelial function.
  • • •  

Inflammatory Conditions – Many times elevated copper levels in the blood indicate inflammation, which itself is a cardiovascular disease risk factor. That’s why it is more accurate to look at enzyme activity or leukocyte copper levels than just blood copper levels.

• Diabetics have a reduction in liver copper content. In fact, diabetes itself can cause an imbalance of copper and a loss in copper utilization in the heart. That can contribute to the pathogenesis of diabetic arteriopathy. Inflammation is also raised during hyperglycemia, hyperinsulinemia, glucose intolerance and diabetes. Patients with peripheral arterial disease show higher blood pressure, high triglycerides, lipids and elevated serum copper because inflammation raises copper. Thus, diabetes can cause copper dysregulation and lead to cardiovascular disease development.
• Other inflammatory conditions like rheumatoid arthritis or infections exhibit elevated copper levels. It is also known that diets low in copper can cause osteoporosis. Copper deficiency reduces bone integrity, leading to brittle bones and fractures by decreasing lysyl oxidase. Low serum copper, iron and zinc are a risk factor for osteoporosis. Excessive intake of milk, high in calcium and low in copper, may exacerbate this problem instead of mitigating it.
• There is an epidemiologic association between osteoporosis, ischemic heart disease and a diet low in copper. Osteoblast activity, osteoblasts are the cells that build our bone, is decreased in copper deficiency and human osteoporosis. A supplementation trial with trace minerals that included copper, zinc, manganese and calcium improved bone density compared to either calcium only or trace minerals only. Decreased copper has been found in people with bone spurs, ischemic necrosis of the arteries, fractures and decreased lumbar bone density.

Oxidative Stress – Copper inhibits oxidative stress and reactive oxygen species (ROS) via superoxide dismutase (SOD). The superoxide anion causes lipid peroxidation in addition to other problems, which can be neutralized primarily by copper-zinc superoxide dismutase (Cu,Zn SOD). Excessive oxidative stress is a key contributor to the pathogenesis of many diseases, primarily by raising inflammation.

• Endothelial dysfunction, which is when the lining of the arteries is damaged and there is decreased arterial relaxation, precedes cardiovascular disease and is caused by reduced nitric oxide availability. A low copper intake can be a major contributor to reduced nitric oxide status. This is because copper is a cofactor for the function of superoxide dismutase, which inhibits the free radical superoxide anion, which sequesters nitric oxide to form the toxic peroxynitrite. Thus, a copper deficiency can result in a “nitric oxide steal”, transforming it into a damaging and inflammatory molecule. Polyphenol-rich blackcurrant powder/juice may improve nitric-oxide mediated relaxation of coronary arteries via a copper- and iron-dependent antioxidant effect.
• Low dietary copper intake increases free radical production in healthy men, which may increase the risk of colon cancer. Elevated reactive oxygen species cause death of endothelial cells, which also leads to cardiovascular disease. Reperfusion injury, which occurs after a blocked artery is re-opened, is also driven by ROS. Maintaining adequate copper intake helps to reduce the amount of ROS by regulating extracellular SOD.
• Copper seems to increase the activity of glutathione peroxidase, which is needed for handling hydrogen peroxide. In fact, copper deficiency has been shown to decrease glutathione peroxidase. Through an overall reduction in oxidative stress, ensuring adequate levels of copper can boost glutathione levels, which is the main antioxidant in the body that protects against oxidative stress. Thus, copper acts as an antioxidant mineral. In fact, a lack of glutathione may reduce the ability of the body to store copper as a complex with metallothionein. Hence, a low copper status can increase oxidative stress, resulting in a reduction in glutathione, which leads to further loss of copper and dysfunctional copper utilization. In other words, a low intake of copper can lead to an increased loss of copper.

Mitochondrial Function – Copper is a co-factor for respiratory complex IV in the mitochondria. A copper deficiency impairs immature red blood cell bioenergetics, which alters the metabolic pathways, turning off the mitochondria and switching over to more glycolysis (sugar burning). As a result, there is a reduction in energy production and excessive lactate production from glycolysis. Lactic acidosis or the buildup of lactic acid is associated with several cancers and inflammatory diseases. During oxygen shortage, which can accompany copper deficiency anemia, lactic acid can begin to accumulate.

• Copper also plays a role in burning fat. Obese patients require more copper than the RDA (typically exceeding 1.23 mg/day). Norepinephrine, the hormone that promotes fat burning and alertness, requires copper for its synthesis. The transcription factor in the hypothalamus called HIF-1 alpha, is also copper-dependent, and it has a role in preventing obesity.

Metabolic Syndrome – Copper deficiency has a detrimental role on your metabolic health and condition. Metabolic syndrome is a condition in which at least three or more of the five are present: high blood pressure, central obesity, high fasting triglycerides, high blood sugar and low serum HDL cholesterol. It is associated with cardiovascular disease and type 2 diabetes by causing inflammation. Metabolic syndrome doubles the risk of cardiovascular disease and increases all-cause mortality by 1.5-fold.

• In rats, copper deficiency leads to impaired glucose tolerance. Lower copper intake is associated with increased blood sugar levels in humans as well as rats. Copper deficiency, induced by high fructose intakes, impairs insulin binding and reduces insulin sensitivity. Diabetes can disrupt copper metabolism and copper deficiency can alter glucose metabolism. Accumulation of iron ions in the pancreas, due to copper deficiency and a lack of ferroxidase activity, is thought to cause diabetes.
• Low copper intake also raises cholesterol and triglycerides and copper supplementation can lower their levels in the blood. In rats, there is an inverse relationship between serum copper and ceruloplasmin and levels of cholesterol and triglycerides. Copper deficiency increases the activity of hydroxymethylglutaryl-coenzyme A reductase (HMGA-CoA reductase), which is the rate-controlling enzyme for cholesterol synthesis, and hence increases cholesterol levels. In rats, a copper deficiency increases hepatic fatty acid biosynthesis two-fold.
• Copper deficiency also impairs thyroid hormone production. The thyroid is central to regulating metabolic rate and energy balance. There is a positive correlation between serum copper and thyroid hormones in children with congenital hypothyroidism. The ratio of copper and selenium influences thyroid functioning in patients with hypothyroidism. In thyroid disease, the metabolism of zinc, copper, manganese and selenium is abnormal. Low copper status also reduces the conversion of T4 into T3. Serum copper is also regulated by thyroid hormones, which stimulates the synthesis and the export of ceruloplasmin. Less thyroid hormones (hypothyroidism) = decreased ceruloplasmin = copper deficit. In fact, thyroid hormones are known to be needed for kidney sodium reabsorption. Ironically, sodium is needed to bring iodine into the thyroid gland (as well as other tissues such as lactating breast, salivary glands, stomach and intestines) to make thyroid hormones. Indeed, two sodium ions are needed to transport one iodide molecule into these tissues. Thus, thyroid hormone production and sodium status are interdependent on one another.

Kidney Health – Ceruloplasmin protects the kidneys as it acts as an antioxidant. The development of kidney dysfunction may occur in part due to a lack of copper, with kidney function improving upon copper supplementation. One group of authors concluded, “Copper deficiency can worsen nephrotic syndrome by decreasing the ceruloplasmin activity, which protects the glomeruli.” Additionally, kidney damage can increase the loss of copper in the urine. Patients with kidney damage tend to develop moderate copper deficiency. An easy indication of copper loss is spillage of albumin (protein) into the urine. This is because most copper in the blood is bound to the protein ceruloplasmin. The urinary losses of copper can be 8-32 times higher than normal in those with kidney damage.

Reproductive Health – Both copper transport as well as ceruloplasmin’s ferroxidase activity are exhibited in the testicles, primarily helping in the processes of spermatogenesis. Thus, copper is important for male reproductive systems. Additionally, the copper-dependent cytochrome c oxidase has an integral role in energy metabolism in the testes, enabling the production of ATP needed for sperm motility. Essentially, if a man is deficient in copper, their sperm does not swim as well. On top of that, a copper deficiency can also make the sperm more vulnerable to oxidative stress and DNA damage. When couples are having difficulties getting pregnant, it might be due to inadequate copper status. Foods high in copper like liver, oysters and clams are also considered fertility-boosting foods.

Immune System – Micronutrients, including copper and iron, are needed for modulating immune function and reducing the severity of infections. A copper deficiency has been shown to cause thymus (one of the main organs that produces immune cells) atrophy, reducing the amount of circulating neutrophils and decreasing the ability of macrophages to kill pathogens. Repletion of copper appears to be able to reverse this. By causing iron deficiency, a copper deficiency can also reduce phagocytosis and lymphocyte proliferation. In fact, infants with copper deficiency have been documented to have recovery in their immune health with copper supplementation. Copper is also essential for the production of interleukin-2, which is a cytokine that helps us fight infections.

Here are the enzymes and functions that are dependent on copper and the consequences of a copper deficit:

Copper-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Cytochrome c oxidase: Cellular respiration: Decreased energy production
• Superoxide dismutase: Dismutation of superoxide anion radical: Increased oxidative stress
• Catalase: Catalyze the conversion of hydrogen peroxide into water: Increased oxidative stress and lipid peroxidation in the heart
• Glutathione: Scavenge free radicals: Increased oxidative stress
• Glutathione peroxidase: Eliminates hydrogen peroxide: Increased oxidative stress
• NADPH: Free radical protection and increase nitric oxide: Reduction in glutathione and increased oxidative stress
• Tyrosinase: Converts tyrosine to dopamine: Depression
• Dopamine-B-hydroxylase: Converts dopamine to norepinephrine: Depression, decreased “fight or flight response”, potentially decreased ability to survive stressful events, obesity
• Peptidylglycine alpha-amidating monooxygenase: Neuropeptide synthesis and peptide hormone processing: Brain processing problems
• Lysyl oxidase: Conversion of procollagen to tropocollagen and of pro-elastin to elastin in the connective tissues: Decreased strength of blood vessels, cartilage, heart, bones, enamel, ligaments and damage to these tissues
• Cartilage matrix glycoprotein: Formation of extracellular matrix and copper transport in cartilage cells: Decreased tendon strength, loss of cartilage tissue and osteoarthritis
• Soluble pyridoxal-dependent monoamine oxidase: Oxidation of catecholamines to aldehydes: Reduced glucose uptake in fat cells and reduced leukocyte transmigration into endothelium decreasing pathogen killing
• Ceramide galactosyl transferase: Myelinogenesis: Myelopathies and neurological disorders
• Prostaglandin GG2 or GH2 reductase: Synthesis of prostaglandin F2- alpha: Inflammation, growth deficiency
• Beta-oxidation: Governs fat burning: Metabolic syndrome, obesity & insulin resistance
• Ceruloplasmin: Copper and iron transportation: Anemia, fatigue, iron overload
• Hemoglobin: Tissue oxygenation and energy production: Anemia, fatigue, poor energy production
• Hepcidin/Hephaestin: Intestinal iron absorption/oxidation of ferrous to ferric iron: Anemia

In humans, copper levels are high in the organs during childhood and start declining throughout later stages of life. During old age, hepatic and aortic copper decreases substantially, which is inversely associated with the concentration of calcium in the arteries.

The functions of copper are listed below:

1. Energy production (cytochrome c oxidase, composed of copper and iron)
2. Detoxification of superoxide anions (superoxide dismutase converts superoxide to oxygen and hydrogen peroxide)
3. Synthesis of collagen and elastin (copper makes up lysyl oxidase)
4. Production of hemoglobin (ceruloplasmin catalyzes the oxidation of iron, which is necessary for iron to bind to its transport protein, transferrin)
5. Melanin production (tyrosinase converts tyrosine to melanin and is a copper containing enzyme)
6. Myelin production (the synthesis of phospholipids in myelin sheaths in peripheral nerves are dependent on copper)
7. Fat burning and beta oxidation
8. Inhibition of inflammation through antioxidants
9. Synthesis of thyroid hormones (thyroxine)

In conclusion, copper has a central role in energy production and energetic processes. Copper deficiencies can cause many health problems, including anemia, chronic oxidative stress, cardiovascular disease and metabolic syndrome. Now that we’ve covered the extensive history and origins of copper in medical practice, we shall turn to covering how to obtain the right amounts of copper in balance with the other minerals for optimal health.

Chapter 8: Getting the Right Amount of Copper, Zinc, and Iron

“Iron deficiency anemia” is not necessarily a disease of iron deficiency. In fact, it can be caused by copper deficiency. Unfortunately, most doctors and medical practitioners are not aware of this as they try to fix symptoms of anemia with supplemental iron. Making matters worse, high iron intakes can block copper absorption, increasing copper requirements and causing copper deficiency in the process. On the flip side, chelation or binding of iron, has been shown to reverse copper deficiency.

There are many other factors that can cause an iron deficiency anemia, such as inflammation (as found in those with obesity or metabolic syndrome), bleeding, malnutrition, copper deficiency, infections, and lack of other nutrients but a lack of dietary iron tends to make all the headlines. On the flip side, insulin resistance can lead to liver iron overload and frequent blood donations can improve hyperinsulinemia.

The Copper-Iron Deficiency Anemia Epidemic

Increasing iron intake does not seem to eliminate iron deficiency anemia. It might work in some people who are severely deficient in iron, such as during pregnancy or infections, but most of the population is already getting plenty of iron. Unfortunately, these warnings are ignored by the grain lobbyists who push further increases in iron enrichment.

“Copper metabolism is altered in inflammation, infection, and cancer. In contrast to iron levels, which decline in serum during infection and inflammation, copper and ceruloplasmin levels rise.” This is why so many doctors fear “copper overload” and don’t take copper deficiency seriously, i.e., because they rarely see low copper levels on a blood draw.

The estimated safe and adequate copper intake in 1989 was set at 1.5-3.0 mg/day (Food and Nutrition Board also suggests this), which exceeded the previous required estimates of 1.2-2.0 mg/day. Why then is the current RDA set so low at just 0.9 mg at minimum? Even the World Health Organization recommends at least 1.3 mg a day. The reason is likely because if we kept the RDA at 1.2-3.0 mg/day, virtually no one in the United States would be meeting that requirement, and that would then require another mineral fortification.

Balance studies suggest that a daily intake of 0.8 mg leads to net copper loss whereas net gains are seen with 2.4 mg/day.

Men and women fed diets low in copper, around 1 mg/day, develop increases in blood pressure, cholesterol, glucose intolerance, and abnormal electrocardiograms.

Data from 10 dietary surveys shows that only 14% of typical diets in Belgium, Canada, the UK and the U.S. exceed 2 mg of copper a day. Only 3.2% of diets exceed 3 mg/day, 61% get less than 1.5 mg/day, and 1/3rd obtain less than 1 mg/day.

There is around 50-120 mg of copper in the human body. Copper is mainly stored in the liver, but it is also found in the heart, brain, kidneys and muscle. About 1/3rd of total body copper is in the liver. However, copper is present in almost every tissue of the body. The daily copper turnover is estimated to be around 1 mg through fecal loss. Thus, total body copper stores can be depleted in a few months if daily intake is not near this level of intake. More importantly, this does not take into account copper losses in sweat, which can be quite significant. Overweight people appear to require more copper than normal weight ones, generally needing more than 1.23 mg/day. In obese children, copper levels in the blood are lower, but slightly higher in the plasma, than in controls. They also have lower iron levels, which may be due to inflammation caused by excess body fat. It is inflammation that raises copper and lowers iron in the blood.

Furthermore, certain medical conditions can also increase copper excretion. For example, patients with nephrotic syndrome have an 8-32-fold greater urinary loss of copper than normal patients. Fructose consumption also increases the need for copper and promotes copper deficiency, which increases oxidative stress, causes fatty liver and damages the intestine.

Things that are caused by copper deficiency and/or raise demand for or reduce copper levels:

• “Iron” deficiency anemia
• Sweating (exercise or sauna)
• Burn injuries
• Malabsorption diseases like celiac disease, short bowel syndrome and IBS
• Pseudoscurvy
• Gastric bypass surgery and colon removal
• Nephrotic syndrome, kidney damage and renal failure
• Neuropathy, myelopathy and myelodysplastic syndrome
• Multiple sclerosis and hypomyelination
• Brain atrophy, damage or injury
• Muscle wasting or sarcopenia
• Cardiomyopathy
• Progressive corneal thinning
• Liver damage, cirrhosis and fibrosis
• Non-alcoholic fatty liver disease and fatty liver
• Hemorrhages (subarachnoid hemorrhages, etc.)
• Aneurysms or blood vessel tears (aortic dissections, etc.)
• Pregnancy (for fetal neuropsychological and physical development)
• High iron infant formulas
• Obesity and excess bodyweight
• High fructose consumption (e.g., added sugars)
• Processed food diet, iron fortified foods and refined grains
• Excess iron supplementation/consumption
• Excess zinc supplementation/consumption
• Zinc denture adhesives
• Tooth wear
• Proton pump inhibitors, diuretics and antacids
• Hypothyroidism
• Osteopenia/osteoporosis and tendon injuries

The upper safe threshold is deemed to be 10 mg/day for adults. Taking 10 mg/day of copper for 12 weeks has not been seen to cause liver damage, but one case reports that a long-term intake of 60 mg/day resulted in acute liver failure. Intakes of 7-7.8 mg/day for 4-5 months in healthy male volunteers between the ages of 27-48 may cause some negative side effects, such as decreased antioxidant defense, suppressed immunity and increased excretion of copper. However, it seems that the body’s own homeostatic regulation of copper absorption is being automatically regulated to minimize the amount of excess copper retention.

When copper intake was at 1.6 mg/day, copper retention was 0.06 mg/day but increased to 0.67 mg/day at intakes of 7.8 mg/day. So, as copper intake increases, its absorption levels slow down to prevent overload. High and low copper intakes exceed these regulatory mechanisms, causing either copper depletion or retention. A low copper consumption for 6 weeks does not appear to significantly change copper absorption compared to high copper consumption of 6 mg/day.

Usually, copper deficiency occurs during malnutrition, in patients receiving parental care with insufficient amounts of copper, and when an individual ingests excess quantities of zinc on top of a low copper intake (zinc is a copper absorption antagonist but zinc may not be an issue if the intake is 50 mg per day or less and copper intakes are at 1 mg or above). Copper deficiency has also been seen in infants fed only cow’s milk, lightweight preterm infants and the elderly. Pregnant and lactating women are also at risk of copper deficiency or people with malabsorption diseases. Bile eliminates most copper, whereas the kidneys typically only eliminate ionic or loosely bound copper.

Copper Deficiency Testing

The main symptoms of copper deficiency include anemia, secondary iron deficiency, neutropenia, and bone abnormalities. Additional signs include hypopigmentation, growth impairment, immune system suppression, abnormal electrocardiograms and dysregulated glucose and cholesterol metabolism.

Symptoms of copper deficiency include:

• Anemia
• Defective keratinization of the oral cavity
• Neutropenia
• Hypopigmentation of hair and skin
• Abnormal bone formation/bone fragility
• Cartilage damage, joint pain and arthritis
• Reduced immunity
• Vascular/blood vessel issues
• Cardiac hypertrophy
• Heart murmurs and valvular regurgitation
• Fragile collagen/elastin (fragile organs/tissues) – tendon/tissue ruptures/tears
• Aneurysms of blood vessels (rupture of heart/blood vessels)
• Increased lipid accumulation in the heart
• Abnormal EKG – changes in ST segments, prolonged PR intervals and R wave duration and amplitude
• His Bundle electrical abnormalities
• Increased QT intervals, inversion of the T wave and increased QRS amplitudes and notching
• Decrease in ATP levels and energy
• Increased lactic acid
• Decreased ventricular contractility in the heart

Approximately 60-70% of symptomatic copper deficiency occurs with anemia and more than 50% are normocytic anemia.

C-reactive protein has been associated with an elevation of copper. Usual plasma copper tests are insensitive and not entirely accurate. Low copper levels in the liver would likely be a better determinant but a more practical strategy would be to measure leukocyte copper levels, which are more reflective of total body copper status and are depleted in those with significant atherosclerosis or coronary artery disease.

Unfortunately, measuring copper levels in the liver requires a biopsy and hence it is not very practical. Hair mineral analysis is a potential option to add to other measurements for an overall assessment of trace mineral status. Scalp hair remains isolated from other metabolic activities and is a unique indicator of elements concentrated in an individual at a given time point. Hair analysis has been used for successful assessment of heavy metal toxicity. Red blood cell copper may also be a better indicator of copper status versus serum levels and may reveal an undiagnosed pandemic of copper deficiency.

Best to Worst Ways to Diagnose Copper Deficiency:

1. Liver copper levels
2. Leukocyte copper levels
3. Red blood cell copper levels
4. Blood copper levels and ceruloplasmin

Copper and Iron in Food

The RDA for iron is 8 mg for adult men and 18 mg for adult women. During pregnancy, the RDA increases to 27 mg. Normal ranges for serum ferritin are 20-250 ng/ml for adult males and 10-120 ng/ml for women. A serum ferritin below 30 suggests iron deficiency. Numbers above the reference range may indicate oxidative stress or just iron overload. People, especially children, who take supplements may overdose on iron. You can get iron poisoning from doses as low as 10-20 mg/kg.

Our bodies have a hard time eliminating iron. Losses only occur, at least in a significant amount, during bleeding, blood donation, menstruation in women or through chelation. That is why females are more susceptible to anemia and iron deficiency, whereas men are more prone to iron overload. Common iron chelators include coffee, spirulina, chlorella, green tea, beans, whole grains and vegetables. That is why, although things like spinach and beans contain high amounts of iron, it is harder to reach iron overload eating them because a large proportion of the iron gets chelated and/or not absorbed.

Iron and zinc are copper antagonists. Foods are not fortified with copper, which contributes to this epidemic of copper deficiency. Unsaturated fats (omega-6 seed oils) are also lacking copper because transition metals are removed by chelation to increase shelf-life. At the same time, foods high in copper, such as liver, oysters, lobster and crab are eaten less frequently

Vermont spring water appears to have the highest copper levels at 1.4 mg of copper per liter of water, whereas soft municipal tap water ranges from around 0.17-0.73 mg/liter. In other words, natural spring waters may be is 5 to 10-times higher in copper versus tap water.

Muscle meat is extremely low in copper but high in zinc and iron. Heme iron, as found in meat, is particularly well absorbed compared to non-heme iron. The highly bioavailable iron in cooked meat may also reduce the absorption of copper. Excess cystine and cysteine consumption enhances copper deficiency in rats. Foods high in cystine/cysteine are animal proteins like poultry, beef, pork, eggs, fish, etc., and in smaller amounts in lentils and oatmeal. These foods are also highest in iron. Zinc absorption is also greater when eating animal protein compared to plant foods, which inhibits copper absorption. This might be why vegetarians or vegans may need more zinc than omnivores but less copper.

• Total copper absorption is higher with a lacto-ovovegetarian (dairy, eggs, and vegetarian) diet (0.48 mg/day) compared to a non-vegetarian diet (0.40 mg/day) because of its higher copper content. Moreover, the “antinutrients” in plants (phytic acid and phytates) can increase copper absorption by antagonizing zinc.
• Increasing the intake of plants and reducing the intake of muscle meat can help to improve copper status; or simply eat other animal foods, such as liver and shellfish, which contain copper. Importantly, when you accumulate iron, your copper requirements increase.
• A higher copper intake may explain why some studies show that vegans live longer than those eating a Standard American Diet. Indeed, the daily copper intake is 27% higher in vegetarians compared to omnivorous adolescent females. These studies however are including people who do not frequently incorporate copper-rich organ meats like liver and rely mainly on high iron muscle meat, which is the issue. Despite the reduced bioavailability, the higher copper content of plant-based diets seems to at least provide an adequate amount of copper.
• Foods rich in fructo-oligosaccharides like chicory root, blue agave, artichoke, asparagus, Yacon root, garlic, and green bananas, have also been shown to enhance the absorption of copper, zinc and selenium. Soybean protein, however, seems to reduce copper absorption. A high fiber diet improves copper absorption because of fructo-oligosaccharides and inulin.

Zinc/Copper Ratio

Zinc is a copper antagonist, which is why ingesting large doses of zinc can lead to copper deficiency by inhibiting its absorption and increasing its secretion. A high concentration of zinc in the small intestine triggers the expression of metallothionines, which bind to copper.

The golden rule when supplementing with zinc, is that at a minimum, for every 40mg of zinc, 1 mg of copper should be employed.

High copper and phytate intake may be a protective factor against the Standard American Diet high in zinc and iron (phytate can also bind free iron). Phytic acid decreases the ratio of zinc to copper that gets absorbed in the intestinal tract. This is not to say that you need to eat fiber or phytic acid, but it’s important to balance the zinc/copper ratio, and that means sourcing more than just muscle meat and eggs.

Organ meats like liver have a much more appropriate iron-zinc to copper ratio than muscle meat. Per ounce of beef liver, you get 4.1 mg of copper or 4.5 times the RDA for copper of 0.9 mg. Thus, just a little bit of liver goes a long way. However, this is also why it is not recommended to consume more than 1 oz. of beef liver per day as total intakes of copper at or over 10 mg for several months could cause unwanted side-effects. Although liver is high in cholesterol, it may be an antidote to the hypercholesterolemic effects of meat, which may actually be due to the low copper content of muscle meat. Liver, heart, kidney, suet, etc. have the fat-soluble vitamins like K2, A, D as well as CoQ10. Per calorie, liver is one of the most nutrient dense foods in the world. It is also relatively low in calories compared to muscle meat (~130-150 vs ~150-200 calories/3.5 oz).

• You can cover nearly all your needs for most vitamins and minerals by eating a single ounce of liver. Unfortunately, most people find organ meats disgusting but a simple way around this is to eat a blend of ground muscle meat with liver/heart (75% muscle meat/25% liver and heart). Organ meats and offal have been completely neglected in the modern industrialized diet landscape, whereas they are relatively common in France and other Mediterranean countries.
• Oysters are another example of this as they’re high in copper, which seems more than sufficient to counteract the inhibitory effects of its high zinc content.

Exercise stimulates the growth of muscle and bone, which are made-up of larger amounts of zinc compared to copper (zinc/copper ratios 56 and 120, respectively) and thus exercise tends to protect against a diet higher in zinc to copper (i.e., more zinc gets directed towards muscle and bone growth). This may be why weightlifters are somewhat protected from their high intake of meat, as the zinc is needed for muscle and bone growth. This also suggests that weightlifters need more zinc, in order to develop larger muscles and stronger bones. Thus, zinc requirements go up when building muscle, and this is likely why many weightlifters crave muscle meat (for the high zinc content).

The zinc to copper ratio of cow’s milk is 38, whereas that of human milk is between 4 and 6, this might explain the health benefits of populations that breast feed for several years versus in the United States, where children are typically switched over to cow’s milk at 9-12 months of age. A zinc/copper ratio of 38 leads to copper deficit in infants and is clearly not healthy for infants or adult humans. Additionally, a higher zinc to copper ratio (as found in cow’s milk) positively correlates with mortality due to coronary heart disease in 47 cities in the United States.

Thus, an optimal intake of zinc in an adult can range anywhere from 20-80 mg/day, depending on the person and the situation. The optimal intake of copper, however, seems to sit at around 3 mg/day, providing an optimal Zn/Cu ratio of anywhere from 4-20:1.

Foods with a high Zinc:Copper Ratio (these foods must be balanced with appropriate amounts of copper from other food sources):

• Oysters
• Muscle meat
• Breakfast cereal
• Cow’s milk
• Prepackaged meat
• Mollusks/shellfish

Foods with a low Zinc:Copper Ratio (these will need to be paired with foods higher in zinc):

• Organ meats/liver
• Seaweed/spirulina
• Lentils/beans/chickpeas
• Dark chocolate/cacao
• Vegetables

The takeaway is that you shouldn’t make these high zinc:copper ratio foods the only ones that you eat in your diet. Additionally, you should not overconsume high copper containing foods either, like eating 3 oz. of liver every day. As a rule of thumb, eat around 0.5 to 1 oz. of liver/day for copper and at least 12 oz. of red meat for zinc, iron, B12 and protein.

Copper and Molybdenum

Another copper inhibitor is molybdenum (Mo). It is a mineral found in foods like pork, lamb, beef, beans, eggs and cereal grains in small amounts. Molybdenum and copper have been found to have antagonistic roles with each other. Indeed, a Mo/Cu ratio of 2.5/1 in animals can lead to copper deficiency and altered immune responses during infection.

Patients with type-2 diabetes have been shown to have higher serum and urine copper levels due to molybdenum removing it from tissues and eliminating it through urine. Those with severe nephropathy have a higher urine level of Cu/Mo. Thus, excess molybdenum, when combined with sulfur, may promote the excretion of copper through urine or bile via binding with protein-bound and free copper.

In animals, molybdenum overload has been shown to disrupt carbohydrate metabolism and increase oxidative stress by reducing copper-dependent enzymes like ceruloplasmin, superoxide dismutase, and myocardial cytochrome c oxidase. The glucose intolerance is a secondary symptom of copper deficiency.

• Moose in Sweden were getting symptoms of diabetes and muscle wasting, caused by excess molybdenum and copper deficiency. The increased molybdenum consumption originated from an increased pH of the soil, which increased molybdenum content of vegetation, caused by liming and other practices. However, these effects may not be as pronounced in humans, as the formation of molybdenum-sulfur compounds that bind copper are believed to formed in the rumen.

Copper Absorption

Copper is absorbed in the gastrointestinal tract and is transported to the liver.

Liver damage, cirrhosis or fibrosis increase the demand for copper and decrease its absorption. Fibrate medications (such as bezafibrate, fenofibrate, gemfibrozil) may be able to restore low copper levels in NAFLD disease and increase concentrations of hepatic Cu-Zn SOD. Malabsorption diseases like celiac disease, short bowel syndrome and IBS also reduce copper absorption. Copper deficiency has been seen in patients with celiac disease and it can cause anemia and thrombocytopenia. Gastric bypass surgery or colon removal can cause copper deficiency.

The oral bioavailability of copper can range from 12-75%, depending on the amount of copper in the diet. The average bioavailability of most normal diets is between 30-40% on the typical Western diet. That number can be lower in the presence of excess zinc, molybdenum, iron or fructose/added sugars. The refining of grains and cereals can reduce the copper content by up to 45%.

Indiscriminate use of multivitamins that often contain zinc and iron can be problematic for people low in copper.

Copper absorption occurs in the stomach and the small intestine, but the most efficient absorption takes place in the ileum and duodenum. For optimal absorption, copper needs acid from the stomach to be liberated from food. During absorption, excess copper is transiently stored in the enterocytes by binding to metallothionine. Once inside the enterocyte, cuprous ions bind to different copper chaperones to be distributed to various organelles and cell compartments. Thus, damage to the microvilli of enterocytes, which contain micronutrient absorption transporters, will decrease copper absorption. It has been shown that the overconsumption of refined sugar and fructose damages the enterocytes, which will likely reduce copper absorption.

• Iron can compete with copper for absorption via the DMT1 (divalent metal transporter 1) transporter. Iron deprivation or iron deficiency due to chronic disease or malnutrition, can lead to copper overload, possibly due to absorption increases in ATP7A, which brings copper into the portal circulation. Zinc also competes with copper absorption via DMT1.
• Sodium may enhance copper absorption or retention and people on amiloride may need more copper as it appears to reduce copper and sodium absorption in the intestine. Thus, low salt diets may reduce, whereas normal salt diets may improve copper absorption.
• In the presence of excess copper, CTR1 reduces copper absorption by enterocytes. However, when enterocytes are damaged because of intestinal tract injuries, copper deficiency may occur.
• Fructose increases the requirements for copper and exacerbates the effects of copper deficiency. Thus, added sugars are a tax on copper status.

Approximately 0.5-2.5 mg of copper is excreted via feces every day. Biliary copper secretion cannot be reabsorbed, as it is prevented by the binding to bile salts and comes out in the feces. Thus, the body has the ability to get rid of copper excess through bile excretion, which is regulated by the liver (liver cells excrete excess copper into bile). Low blood copper levels, or low ferritin levels, leads to copper being released into the blood circulation. To prevent copper overload, surplus copper can be excreted through the natural shedding of the intestinal epithelial cells.

Copper absorption in the stomach is stimulated by an acidic pH and is inhibited by zinc and cadmium. Stomach acid frees up copper bound to food and facilitates peptic digestion, which releases copper from natural organic complexes. That is why proton pump inhibitors or other acid suppressing over the counter therapies or medications can reduce copper absorption as it reduces the release of copper from natural organic complexes in food.

Cadmium is a common toxic heavy metal that has accumulated in the environment due to pollution. Ironically, zinc helps to reduce the absorption of cadmium.

Vitamin C can enhance, or inhibit, copper absorption. If taken prior to (around 75 minutes before) or with copper, vitamin C reduces copper absorption by blocking the binding of copper to metallothionein. However, if vitamin C is taken after copper ingestion (75 minutes after) it increases ceruloplasmin and lysyl oxidase activity. Vitamin C also seems to help facilitate the transfer of copper ions into cells, reacting with the copper carrying protein ceruloplasmin, reducing cupric copper (CuII+) to cuprous copper (CuI+) making the bound copper atoms more freely available and facilitating their cross-membrane transport. Moreover, histidine, may aid the transport of copper from albumin into certain cells. Additionally, glutathione appears to help facilitate the transfer of copper to metallothionine and superoxide dismutase. Thus, cysteine and glycine, which help to increase glutathione levels, may also help with copper transport in the body.

In large doses, vitamin C may decrease copper status by increasing iron and zinc absorption. However, there may not be enough vitamin C in whole foods like fruit and vegetables to inhibit copper absorption or deplete it.

• That is why it is better to focus on getting vitamin C and potassium from whole foods and use supplemental doses only acutely during sickness or an infection. On the flip side, Vitamin C + E can also combat copper toxicity-induced lipid peroxidation and liver damage. They have also been shown to reduce the oxidation of HDL cholesterol caused by excess copper.

Copper homeostasis is maintained in the liver. Importantly, the thyroid gland regulates more than 5% of all the genes expressed in the liver, including copper metabolism.

• Thyroid hormones stimulate the synthesis and export of ceruloplasmin from the liver into the serum. Thus, being hypothyroid may hinder copper homeostasis and utilization in the body.

Only certain genetic disorders, such as Wilson’s disease (WD) or Menke’s disease (MD) are known to disturb copper metabolism in a life-threatening way, by affecting the copper transporting proteins ATP7A and ATP7B:

• Wilson’s disease is characterized by autosomal recessive mutations in the gene encoding ATP7B, which affects 1 out of 30,000-100,000 people. WD patients suffer from excessive copper accumulation in the organs, mostly the liver and brain. This can be treated with copper-chelating agents like penicillamine, trientine and ammonium tetra-molybdate. Increased zinc intake or supplementation can also reduce the copper absorbed from diet.
• Menke’s disease is a condition of ATP7A mutations, which occurs in 1 out of 40,000-350,000 people. Copper absorption is completely absent in Menkes disease, causing growth retardation, hypopigmentation, hypothermia and neurological problems. The bottleneck occurs in the intestines where copper absorption is blocked, which is why the only copper replacement strategy involves subcutaneous injection of copper-histidine.

One of the biggest chelators of copper is glyphosate. Deficiencies in trace minerals like iron, molybdenum, copper and others is associated with celiac disease and it can also be attributed to glyphosate’s ability to chelate these metals. Glyphosate is one of the most common pesticides in the U.S. used on almost all types of fruit and vegetables. Not only does it reduce the mineral content of the vegetation, but it also disrupts the microbiome potentially promoting malabsorption diseases.

• Glyphosate is a strong chelator thanks to its ability to form strong complexes with transition metals. Glyphosate has also been shown to decrease iron, magnesium, manganese and calcium levels in non-GMO soybeans.

It is not difficult to obtain the optimal amount of copper from diet, which we deem to be around 3 mg/day. If you are already deficient in copper, then intakes of above 2.6 mg/day are likely needed for several weeks if not months. Dietary copper intake should not exceed 10 mg/day. However, excess copper will typically be excreted or its absorption will be reduced. The highest copper-containing foods are beef liver, oysters, shellfish and beans. They also have a lower zinc-copper ratio (except oysters and mollusks), which improves copper absorption. Generally, it is recommended to eat liver at least once a week (3 oz. at a time), or if eaten several times per week, 0.5 to 1 oz. at a time. Eating plant fibers, phytate and phytonutrients can help to chelate iron and maintain a better copper status, but they can also reduce zinc absorption. Thus, it is important to balance plant foods with animal foods. To not impose additional demands for copper on the body, avoid added sugars and fructose-sweetened beverages.

Chapter 9: Zinc for the Immune and Endocrine System

Zinc is another essential mineral needed for many processes in the body, including postnatal development, protein synthesis, wound healing and immune system functioning. You also need zinc for a proper sense of taste and smell. Zinc acts as a catalyst for over 300 enzymatic reactions and over 1000 transcription factors. DNA/RNA transcription and replication factors are zinc-dependent, which will not work in the absence of zinc.

DNA synthesis is impaired by dietary zinc deficiency. Thus, zinc affects gene expression. Apoptosis, or programmed cell death, is regulated by zinc. However, in some instances, zinc can protect against apoptosis during gamma irradiation, hyperthermia and cold shock. In other words, zinc can make our cells more resilient to certain stressors. This is a good thing if you are fighting off an infection or are dealing with a lot of oxidative stress.

Deficiencies in zinc cause growth retardation, hormonal imbalances, impotence, delayed wound healing, frailty, hair loss, diarrhea, skin lesions and increased susceptibility to infections. Zinc deficiency during pregnancy is associated with an increased risk of premature delivery and abortion. Since the early 1960s, it has been noted that zinc deficiency can cause anemia, dwarfism, growth retardation and hypogonadism independent of iron deficiency.

Zinc deficiency is not widespread in Western countries, but it does affect a lot of people in the third world and most people in the Western world are not consuming optimal amounts of zinc. Stunted growth in childhood is typically caused by zinc deficiency, especially in low-income countries where the intake of animal foods tends to be lower.

Zinc and Health

Zinc helps to catalyze the calcification of bone. Zinc deficiency causes skeletal abnormalities by reducing parameters of calcium metabolism in the bone. Zinc is also needed for collagen synthesis and zinc deficiency can increase damage to the body’s soft tissue. Supplementation with arginine, glutamine, vitamin C and zinc has been shown to increase collagen synthesis during the first 2 days after inguinal hernia repair. Zinc also helps those with bed sores.

Zinc speeds up wound healing. Wounds do not heal as fast with zinc deficiency. Oral zinc sulfate improves foot and leg ulcers. Zinc deficiency exacerbates ulcers by increasing oxidative stress in the skin. Zinc sulfide nanoparticles improve skin regeneration. Healing of the aorta requires zinc. Think of zinc as a healing mineral. Zinc can be thought of as our adamantium and the source of our healing power.

Zinc may help to protect against atherosclerosis. 

• Zinc, especially when taken with appropriate amounts of copper, prevents the oxidation of LDL cholesterol, which is one of the main mechanisms for atherosclerosis. Excess iron promotes LDL oxidation, whereas zinc protects against this. Zinc supplementation at doses over 50 mg/day can reduce HDL cholesterol, however, if copper status is maintained, this will likely not occur. Atherosclerosis develops in parallel with the decrease of zinc absorption, greater prevalence of zinc deficiency and increased inflammation that happens during aging.
• The preventative effect of zinc on cardiomyopathy is mediated by metallothionine, the main protein zinc is bound to. Metallothionine has an antioxidant effect, including in the heart. It controls the amount of zinc in tissues. Zinc deficiency causes a deficiency in metallothionine, which results in increased reactive oxygen species in the cell, enhanced oxidative stress, inhibition of cytochrome c oxidase activity, impaired mitochondrial function and eventually cellular death, especially in the liver, kidney and connective/collagenous tissues. Metallothionine expression protects against the toxicity of cancer treatment drugs like doxorubicin. In other words, if you are zinc deficient you will likely experience worse chemotherapy side effects. Zinc has also been shown to protect metallothionine-deficient mice from alcohol-induced myocardial fibrosis. Selenium promotes the release of zinc from metallothionine and their combination improves immunity in the elderly after influenza vaccination. Inflammation also makes metallothionine use zinc, which explains why zinc levels are low in inflammatory conditions such as atherosclerosis. High homocysteine also impairs metallothionine and disrupts redox homeostasis.
• Zinc supplementation may help heal unstable plaque by promoting calcification, which is less likely to rupture. Statins work by reducing inflammation and promote the calcification of unstable plaques. Statin drugs, however, also reduce zinc levels by 8%. Thus, their benefits are limited and are they are not without side effects. Elevated serum copper, with low zinc and magnesium, is associated with an increased risk of cardiovascular disease mortality. A low urinary zinc, which is indicative of zinc deficiency, is associated with atherosclerosis severity. In atherosclerosis, there is a significant decrease in plasma, aorta, liver, myocardium and pancreas zinc levels. Patients with myocardial infarctions have low plasma zinc levels, averaging just 67 mcg/dL, instead of the 75-125 mcg/dL that is considered normal.

Zinc is important for brain development, learning and plasticity. Zinc deficiencies are implicated in brain disorders. Zinc supplementation in malnourished schoolboys has been shown to increase cortical thickness significantly more than in those who have received all the essential amino acids, vitamins and minerals without zinc.

• Zinc is needed for synthesizing many neurotransmitters, such as serotonin and melatonin. Taking zinc has been shown to improve sleep in humans.
• Zinc homeostasis regulates the central nervous system. Dysregulated zinc homeostasis and excess synaptic zinc concentrations, typically induced by inflammation, can cause neurotoxicity and mitochondrial damage. Zinc also regulates the activity of the adrenal glands and cortisol levels.

Zinc and other trace minerals like copper and selenium are needed for the production of thyroid hormones. On the flip side, you need adequate amounts of thyroid hormones to absorb zinc, which is why hypothyroidism can cause an acquired zinc deficiency. Hypothyroidism reduces zinc absorption in the intestine. Zinc is required to activate the T3 receptor, hence zinc deficiency impairs T3 receptor action. Zinc deficiency is associated with hypothyroidism and severe alopecia, i.e., hair loss. Supplementing with zinc in those who are deficient improves thyroid function. Thus, it’s a vicious cycle of zinc deficiency impairing thyroid hormone function, which drives more zinc deficiency.

• The overconsumption of sugar, especially in conjunction with copper deficiency, also drives zinc deficiency through the promotion of fatty liver disease. Indeed, since the liver produces the active thyroid hormone T3, and active thyroid hormones are required for the absorption of zinc, damage to the liver will reduce zinc status. Considering that millions of people have hypothyroidism, a zinc deficit may be more rampant than originally thought.

Zinc is important for glucose metabolism and insulin production. Zinc helps with the uptake of glucose into the cell and with insulin synthesis. Zinc deficient rats and humans have impaired glucose tolerance. A 2012 systematic meta-analysis that included 22 studies concluded that zinc supplementation has a beneficial effect on glycemic control and lipids in patients with type-2 diabetes. In type-1 diabetes, a combination of zinc and vitamin A (10 mg zinc a day and 25,000 IU vitamin A every other day) can improve apolipoprotein-B/A1 ratios (essentially LDL+VLDL/HDL ratios).

• Zinc is required for pancreatic carboxypeptidase, which may be needed for insulin maturation and secretion. Furthermore, zinc supplementation has been shown to improve insulin resistance and metabolic syndrome in obese children.
• Zinc deficiency may also lead to metabolic acidosis by reducing carbonic anhydrase activity. Carbonic anhydrases are a family of enzymes that catalyze the conversion of carbon dioxide and water to bicarbonate and protons. Most carbonic anhydrases contain a zinc ion at their active site and are thus classified as metalloenzymes. Without carbonic anhydrases, tissue oxygenation decreases, and lactic acidosis increases. Zinc losses increase in urine and sweat during exercise. Additionally, zinc needs increase during exercise to help working muscle, as well as after exercise to repair and build muscle. Thus, many athletes are at risk of zinc deficiency, which can impair performance and decrease the lactate threshold (i.e., when lactate accumulates faster than it can be removed). In zinc-deficient rats, lactic acid buffering agents like lactic dehydrogenase (LDH), malic dehydrogenase (MDH), alcohol dehydrogenase (ADH) and NADH diaphorase are lower.

A zinc deficiency may lead to the following:

• A reduction in growth, development and maturation
• Acne, dermatitis, psoriasis, eczema and dry skin
• Loss of taste and smell
• Reduced appetite
• Night blindness and vision impairment
• Frequent sickness and infections
• Frequent pneumonia and respiratory infections
• Frequent diarrhea and enteropathy
• Loss of cognition and impaired learning
• Behavioral abnormalities, ADHD and depression
• Schizophrenia and psychiatric disorders

Here are the zinc-dependent enzymes, functions and consequences that may occur with a deficit

Zinc-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Metallothionine: Protection against oxidative stress: Increased oxidative stress and tissue damage
• Zinc,Copper Superoxide Dismutase: Protect against oxidative stress: Increased oxidative stress and tissue damage
• p53: DNA damage repair: DNA damage and DNA mutations
• Poly (ADP-ribose) Polymerase: DNA damage repair: DNA damage and DNA mutations
• Glutathione Synthesis: Protect against oxidative stress: Increased oxidative stress and weaker immunity
• Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
• Nitric Oxide Synthase: Cardiovascular function, antiviral effects: Oxidative stress, atherosclerosis, and hypertension
• Thyroid Hormones: Regulate metabolic rate, body temperature and energy balance: Chronic fatigue, frailty, weight gain, metabolic syndrome and decreased immunity
• Luteinizing Hormone: Precursor to testosterone Hypogonadism and low sex hormones
• Growth Hormone: Physical repair, fat burning: Frailty, aging and muscle loss
• Insulin Secretion: Shuttle nutrients into the cells: Insulin resistance and metabolic syndrome
• Serotonin: Promotes melatonin production and relaxation: Chronic stress, insomnia and altered mood
• Melatonin: Promotes sleep onset and antioxidant activity: Sleeping problems, poor metabolic health, increased oxidative stress and neurodegeneration
• Dopamine Transporter: Feeling of reward and motivation: Depression and apathy
• Glycolysis Oxidation of glucose and lactate: Lactic acidosis and glucose intolerance
• Beta-Oxidation: Oxidation of lipids and triglycerides: Dyslipidemia and obesity
• Autophagy: Removes cellular waste material and dysfunctional organelles: Mitochondrial dysfunction, excess inflammation and impaired immunity
• Lysosomes: Engulf debris and mediates autophagy: Waste material accumulation
• Carboxypeptidase: Digestive enzyme and digestion of protein: Digestion problems and nutrient deficiencies
• Carbonic Anhydrase: Conversion of carbon dioxide and water to bicarbonate and protons: Anemia and reduced tissue oxygenation
• Alkaline phosphatase: Helps to break down proteins: Liver dysfunction

Zinc and the Immune System

Even a modest zinc deficiency can impair the functions of macrophages, neutrophils, natural killer cells and the complement system, reducing their cytotoxicity. Zinc is needed for the production of T cells. People with zinc deficiency show reduced natural killer cell cytotoxicity, which can be fixed with zinc supplementation.

Zinc is an essential cofactor for thymulin, which is a thymic hormone. Without zinc, thymulin can’t bind to zinc and this impairs immunity. With the help of zinc, thymulin helps to differentiate immature T cells, preserving the balance between killer T cells and helper T cells. Autoimmune diseases with a T cell imbalance, such as rheumatoid arthritis, are associated with a zinc deficiency. Thymulin also modulates the release of cytokines.

Zinc is needed for the interaction between the natural killer cell inhibitory receptor p58 and major histocompatibility complex (MHC) class I molecules. A deficiency in zinc impairs natural killer cell activity, phagocytosis of macrophages, cytotoxicity of neutrophils and generation of the oxidative burst needed to kill pathogens. Zinc ions have been shown to stimulate the production of lymphocytes, which attack invading pathogens. The addition of zinc releases interleukin-1, interleukin-6, tumor necrosis factor-α and interferon gamma in human peripheral blood mononuclear cells, which help us fight infections.

Low zinc status has been associated with an increased risk of pneumonia, respiratory tract infections, diarrhea and other infectious diseases.

Zinc administration helps patients with hepatitis C virus-induced chronic liver disease. It is also noted that zinc deficiency is related to different autoimmune diseases such as type-1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus, autoimmune hepatitis, celiac disease and Hashimoto’s thyroiditis. A significant number of COVID-19 patients are zinc deficient, which is associated with worse COVID-19 outcomes. Zinc has been shown to inhibit the replication of viruses like SARS and arterivirus.

Zinc enables the calcium-binding protein calprotectin to inhibit the reproduction of bacteria through neutrophil degradation. Prophylactic zinc intake before LPS treatment in a porcine sepsis model has been shown to reduce the inflammatory response. Thus, doses of zinc before an LPS infection may be protective.

Extremely large doses of zinc (up to 400 mg/day) have been shown to impair immune function. In vitro, doses 7-8 times the physiological level inhibit T cell function and reduce interferon-alpha production.

Typical ratios for the general population are 15-20 mg/1 mg zinc/copper or (30-40 mg/2 mg copper), in elderly populations usually 40 of zinc with 1 mg of copper is used once to twice daily. In the AREDs study, 40 mg/1mg of zinc/copper twice daily significantly lowered mortality by 27%, which was seemingly driven by a reduction from deaths from respiratory causes.

Zinc Absorption and Bioavailability

The human body contains about 2-4 grams of zinc, out of which about 0.1% gets depleted every day. Only 1/1000 of the total zinc pool gets renewed on a daily basis. Zinc’s biological half-life is 280 days. Up to 57% of zinc in the body is located in muscle and 29% in bone. There is no separate storage site for zinc in the body, which is why it needs to be obtained from dietary sources on a regular basis.

Red meat avoidance is thought to contribute to iron and zinc deficiency, especially in young premenopausal women. Vegetarian diets, as well as a preference of poultry, fish and dairy over red meat has been shown to increase the risk of zinc deficiency. The requirement of zinc for vegetarians is at least 50% higher than omnivores because zinc is not particularly bioavailable in plant-based foods. Thus, adult vegetarian males might need up to 16-20 mg/day and vegetarian females 12-14 mg/day of zinc.

Children in certain U.S. middle- and upper-income families, have been seen to have impaired taste acuity, low hair concentrations of zinc and poor growth. This is due to “picky eating”, but technically, it is due to not eating zinc-rich animal foods like red meat. When giving these children zinc at 2 mg/kg of body weight, their ability to taste, appetite and growth rate improves.

Phytate, phosphate and other phytonutrients are able to chelate zinc, including other minerals. Phytate is a mineral chelator that affects zinc bioavailability. In Korean adults, lower zinc bioavailability because of phytates is related to a higher risk of atherosclerosis. Foods high in phytates like grains bind to zinc, iron and calcium and reduce their absorption, which is why diets high in phytates can cause zinc and iron deficiency.

The demonization of all grains, especially in those who consume large amounts of muscle meat but not organ meats, may be a leading contributor of copper deficiency. On the flip side, a high intake of grains and low intake of animal protein can lead to dwarfism, as observed in Middle Eastern countries such as Turkey, Morocco, Tunisia, Iran and Egypt. The high phytate content of bread in some regions like Iran, where the diet is primarily made up of grains, contributes to zinc deficiency.

• Phosphates in clay bind to zinc, which is why geophagia (clay eating) is known to cause Iranian dwarfism. Zinc deficiency has been observed in regions like Egypt and Iran, who typically consume adequate amounts of zinc in their diet, but this is on top of excessive amounts of phytate and fiber.

It has been observed that the rising CO2 levels in the atmosphere can reduce the amount of zinc and iron in common crops, such as rice, wheat, peas and soybeans, with projections that a 10% drop in these minerals will occur by the end of the century. This puts developing countries, which are particularly dependent of these crops, in greater danger of zinc/iron deficiencies.

Supplementing 400 mcg of folic acid every other day for 4 weeks has been shown to reduce zinc excretion by 50%. However, polyphenols, such as resveratrol and quercetin, may enhance the uptake of zinc into certain cells via metallothionine.

Another inhibitor of zinc absorption is calcium, which enhances phytate’s ability to reduce zinc absorption. The ratios between phytate-zinc and phytate-zinc-calcium can predict the risk of zinc deficiency.

A high intake of other minerals like copper, magnesium, calcium, iron and nickel also reduces the absorption of zinc.

Ferrous iron (Fe 2+) supplements can reduce zinc absorption and lower plasma zinc levels. That is why experts recommend taking iron supplements away from food. However, when zinc and iron are consumed together in a meal, this effect does not seem to happen.

Certain antibiotics can inhibit the absorption of zinc. Taking these either 2 hours before, or 4-6 hours after zinc intake, can minimize this effect. Zinc reduces the absorption of penicillamine, which is used to treat rheumatoid arthritis. Diuretics like chlorthalidone and hydrochlorothiazide increase zinc excretion by as much as 60%. ACE inhibitors, like lisinopril and other blood pressure lowering medications in this class that end in “pril” deplete zinc. Omeprazole, a common antacid/heartburn medication, has been found to lower serum zinc levels. This is because proton pump inhibitors reduce zinc absorption from food due to a reduction in stomach acid.

Inflammation and certain disease states also promote zinc excretion. Picolinate complexes are more easily absorbed by the body. Zinc picolinate has been seen to improve zinc status in children with a genetic mutation that prevents them from absorbing zinc from cow’s milk.

Factors that increase the demand for zinc:

• Intestinal malabsorption conditions and gut issues, like inflammatory bowel disease, Crohn’s, sickle cell anemia, cystic fibrosis as well as diabetes, which can cause secondary zinc deficiency.
• Chronic diarrhea can lead to an excessive loss of zinc, whereas supplementation can help to offset these effects.
• Infections, like hookworm, can result in zinc deficiency, leading to physical and mental developmental problems in children. Hookworms can also promote iron deficiency.
• Kidney diseases and liver diseases such as liver cirrhosis and non-alcoholic liver disease, alcoholism and chronic inflammation can increase the urinary excretion of zinc. Liver cirrhosis patients show abnormally high levels of zinc in the urine.
• Mercury exposure and heavy metal toxicity can cause zinc deficiency
• Zinc demand increases during pregnancy, nursing and growth periods. Pregnancy is hallmarked by an increased zinc retention and a lack of nutrition can lead to harm to the fetus that may have long lasting consequences.
• Bariatric surgery causes impaired zinc absorption and promotes zinc deficiency
• Obesity can increase zinc excretion due to kidney damage. In obese subjects, plasma zinc concentrations are significantly lower. Low serum zinc levels in obese patients have been correlated with higher urinary zinc excretion.
• Athletes also have a lower serum zinc level than nonathletes due to increased zinc demands and losses during exercis

Supplemental doses of 80-150 mg/day of zinc can be immunosuppressive if not taken with copper. The lowest median effective dose of supplementary zinc is deemed to be 24 mg/day. Using zinc-containing nasal gels or sprays has been associated with a loss in the sense of smell.

Men taking over 100 mg/day of zinc experience a 2.9-fold increase in the risk for metastatic prostate cancer, which is likely due to copper deficiency.

Best to worst ways to measure zinc status and zinc deficiency:

• The best way to measure zinc deficiency is neutrophil zinc levels.
• Zinc concentrations in leukocytes or lymphocytes can be much more reflective of zinc status because they are associated with growth development and immunity. The ratio between CD4+ and CD8+ T cells has also been proposed as a test for zinc deficiency.
• The levels of zinc in hair can reflect dietary intake of zinc, at least in animals. There is also a correlation between zinc concentrations in plasma and hair. The advantage of hair tests is that it can reflect intakes over several months, giving it a more accurate measurement of the body’s zinc status.
• Zinc-dependent enzyme activities such as superoxide dismutase, metallothionine and others in organs can be another way to measure zinc deficiency. In zinc-deficient animals, zinc-metalloenzymes and zinc itself are reduced.
• Plasma and serum zinc levels are most commonly used to assess zinc deficiency, but they do not reflect cellular zinc status. Clinical symptoms of zinc deficiency can be seen even in the absence of low zinc indicators. What’s more, plasma and serum zinc values fluctuate diurnally and drop after meals and exercise.
• The most accurate measurement of zinc deficiency is neutrophil zinc levels and possibly hair mineral analysis. Neutrophil zinc levels in healthy individuals tends to average around 108 ug of zinc/10 10 cells, whereas those who are deficient in zinc average 82 ug of zinc/10 10 cells. Normal zinc values range from 150-240 mcg/g of hair, whereas less than 70 mcg/g may indicate zinc deficiency. Zinc concentration in hair depends on the rate of hair growth and the delivery of zinc to the root, and hence, it is not 100% accurate. Environmental contamination can also affect copper and zinc levels in hair. Thus, hair mineral analysis, in addition to neutrophil or perhaps lymphocyte or red blood cell zinc levels, and leukocyte copper levels, should be implemented for assessing suspected zinc and copper deficiency more accurately.

Getting the Right Amount of Zinc from Diet

Since zinc is a copper antagonist, too much dietary zinc can lead to copper deficiency. Accordingly, too much zinc in relation to copper is associated with hypercholesterolemia and increased coronary heart disease mortality. At the same time, excess iron supplementation inhibits zinc and copper absorption, which can weaken the immune system and cause copper-deficient anemia. Thus, it is necessary to balance these three minerals – iron, zinc and copper.

Generally, most people should avoid iron supplements and focus on eating iron/zinc/copper rich foods. Here are some guidelines for meeting those guidelines:

• Consume copper-laden organ meats, such as liver, into your diet (0.5-1 oz. per day or 1-3 oz. two to three times per week). Oysters and mollusks are the highest sources of zinc and can be consumed perhaps 1-2 times per week. Other high copper foods include shellfish (lobster and crab), dark chocolate, certain seaweeds, nuts, lentils and beans.
• Daily zinc and iron requirements can be met with appropriate intakes of red meat based on your body’s protein and iron/zinc requirements. The RDA for protein is 0.36 g/lb. of bodyweight or 0.8 g/kg, however, many experts consider this to be inadequate. In fact, a higher protein intake has been found to be superior in terms of weight loss, satiety, body composition, wound healing and bone density. Thus, a more appropriate intake for most people is at least 0.6-0.7 g of protein/lb. of body weight or 1.2-1.4 g/kg. The optimal daily protein intake for muscle growth and hypertrophy appears to be 0.8-1.0 g/lb or 1.6-2.2 g/kg of body weight.
• If you are eating a vegetarian diet, a diet high in phytates, and/or are using zinc inhibitors such as certain medications and antacids, then your zinc demand increases. Thus, you may need up to 50- 100% more zinc every day.

Zinc supplementation is not needed when you are getting enough of it from diet. Zinc supplementation is mostly beneficial for fixing deficiencies quickly or trying to help with an acute infection. Chronic intakes of zinc over 80-100 mg/day can promote copper depletion, especially if dietary copper intake is not concomitantly increased. The idea is to try and obtain anywhere from 20-80 mg of zinc, 8-18 mg of iron and 3 mg of copper each day. This will of course depend on the person.

Chapter 10: Hypothyroidism and Hyperthyroidism: The Sodium-Selenium-Iodine Connection

Thyroid cells absorb iodine from food and combine it with the amino acid tyrosine, which is used to create thyroid hormones such as thyroxine (T4) and triiodothyronine (T3). Most of the effects of thyroid hormones are performed by the active thyroid hormone T3. There are also T0, T1 and T2, which act as hormone precursors and byproducts. Thyroid hormones, primarily T3, are then released into the bloodstream to affect your body temperature, growth, daily caloric needs, heart rate and metabolic rate.

The production of thyroid hormones requires certain minerals, in particular, iodine, selenium, sodium, zinc and magnesium. Only 20-50% of all iodine in the body is found in thyroid hormones or the thyroid gland, whereas the other 50-80% is concentrated in non-thyroid tissues.

Symptoms of hypothyroidism include chronic fatigue, weight loss plateaus or weight gain, low testosterone and sex drive, cognitive dysfunction, intolerance to cold, joint pain, constipation, hair loss, brittle skin, water retention, depression and high cholesterol levels.

Cellular uptake of the thyroid hormones T4 and T3 is dependent on energy (ATP), magnesium and sodium. One of the main thyroid hormone transporters is the sodium-iodide symporter (NIS). The NIS transports two sodium cations (Na +) and one iodide anion (I −) into the thyroid gland. Albumin also appears to also have an essential role in thyroid hormone transportation.

Iodine, Hypothyroidism, and Goiter

Thyroid hormone levels are regulated by thyroid-stimulating hormone (TSH), also known as thyrotropin. TSH promotes the uptake of iodine by the thyroid and stimulates the synthesis and release of T4 and T3. Thyroid hormone production works in a negative feedback loop with TSH. This is why people with hypothyroidism have high TSH levels because their body is trying to make more thyroid hormones.

In the presence of iodine, T4 gets synthesized and is transformed into T3 based on needs. The formation of thyroid hormones is initiated by thyroglobulin (Tg), which gets synthesized by TSH when thyroid hormones are low. If iodine is overconsumed, the activity of sodium-iodide symporter (NIS) decreases in order to slow down the synthesis of thyroid hormones.

Iodine is an essential trace mineral needed for thyroid functioning, thyroid hormone synthesis, physical and mental development and metabolism. It can only be obtained from diet or supplements. Low iodine status is one of the biggest risk factors for hypothyroidism. Iodine is the heaviest, yet least abundant, element that occurs in several oxidation states, such as iodide (I −) and iodate (IO −3).

Iodide combined to DHA and arachidonic acid in cell membranes protects them from oxidative damage. Indeed, iodide acts as an electron donor in the presence of hydrogen peroxide and peroxidases. Thus, iodine/iodide is important for protecting against lipid peroxidation and oxidative stress. In fact, it is thought that the high levels of iodine in algae played an important antioxidant role when they first started to produce oxygen 3 billion years ago.

• T4 and rT3 have been shown to be more potent at inhibiting lipid peroxidation compared to vitamin E, glutathione or vitamin C. Thus, iodide and thyroid hormones act as antioxidants.

Iodine contributes to 65% of the molecular weight of T4 and 59% of T3. Only about 10-20% of T3 is secreted by the thyroid gland itself, whereas most of it is produced from T4. Up to 80% of T3 gets created outside of the thyroid gland through deiodination of T4 with the help of type I deiodinase in the liver and kidneys. Skeletal muscle can also initiate the conversion of T4 into T3.

An iodine-replete adult contains about 25-50 mg of iodine out of which 20-50% is stored in the thyroid. The iodine gets transported into the thyroid as iodide by the sodium-iodide symporter (NIS). This NIS-mediated delivery of iodide into the follicular cells of the thyroid gland is the first step in the synthesis of thyroid hormones. That is why the concentration of iodine in the thyroid gland is 20-50 times greater than in the plasma. The remaining iodine that is left in the bloodstream will be excreted through urine.

The size of the thyroid gland is dependent on iodine intake, whereby an excessive or deficient intake of iodine can lead to goiter. Iodine-induced goiter was first described in the 19th century and it has also been documented in children. Excessive iodine intake is thought to contribute to goiter in Sudan, Ethiopia, Algeria and China. It can also lead to reversible hypothyroidism.

Hypothyroidism from excess iodine intake may happen because of thyroid autoimmunity, characterized by elevated anti-thyroid antibodies. Excess iodine is considered a risk factor for the development of thyroid autoimmune disease. Autoimmune thyroiditis and hypothyroidism are more common the older you get with antibodies peaking at 45-55 years of age. Urinary iodine levels > 300 μg/L are considered excessive in children and adults and levels > 500 μg/L are considered excessive in pregnant women.

• The relationship between iodine intake and thyroid disorders is U-shaped. Both too low, as well as excessive iodine intake, results in hypothyroidism, hyperthyroidism and potentially autoimmune thyroiditis.

Excess iodine can also cause hyperthyroidism, which happens after the iodine-deficient thyroid gland nodules escape the control of TSH and start overproducing thyroid hormones. Graves’ disease is the most common form of hyperthyroidism. Other autoimmune thyroid disorders include Hashimoto’s thyroiditis, post-partum thyroiditis and autoimmune arthritis. Hashimoto’s thyroiditis is associated with a significantly higher risk of papillary thyroid carcinoma. Thyroiditis refers to inflammation of the thyroid gland. Inflammation also promotes hypothyroidism by blocking T4 conversion to T3. Low thyroid individuals have a higher risk of hip fractures and non-spine fractures.

Here are the iodine-dependent enzymes, functions and consequences that may occur with a deficit in iodine:

Iodine-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Thyroid Hormones: Regulates metabolic rate, body temperature and energy balance: Chronic fatigue, frailty, weight gain, metabolic syndrome and decreased immunity
• Thyroglobulin: Initiates thyroid hormone synthesis: Low thyroid function
• Sodium-Iodine Symporter: Transports iodine into thyroid cells: Iodine deficiency and impaired thyroid function
• Apoptosis: Programmed cell death and elimination of premalignancies: Accumulation of dysfunctional cells
• Mucinase: Breaks down mucus and bacteria: Increased risk of infection
• Brain Receptor Formation: Proper cognitive and mental development: Increased risk of cretinism and mental retardation

Hypothyroidism is about 10 times more prevalent in women than in men because they have higher iodine requirements during lactation and pregnancy.

Here are the risk factors for developing hypothyroidism or hyperthyroidism:

• Pregnancy or lactation
• Iodine deficiency
• Iodine excess
• Rapid transition from iodine deficiency to sufficiency
• Autoimmune conditions
• Genetic risk factors
• Smoking
• Selenium deficiency
• Drugs and pharmaceuticals
• Infections

A meta-analysis discovered that consumption of iodine-rich seafood (>300 mcg/day of iodine) decreased the risk of thyroid cancer. Molecular iodine (I 2) at 3 mg/day has been proposed to be able to suppress benign and cancerous neoplasia due to its antioxidative effects. Radioactive iodine can increase the risk of thyroid cancer and its uptake is higher in iodine-deficient people. Thus, iodine-deficient people are at a higher risk of developing thyroid cancer.

There’s an interrelationship between thyroid dysfunction and hypogonadism or low testosterone in men. Free testosterone levels are reduced in subjects with hypothyroidism and thyroid hormone treatment normalizes that. Testosterone has protective effects on thyroid autoimmunity by reducing titers of thyroid peroxidase and thyroglobulin antibodies. There is an association between erectile dysfunction and hypothyroidism. Hypothyroidism increases the risk of gaining weight and developing obesity, which can promote metabolic syndrome and other chronic diseases.

Hypothyroid patients have elevated lipoprotein(a) [Lp(a)], which is a risk factor for cardiovascular disease. Lp(a) attracts oxidized lipids and can cause inflammation. Those with hypothyroidism also have higher phospholipase A2 (Lp-PLA2), which is a pro-inflammatory enzyme that moves with LDL particles. C-reactive protein (CRP), one of the primary markers of inflammation has been found to be elevated in patients with subclinical hypothyroidism, which increases cardiovascular disease risk.

The body needs thyroid hormones to use cholesterol and cholesterol is a precursor to testosterone and other steroid hormones like DHEA, pregnenolone and progesterone. Thyroid hormones influence cholesterol synthesis, catabolism, absorption and excretion by regulating cholesterol 7alpha-hydroxylase (CYP7A), the rate-limiting enzyme in the synthesis of bile acids. T3 stimulates lipoprotein lipase (LPL) to increase the breakdown of VLDL cholesterol. Furthermore, T3 increases the expression of LDL cholesterol receptors that enable LDL to enter cells to be used for its essential functions instead of staying in the bloodstream. T3 can protect LDL from becoming oxidized by mopping up free radicals.

Hyperthyroidism, or an over-active thyroid, has the opposite effect to hypothyroidism and is associated with low HDL and LDL levels. This is not ideal as very low cholesterol is associated with depression, memory loss and increased mortality.

Thyroid hormones are important for the development of a healthy heart and abnormal thyroid hormone function can cause issues like cardiac hypertrophy and irregular heartbeat. Heart, endothelial and other cells have thyroid hormone receptors which regulate thyroid hormone function. Thyroid dysfunction can affect cardiac output, blood pressure, vascular resistance and heart rhythm.

Administration of iodide, the reduced form of iodine, has been shown to protect the heart tissue from myocardial ischemia reperfusion injury in mice. Smoking increases the risk of atherosclerosis, cardiovascular disease and autoimmune conditions like Graves’ disease. Importantly, smokers appear to have lower levels of thyroid stimulating hormone activity than non-smokers. Smoking is also associated with an increased risk of thyroid disease.

Food and Other Sources of Iodine

Many regions have low soil iodine content, especially those areas that are far inland from the coast. That is why iodine intake in the United States primarily comes from iodized salt, which is in the form of potassium iodide in North America but potassium iodate in other regions due to its better stability in hot/humid climates. Vaporized sea water coming as rainfall is not always able to enrich the soil with enough iodine. This is true even for some coastal areas like the Zanzibar Islands of Tanzania. Mountainous regions and river valleys have the most iodine-deficient soils in the world. Crops and animals grown on low iodine land and consuming low iodine foods become deficient in iodine, which leads to low iodine intakes and iodine deficiency in populations of that region.

Brown algae seaweed accumulate more than 30,000 times more iodine in seawater. East-Asian countries like Japan and Korea include a lot of seaweeds into their diet. The average iodine intake in Japan is 1.2 mg/day from eating seaweeds like kelp, nori and kombu.

According to the World Health Organization, based on estimates from 2002, the proportion of the population with insufficient iodine intake (measured as urinary iodine < 100 mcg/L) is as follows, Americas (9.8%), Western Pacific (24.0%), South-East Asia (39.8%), Africa (42.6%), Eastern Mediterranean (54.1%) and Europe (56.9%).

The Standard American Diet is typically low in iodine unless it includes things like pastured eggs, cranberries, milk, yogurt, shrimp, oysters, tuna/cod or seaweed.

Dairy and milk can also be a reliable source of iodine in many diets, including camel milk and goat milk. Vegan diets that lack seafood and dairy dramatically increase the risk of iodine deficiency unless seaweeds or two and a half medium sized potatoes are eaten on a daily basis.

Most commercial bread has extraordinarily little iodine, but it can be fortified with potassium iodate or calcium iodate. Pasta can contain iodine only when cooked in water with iodized salt or when made out of iodized dough. Most fruits and vegetables are a poor source of iodine.

Iodine is especially important during the first 1000 days of life, as infants in that timeframe are more vulnerable to hypothyroidism and developmental issues. Thyroid hormones are needed for the brain’s myelination and neuronal migration. An iodine deficiency during infancy can impair physical and neuromotor development. It also increases the risk of stillbirths, abortions and developmental abnormalities. Impaired thyroid function in iodine-deficient children is correlated with reduced insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and stunted growth.

• A severe iodine deficiency in utero may lead to cretinism, which causes mental retardation, deaf-mutism (a person who is both deaf and unable to speak) and spasticity.
• Selenium deficiency is also thought to contribute to cretinism and lower intelligence as iodine and selenium work together in the formation of thyroid hormones.

Women in regions with high dietary iodine intake have higher amounts of iodine in their breast milk. In Korean preterm infants, subclinical hypothyroidism is associated with high iodine levels in breast milk. Expression of the sodium-iodide symporter (NIS) in mammary glands regulates iodine absorption and contributes to the presence of iodine in breast milk. In the thyroid, NIS is regulated by thyroid stimulating hormone, whereas in breast tissue prolactin, oxytocin and β-estradiol regulate its expression. Some environmental chemicals like perchlorate, pertechnetate, nitrate and thiocyanate can compete with iodine absorption by hijacking the sodium-iodide cotransporter.

Fluoride in drinking water may also inhibit the sodium-iodide symporter activity, causing iodine deficiency.

Infant formulas have to be fortified with iodine to mimic breast milk nutrition. The infant formulas in the U.S. are regulated to contain 5-76 mcg/100 kcal of iodine, whereas in the EU it is 15−29 mcg/100 kcal. If the mother is iodine deficient, their whole-body iodine stores will be more concentrated in their breast milk to safeguard infant dietary requirements. Prenatal supplements containing iodine are being recommended during pregnancy and lactation, but if the mother is already consuming too much iodine it may cause fetal complications.

To get the right amount of iodine, you would want to consume a diet that provides anywhere from 150-300 mcg/day of iodine. That ensures there is circulating iodine in your system in adequate quantities to fuel thyroid hormones.

Raw cruciferous vegetables contain goitrogenic compounds called glucosinolates that if overconsumed may inhibit iodine absorption and cause low thyroid function. Cruciferous vegetables include collard greens, broccoli, kale, cauliflower, cabbage and arugula. Soy, cassava, peanuts, corn, certain beans, millet, pine nuts and strawberries also contain goitrogens. Cooking lowers the amount of goitrogenic compounds, thus, if you consume these foods cooked, then it’s much less likely that there will be any issues.

• Most goitrogenic foods do not have a clinical effect in people who are getting adequate amounts of iodine from their food. It will have a bigger impact in those who are already iodine deficient or are consuming a diet low in iodine. If you have thyroid problems, then it’s not a good idea to eat raw cruciferous vegetables. Nevertheless, the intake of cruciferous vegetables is associated with a reduced risk for cancer and cardiovascular disease. The breakdown products of glucosinolates activate anti-cancer pathways.

Some amino acids can partially inhibit thyroid hormone transport by competing with the receptors. In rat small intestinal cells, tryptophan, phenylalanine and tyrosine inhibit T3 transportation. Leucine has also been found to have inhibitory effects on T3 and T4 uptake by pituitary cells. Large doses of amino acids in isolation, like a tryptophan supplement or a branched chain/essential amino acid supplement, may have a competitive effect, but this may only be an issue for an hour after consumption.

Certain medications can inhibit thyroid hormone uptake into certain tissues by competing with them due to structural similarities. These include certain antiarrhythmic drugs, calcium channel blockers (like nifedipine, verapamil and diltiazem), calmodulin antagonists and benzodiazepines. Some anti-inflammatory drugs like diphenylhydantoin, meclofenamic acid, mefenamic acid, fenclofenac, flufenamic acid and diclofenac inhibit T3 uptake. Medications that have goitrogenic effects include antibiotics like ciprofloxacin and rifampin, steroids, statins and others. However, diabetic drugs like metformin may reduce the goitrogenic effects of type-2 diabetes and obesity. ACE inhibitors such as benazepril, lisinopril and fosinopril are blood pressure medications that can elevate potassium levels when taken together with potassium iodide. Taking potassium iodide with potassium-sparing diuretics can also cause hyperkalemia (high potassium). Certain food chemicals and flavor-enhancers like perchlorate block the thyroid’s ability to absorb and utse dietary iodine. 

Chronic low-calorie dieting can cause irreversible damage to the thyroid. A 2016 study on the Biggest Loser competitors discovered that 6 years after the show the participants had regained 70% of the weight they initially lost and were burning 700 fewer calories per day compared to when they started the show. Despite gaining some lean muscle during the show, their metabolic rate didn’t increase due to the severe calorie restriction they experienced, which mimicked starvation. This is the result of crash dieting and yo-yo dieting, which inevitably disrupts thyroid function.

Prolonged fasting for 72 hours has been shown to decrease serum T3 by 30% and thyroid-stimulating hormone by 70% in healthy men. Similar results have been noted with 4-day fasts. Men typically see greater changes than women. However, T3 and reverse T3 return to prefasting levels after refeeding and returning to eating a normal diet. Thus, alterations in thyroid hormones are an acute adaptive mechanism to food scarcity to preserve energy. Having a lower metabolic rate also protects against muscle loss during fasting.

• Shorter intermittent fasting isn’t nearly as big of a stressor as extended fasting, and it also has less of an effect on thyroid functioning.
• People with hypothyroidism don’t typically need to change their thyroid medication dosage and can safely practice intermittent fasting. Serum T3 and T4 has dropped in some studies but the data is inconsistent. A decline in thyroid hormone levels with fasting is thought to be caused by alterations in protein binding because free thyroid indices stay the same.
• Refeeding with a predominantly carbohydrate-rich diet has been shown to reverse changes in serum T3 and rT3 caused by fasting even when hypocaloric. Carbohydrates, and the glucose they are converted into, are the main fuel for the thyroid and brain, which can raise metabolic rate if insulin/leptin resistance is not induced. In fact, insulin is needed for converting T4 into T3 and raising metabolic rate. This can make exogenous carbohydrates important for certain people, especially those whose thyroid functioning does down on a low-carb diet. Acutely raising leptin by eating some whole food carbs and spiking insulin can improve insulin sensitivity and weight loss. Restoring normal leptin levels has been shown to normalize blood sugar and insulin resistance. Some ketogenic diets may reduce T3 and raise reverse T3. That is why chronic ketosis may not be optimal for thyroid function and insulin sensitivity because it can also induce mild short-term carbohydrate intolerance. Instead, cyclical keto can help to bypass this negative side-effect while still providing the other benefits of ketosis, such as an improved lipid profile and lower blood sugar.

Fructose has been shown to reduce liver T4 uptake in humans and rats. This is thought to be caused by fructose raising lactic acid and uric acid levels, which consume ATP. Physiological stress has also been noted to reduce T3 and T4. Posttraumatic stress disorder is associated with higher rates of hypothyroidism. Thus, the synthesis and transport of thyroid hormones is energy-dependent and can be reduced with fasting, excessive fructose intake and magnesium deficiency.

Here are 12 things that lower thyroid hormones or thyroid hormone uptake:

• Low ATP/magnesium
• Low sodium
• Low iodine
• Chronic calorie restriction
• Prolonged starvation
• Extended fasting
• Severe illness
• Kidney damage
• Liver damage
• Chronic stress
• Excess fructose consumption
• Chronic sleep deprivation

Special salts, like sea salts, do not usually contain iodine, however, Himalayan and other pink rock salts typically do contain some naturally occurring iodine.

Abrupt intake of iodine after a period of deficiency, such as seen with salt iodization, can cause hyperthyroidism and raise thyroid antibodies, especially in young women. Thus, introducing too much iodine when you have been deficient beforehand might trigger autoimmunity against the thyroid. Thus, a more gradual re-introduction of iodine, and from more natural sources (salts or foods naturally containing iodine), may be optimal.

Drinking water contains on average 1-10 mcg/L of iodine. High levels of iodine in groundwater have been reported in Algeria, Argentina, China, Denmark, Djibouti, Somalia, Ethiopia and Kenya. In some places like Somalia, drinking water is the only source of iodine. Long-term exposure to excess iodine from drinking water has been seen to cause hypothyroidism in children. Excess iodine from water is also thought to cause endemic goiter in some regions of China but not in others. Water purified with iodine has also been shown to cause thyroid dysfunction in a few cases of Nigerian workers and U.S. astronauts.

Excess iodine is more toxic in the presence of selenium deficiency, which can lead to damage and oxidation of proteins. In fact, supplemental selenium alleviates the toxic effects of excess iodine, such as thyroid damage and thyroid hormone dysfunction. Acute symptoms of iodine poisoning include burning of the mouth, vomiting, diarrhea, coma and pain in the stomach and throat. Some people are also hypersensitive towards iodine-containing foods and products, which makes them experience rashes and allergies. However, there are no confirmed reports of actual iodine allergy.

Assessing Iodine Status

Under normal circumstances, only 10% or less of circulating iodine gets taken up by the thyroid but during chronic deficiency it can be more than 80%. The half-life of plasma iodine is about 10 hours, but this is reduced in iodine deficiency. Over 90% of iodine is absorbed in the small intestine and 90% of it is excreted within the first 24-48 hours. The half-life of T4 is 5 days and for T3 it is roughly 1.5-3 days. Urinary iodine concentration (UIC) is the most commonly used biomarker for measuring iodine status within a population. Intradiurnal rhythms will offset individual spot urine samples, which is why spot urinary iodine is not recommended for individual assessment.

Thyroid-stimulating hormone (TSH) is often used to assess hypothyroidism, but it is not fully accurate due to individual differences and diurnal variations. Generally, TSH levels start to rise when iodine intake drops below 100 mcg/day. The normal range for TSH is between 0.45-4.5 mU/L and 95% of the disease-free population in the U.S. has their TSH at 0.45 and 4.12 mU/L. T4 and T3 measure hormone levels but not necessarily thyroid hormone function (receptor activation and subsequent effects thereafter). TSH is not accurate for assessing iodine status in adults but it may be accurate for assessing iodine status in newborns because they have a higher rate of iodine turnover than adults.

The Sodium-Selenium-Iodine (SSI) Connection

Selenium is an essential mineral that protects against oxidative damage, promotes DNA synthesis and is needed for metabolism. Selenium is contained in over two dozen selenoproteins in the body, many of which have roles in cell redox homeostasis and antioxidant defense. Selenium has two forms: inorganic (selenate and selenite) and organic (selenomethionine and selenocysteine) both of which are good dietary sources of selenium.

Selenoproteins are involved with thyroid hormone metabolism and antioxidant defense. Selenium is present in selenoproteins as selenocysteine, which is essential for enzymatic activities. In addition to iodine, the thyroid gland is also the highest concentrated source of selenium per gram of tissue in the body due to a high number of selenoproteins.

The main selenoproteins, namely glutathione peroxidase, thioredoxin reductase and deiodinases are expressed in the thyroid gland in large quantities. Here is how they affect thyroid function:

• Glutathione peroxidases (GPx) are selenoenzymes that regulate thyroid hormone synthesis, contributing to the high content of selenium in the thyroid. They also protect thyroid cells against hydrogen peroxide and other free radicals, which would otherwise inhibit thyroid function. Selenium deficiency reduces glutathione peroxidase levels. A study noted that there was an association between higher TSH and decreased selenium/glutathione peroxidase activity.
• Thioredoxin reductases (TrxR) are essential for antioxidant defense and regulation of certain transcription factors. So far, there have been three selenoenzymes in the thioredoxin reductase family identified – TrxR1, TrxR2 and TrxR3. They help protect the thyroid against oxidative damage.
• Deiodinases (DIO) scavenge iodide from iodinated tyrosine inside the thyroid gland during thyroid hormone biosynthesis and are a family of thioredoxin proteins. The breakdown of thyroglobulin (Tg) during thyroid hormone biosynthesis produces 6-7 times more iodinated tyrosine than thyroid hormones; deiodinases are then available to salvage iodide from iodinated tyrosine. Without deiodinase, iodide and left-over iodinated tyrosine would be excreted through urine, reducing thyroid hormone biosynthesis. In fact, mutations in deiodinases causes iodine deficiency and selenium directly controls deiodinase activity. TSH stimulates the conversion of T4 into T3 via deiodinases.

Thus, selenium is important for not only activating thyroid hormones but also recycling them. In other words, iodine does not work without selenium and sodium and a lack in any of these essential nutrients will worsen thyroid function.

Sodium-selenium therapy improves thyroid status and the T3/T4 ratio in cystic fibrosis and congenital hypothyroidism. The more impactful effect seems to be that selenium supplementation improves thyroid parameters by increasing deiodinase activity.

However, selenium supplementation without prior iodine replenishment may exacerbate hypothyroidism because there isn’t enough glutathione peroxidase to clean up the hydrogen peroxide that gets created during iodine-deficient hypothyroidism. Those unleashed free radicals will then begin to damage thyroid cells and interfere with thyroid health. Thyroid function has not been shown to change in healthy subjects receiving additional supplemental selenium if they have no parameters of hypothyroidism.

Selenium deficiency increases thyroid size and risk for goiter. Lower selenium levels are associated with increased thyroid volume and nodule formation. Thus, adequate selenium may protect against goiter as well as thyroid disease. The incidence of goiter in children is associated with the amount of selenium in the local soil – i.e., low selenium in soil, low selenium in food, selenium and iodine deficiency, hypothyroidism and goiter. Fixing iodine deficiency in children with goiter and selenium deficiency does not reduce the volume of goiter or improve thyroid function.

Selenium deficiency leads to the activation of oncogenes (cancer causing genes) due to an increased formation of reactive oxygen species. Thus, selenium might have a role in the prevention of cancer due to its antioxidant and immunomodulatory properties.

Chronic lymphocytic thyroiditis (CLT) can be improved with selenium at a dose of 200 mcg/day given for 3-12 months by decreasing anti-thyroperoxidase (TPO) antibodies. The suppression of antibodies appears to require doses above 100 mcg/day to maximize glutathione peroxidase. CLT is the most common autoimmune thyroid disease in which iodine status is adequate and where genetic factors of selenium deficiency are present. Giving 200 mcg of selenium/day as selenomethionine might help to reduce postpartum thyroiditis by reducing thyroid antibodies. Selenium given at 80 mcg/day for 12 months has also been observed to significantly lower anti-TPO antibodies in patients with Hashimoto’s thyroiditis with normal T4 and TSH levels.

• Anti-TPO antibodies promote the production of inflammatory cytokines by thyroid lymphocytes, making the effects of selenium more pronounced during episodes of inflammation.

Graves’ disease is also correlated with lower selenium levels and selenium is necessary for protecting against the increased oxidative stress that occurs during this condition. Selenium supplementation has also been shown to improve the quality of life in patients with Graves’ orbitopathy.

Selenium deficiency, in combination with an RNA viral infection called coxsackie virus, can lead to Keshan disease, which is a type of cardiomyopathy. Keshan disease originated from parts of China where people got on average 11 mcg/day of selenium. An intake of at least 20 mcg/day is needed to prevent Keshan disease. Observational studies have found an association between lower selenium in people with HIV and increased risk of cardiomyopathy and death. Selenium deficient women also have a higher chance of transmitting the virus to their offspring. Selenium supplementation can reduce hospitalization and HIV viral load.

Selenium supplementation in those who have a baseline deficiency likely provides significant benefits, whereas consuming over 300 mcg/day of selenium may potentially lead to negative consequences:

• Generally, the majority of observational studies and meta-analyses see an inverse relationship between selenium/selenoprotein status and cardiovascular disease risk. The main mechanism appears to be due to selenoproteins’ ability to inhibit oxidative stress, lower inflammation and protecting vascular cells against apoptosis or calcification. Selenoproteins regulate redox and calcium homeostasis. Selenoproteins increase resistance to oxidative stress, whereas selenium deficiency increases damage from oxidative stress.
• Selenoproteins can prevent the oxidation of lipids, which reduces the potential for atherosclerosis. The oxidation of LDL is a bigger risk factor for atherosclerosis and heart disease than total or LDL cholesterol levels alone. Furthermore, lipoproteins become oxidized when oxidative stress exceeds the body’s antioxidant capacity. Supplemental selenium at doses of 100-300 mcg/day has been shown to lower total cholesterol and raise HDL cholesterol, which may help clear the blood from potentially oxidizable lipids. 
• Glutathione peroxidase-3 (GPx3) deficiency, which is a selenium-dependent enzyme, promotes platelet thrombosis and vascular dysfunction. GPx3 can also inhibit the oxidation of LDL cholesterol by eliminating hydroperoxides, thus preventing vascular inflammation and atherogenesis. GPx4 has similar effects. Selenium levels are directly correlated with GPx activity.
• Impairment of selenoproteins during selenium deficiency may be a contributing factor in congestive heart failure and cardiomyopathy. Low selenium status is associated with future cardiovascular death in patients with acute coronary syndrome (someone who has had a heart attack). Selenium deficiency in heart failure patients is independently associated with impaired exercise tolerance and a 50% higher mortality rate.
• Thioredoxins also regulate cardiac function and cardiovascular disease risk. They also affect cardiac remodeling. Trx-1 has been shown to reduce oxidative stress and cardiac hypertrophy in response to oxidative stress.

People with lower selenium status are more likely to experience cognitive decline and neurodegeneration because of increased oxidative stress. Low selenium in the elderly also correlates with worse memory. In France, supplementation with antioxidants, including selenium, has been shown to improve episodic memory and semantic fluency in subjects aged 45-60.

Selenium has detoxifying effects on several heavy metals, such as cadmium, mercury and lead. The mechanisms are mediated by glutathione peroxidases and other antioxidants that help to eliminate these toxic compounds. Mercury toxicity can inhibit selenoenzymes that are needed to combat oxidative stress. Thus, selenium might be a cornerstone mineral for preventing the damage that occurs from heavy metal toxicity.

• This is also one of the reasons why seafood that has higher levels of selenium poses a lower risk for mercury toxicity. Tuna actually contains selenoneine, which is a potent antioxidant. The ratio of selenium to mercury matters more as selenium counteracts the harms from mercury. The consumption of fish can contribute up to 16.7% of the dietary protein intake for humans worldwide.
• The addition of selenium fertilizers has been shown to reduce the accumulation of cadmium and lead into crops like lettuce. Fruit stays firm and ripe longer if sprayed with foliar selenium, possibly due to an increased protecting against oxidation. Selenium also protects plants against environmental stressors like UV-B radiation and extreme temperatures.
• However, in large amounts, selenium can act as an environmental pollutant, killing fish. In most cases, high selenium in the environment is the result of activities like coal burning and mining.

Here are the selenium-dependent enzymes, functions and consequences that may occur with a deficit:

Selenium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
• Thioredoxin reductase: Antioxidant defense, peroxynitrite protection, convert T4: Oxidative stress, atherosclerosis and lipid peroxidation
• Deiodinases: Convert T4 into T3 and iodine transport in thyroid cells: Hypothyroidism
• Thyroid Hormones: Regulate metabolic rate, body temperature and energy balance: Chronic fatigue, frailty, weight gain, metabolic syndrome and decreased immunity
• Glutathione: Scavenge free radicals: Increased oxidative stress

Getting Enough Selenium from the Diet

How much selenium is in food depends on the amount of selenium in the soil. The soil consists of inorganic selenium that the plants obtain and convert into the organic form. Selenocysteine and selenite promote selenoprotein biosynthesis by getting reduced to hydrogen selenite, which is then converted to selenophosphate which supports selenoprotein biosynthesis. In animal and human tissues, selenium is in the form of selenomethionine and selenocysteine.

Ocean waters and rivers also contain quite a lot of selenium, which is why meat, fish and seafood are generally much higher in selenium than plants.

The RDA for selenium is 15 mcg for infants, 20-40 mcg for children and 55 mcg for adults. During pregnancy and lactation, the RDA for selenium increases to 60-70 mcg/day, respectively. Selenium toxicity or selenosis generally occurs if you exceed 400 mcg/day (although the actual level that induces toxicity is likely at 800mcg/day or higher).

Large doses of selenium in individuals without selenium deficiency may promote hyperglycemia and insulin resistance. Symptoms of too much selenium consumption include a metallic taste in the mouth, garlic odor, hair and nail loss and brittleness. Diarrhea, nausea, fatigue and skin lesions are also common.

The low selenium content of New Zealand’s diet was fixed by increasing the import of high-selenium wheat. Selenium levels are well known to be lower in smokers and the elderly.

2-3 Brazil nuts per day will achieve daily requirements. Other options for daily selenium consumption are consuming seafood 2-3 times per week since that will also provide iodine, omega-3s and protein. The majority of selenium is absorbed in the small intestine (50-80%) and excreted by kidneys (60%). Thus, your selenium status is also determined by the state of your digestive and excretory organs.

Here are things that raise the requirement for selenium:

• Hemodialysis removes selenium from blood
• HIV patients have lower levels of selenium because of malabsorption
• Certain medications like cisplatin lower selenium in hair and serum
• Malabsorption conditions like IBS, intestinal permeability, etc.
• Aging
• Heavy metal toxicity and pollution
• Living in a low selenium soil environment
• Hypothyroidism
• Chronic inflammatory conditions like diabetes and cardiovascular disease

Selenium supplements mostly come in the form of selenomethionine, selenium-enriched yeast, sodium selenite or sodium selenate. The human body can absorb up to 70-90% of selenomethionine but only 50% of selenium from selenite. Thus, selenomethionine is the best organic selenocompound for improving selenium status because it is incorporated into proteins in a non-specific way. However, selenomethionine needs to be reduced to hydrogen selenide (H 2 Se) by selenocysteine beforehand, making it less efficient metabolically. Nevertheless, organic selenocompounds like selenomethionine cause less acute toxicity, which is why they are more preferred in short-term therapy.

Naturally, selenomethionine is mostly found in animal tissue and protein, which is why meat and fish tend to be far more bioavailable sources of selenium.

Plasma or serum selenium levels at 8 mcg/dL or above are enough to meet the requirements for selenoprotein biosynthesis. The average serum selenium concentration in U.S. adults over 40 years old is 13.67 mcg/dL. Males tend to have higher selenium levels than females and whites more than African Americans. Blood and urine selenium reflect only recently consumed selenium. Measuring glutathione peroxidase can be an indirect measurement of selenium status. Selenoprotein P may be one of the best markers for measuring total body selenium status.

Other Minerals for Thyroid Health

There are also other minerals relevant to thyroid function, which are summarized below:

• Sodium transports iodide into thyroid cells in order to make thyroid hormones via the sodium-iodide symporter.
• Iodine is essential for making thyroid hormones and governing physical and mental development. It is the main resource for optimal thyroid function, but it cannot work without the other minerals.
• Selenium helps to initiate thyroid hormone biosynthesis, activate thyroid hormones, catalyze the conversion of T4 into T3 and support the recycling of iodide to make more thyroid hormones. It also protects against thyroid damage by inhibiting oxidative stress and heavy metal contamination.
• Zinc also helps to activate thyroid hormones. Zinc deficiency impairs T3 production. Supplementing with zinc has been shown to improve the status of thyroid hormones and promote the conversion of T4 into T3. Zinc deficiency enhances the expression of thyroxine-5’-monodeiodinase, which inactivates thyroid hormones. Hair loss is common in both zinc deficiency and hypothyroidism. However, excess zinc can also cause hyperthyroidism.
• Iron helps to convert inactive T4 into active T3. Iron deficiency also disrupts thyroid hormone synthesis by reducing heme-dependent thyroid peroxidase activity. There is an association between low thyroid and iron deficiency. Disruption in thermogenesis during iron deficiency could be caused by low thyroid function. However, iron overload can also impair thyroid function and promote thyroid autoimmune disease. The importance for iron for thyroid health automatically means that copper is also important, as copper is needed to move iron around the body.
• Magnesium protects against oxidative stress and inflammation which damages the thyroid gland. Magnesium is also essential for making ATP that enables the sodium-iodide symporter to transport iodine into thyroid cells and kickstart thyroid hormone biosynthesis.
• Insulin is the hormone that is responsible for shuttling nutrients into cells. Thus, insulin resistance and chronically suppressed insulin, may lead to nutrient deficiencies and/or excessive loss of minerals through urine. With excessively low insulin levels you may excrete more of minerals out the urine, especially sodium. Carbohydrates and a healthy physiological insulin spike are important for maintaining normal thyroid function. As with everything, chronic excessive intakes of refined carbohydrates can cause many problems, but consuming normal amounts of healthy carbohydrate sources can provide unique health benefits.

Eat mineral dense superfoods like liver, oysters, spinach and seaweed at least 1-2 times per week and foods like pastured meat and eggs on a daily basis. Pay attention to the inhibitors and chelators like phytates and goitrogens but deliberate avoidance is not necessary, unless you already have existing clinical hypothyroidism.

Chapter 11: Potassium, Sodium, and Hypertension

Most people are not aware that they have hypertension because they do not experience any visible symptoms, which is why it is called the “silent killer”. However, if you do experience symptoms of elevated blood pressure, it can include headache, nosebleed, arrhythmia, heart pounding, blurry vision, buzzing in the ears, fatigue, nausea, chest pain, anxiety and tremors.

Systolic blood pressure represents the pressure in blood vessels while the heart contracts or beats. Diastolic blood pressure the pressure in the vessels during rests between heart beats. Hypertension is diagnosed if your systolic blood pressure is ≥ 140 mmHg (millimeters of mercury) and diastolic blood pressure is ≥ 90 mmHg on two different days.

There are many things that cause hypertension, such as obesity, aging, lack of exercise, excess alcohol consumption, smoking and electrolyte imbalances. Insulin resistance and metabolic syndrome are also associated with hypertension. Consumption of more fruit and vegetables has been consistently shown to be associated with lower blood pressure. Part of that is deemed to be because of a higher potassium content that regulates the body’s fluid volume and leads to blood vessel dilation. Consuming excess sodium, typically on top of a low potassium intake, is associated with an increased risk of hypertension.

High potassium intake may protect against stroke mortality, hypertension, arterial endothelial injury, cardiac hypertrophy and kidney damage.

Effects of Potassium on Health

Potassium is the most abundant intracellular cation (an ion with a positive charge) that helps to maintain intracellular fluid volume. The adult human body contains around 1,755 mg of potassium per kg of body weight. Out of that amount, only 2% is located in the extracellular fluid with most of it being found in skeletal muscle. The concentration of potassium in the cell is 30 times higher than outside the cell. This difference creates a transmembrane electrochemical gradient that is regulated by the sodium-potassium ATPase pump (Na + -K + ATPase). The gradient of potassium across cell membranes determines the cells’ membrane potential. The resting membrane potential and the electro-chemical differences across cell membranes are critical for normal cellular function and biology. Transfer of potassium ions across nerve membranes is essential for nerve function and transmission.

Once activated, the sodium-potassium pump exchanges 2 extracellular potassium ions for 3 intracellular sodium ions. Other channels responsible for maintaining differences in cell membrane potential are the sodium-potassium chloride (Cl) symporter and sodium-calcium (Ca) exchanger. The ATPase is also stimulated by activation of β-adrenergic and insulin receptors, which are stimulated by epinephrine/norepinephrine and insulin, respectively. Consequently, simultaneous stimulation of both the β-adrenergic and insulin receptors increases the influx of potassium into the cell but causes sodium to leave the cell via the Na + -K + ATPase.

Triiodothyronine (T3) and thyroxine (T4) increase Na-KATPase subunits by increasing gene expression (although the effect is the opposite in the thyroid gland, as thyroid hormones will have a negative feedback effect on the Na-K-ATPase). The Na-K-ATPase provides the sodium gradient to absorb iodide via the sodium-iodide symporter, thus reducing its activity will reduce iodine transport into the thyroid gland, thus reducing thyroid hormone synthesis.

Insulin substrate receptor-1 (IRS1) and intracellular glucose transport proteins (GLUT4) facilitate the influx of glucose into the cell. Downstream signaling events to that, involving cyclic adenosine-monophosphate (cAMP), protein kinase A (Akt), and IRS1-phosphatidylinositide-3-kinase (PI3-K) regulated pathways also mediate the influx of glucose as well as potassium into the cell. The fastest potassium exchange occurs in the kidneys and the slowest in muscles and the brain.

Metabolic acidosis, or a drop in extracellular pH, increases the loss of intracellular potassium into the extracellular space via transporters that regulate pH in skeletal muscle. Organic acidosis, caused by an accumulation of lactic acid or uric acid, lowers intracellular pH, which stimulates the movement of hydrogen out of the cell via the sodium-hydrogen transporter and bicarbonate into the cell via the sodium-bicarbonate transporter. As a result, intracellular sodium increases, which maintains Na+-K+ ATPase activity limiting the loss of potassium from the cell. Thus, organic acidosis, say from lactic acid build up from excessive exercise, causes a much smaller loss of intracellular potassium than does metabolic acidosis.

• Metabolic acidosis promotes a net efflux of calcium from bone by increasing osteoclastic resorption and decreasing osteoblast formation. Neutralization of acidosis with potassium bicarbonate (KHCO3), but not sodium bicarbonate, improves calcium and phosphorus balance, reduce bone resorption, reduces calcium excretion through urine and reduce the age-related decrease in growth hormone secretion without salt restriction.
• Potassium citrate has been shown to have beneficial calcium-retaining effects in bone. Increasing potassium consumption improves bone density in elderly women and may prevent osteoporosis. Greater potassium intake from fruits and vegetables is associated with higher bone mineral density thanks to potassium citrate’s (and the bicarbonate that is formed from it) ability to balance acid.

Fixing low grade metabolic acidosis with potassium bicarbonate has been shown to increase 24-hour mean growth hormone secretion as well as provide a nitrogen sparing effect that helps to prevent muscle loss in postmenopausal women. In patients on bed rest, potassium bicarbonate (3,510 mg/day) and whey protein supplementation (0.6 g/kg of body mass per day) for 19 days has been noted to mitigate the loss of muscle function due to inactivity.

• Prolonged periods of inactivity, like hospitalization or spaceflight, can cause muscle wasting and weakness, which increases the risk of fractures. Higher protein intake has been shown to mitigate muscle loss and catabolism. Taking whey protein alone, without balancing it with some form of base, might create a net acidic environment promoting bone demineralization. Thus, increased protein consumption, particularly from protein powders, would likely warrant increased intake of alkaline foods or beverages.
• To be clear, the body tries to maintain a normal pH in the blood, even with a surplus of acid. Thus, measuring blood pH levels is not the best way to determine acid-base balance. Typically, levels of bicarbonate in the blood will drop faster than blood pH and are a better marker of overall acid-base balance, as is urinary pH levels. You can have an acidic urine (indicating acid surplus) but a normal blood pH.

The alkaline theory has already been tested in several studies of patients with kidney disease showing that consuming an alkaline diet (either via fruits/vegetables or sodium bicarbonate supplementation) over several months can improve metabolic acidosis and kidney function. In postmenopausal women, an alkaline treatment (potassium bicarbonate supplementation) improved calcium and phosphorus balance, reduced bone resorption and increased bone formation and reduces their urinary nitrogen (i.e., muscle) loss. These findings have been confirmed in middle-aged and elderly men, whereby alkaline therapy (potassium bicarbonate) has a muscle protein-sparing effect.

Animal proteins, when broken down, release their sulfur-containing amino acids that provide an acidic load (sulfuric acid), which cannot simply be breathed out of the body.

Added sugars and grains also contribute to the dietary acid load and are typically overconsumed in the Western world. The lack of potassium/bicarbonate-forming foods in the western diet exacerbates the metabolic acidosis caused by eating the processed, industrialized foods, promoting osteoporosis, inflammation and kidney stones.

Bicarbonate-forming and potassium-rich foods are thought to improve bone health, thanks to regulating the acid-base homeostasis as well as their antioxidant content. Fruits and vegetables are the only foods that contain both potassium and bicarbonate-forming substances, giving them a negative potential renal acid load (PRAL). Eating acidic foods isn’t necessarily harmful as long as other variables like potassium/calcium/magnesium intake, bicarbonate-forming foods, metabolic and kidney health are taken into account.

Potassium, Sodium, and Blood Pressure

The low salt guidelines are not really warranted for most people and may actually cause other problems, such as insulin resistance, hypothyroidism, increased heart rate, heart failure, kidney damage, high triglycerides and cholesterol.

Chronic salt restriction may cause “internal starvation”, making the body raise insulin levels because insulin helps the kidneys retain sodium. That is why a high salt intake can be more dangerous if you are diabetic or have insulin resistance because your body is holding onto more sodium. On the flip side, healthy kidneys can handle excess sodium with ease. Salt sensitivity is primarily driven by insulin resistance and sympathetic overdrive.

The body needs sodium for nerve function, muscle contraction and cell metabolism. You would be fine without ever eating another gram of sugar, but you wouldn’t survive very long without salt.

Regular table salt (sodium chloride) can raise blood pressure significantly more than sodium bicarbonate or sodium acetate. Table salt is 100% sodium chloride, whereas many unrefined salts are anywhere from 92-97% sodium chloride, where the other 2-8% are composed of other minerals like calcium, magnesium and iodine. Sodium bicarbonate has actually been shown to lower blood pressure slightly in hypertensive individuals.

Modern diets that are high in salt wouldn’t be such a big issue if they also didn’t lack bicarbonate and potassium. Thus, it isn’t the dietary salt that’s the problem, it is the lack of the other alkaline minerals (calcium, magnesium and potassium) and base-forming substances/bicarbonate. Fruit and vegetables contain potassium phosphate, sulfate, citrate, bicarbonate and others, but not chloride, which can be added to salt substitutes and supplements (think magnesium chloride). Potassium bicarbonate has a natural sodium-excreting effect, reversing sodium chloride-induced increases in blood pressure.

Low potassium levels in the blood usually occurs alongside with low magnesium levels, both of which can promote cardiovascular complications. This is because low potassium levels can be caused by magnesium deficiency.

There are many ways potassium can help with hypertension and cardiovascular disease:

• Inhibits free radical production in vascular endothelial cells and macrophages
• Inhibits proliferation of vascular smooth muscle cells
• Inhibits platelet aggregation and arterial thrombosis
• Reduces renal vascular resistance
• Reduces atherosclerotic lesion formation
• Lowers blood pressure and water retention
• Increases endothelial vasodilation
• Reduces inflammation, oxidative stress
• Improves insulin sensitivity
• Reduces catecholamine related vasoconstriction

Potassium also has a beneficial effect on blood sugar management and insulin resistance. These problems may become a bigger issue for hypertensive people who are prescribed potassium excreting thiazide diuretics. Thiazide diuretics are the preferred pharmacological treatment for hypertension but have a tendency to reduce glucose tolerance and increase the risk of type 2 diabetes. Thiazide diuretics lower serum potassium, which may actually be caused by an increased urinary loss of magnesium, and diuretic-induced hypokalemia has been shown to reduce glucose tolerance by reducing insulin secretion.

• Potassium-sparing diuretics, such as amiloride and spironolactone, however, reduce potassium and magnesium excretion and in some instances can even cause hyperkalemia (too high potassium), particularly in those with kidney issues.

Potassium is an essential activator of pyruvate kinase, which is the enzyme involved with the last step of glycolysis, whereby energy is produced from glucose. One of the binding sites of pyruvate is dependent on potassium ions.

Here are the potassium-dependent enzymes, functions and consequences that may occur with deficient potassium:

Potassium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Sodium-Potassium ATPase: Regulates transmembrane electrochemical gradient, nerve function and fluid volume: Sodium/calcium overload, hypertension, arterial calcification and nerve dysfunction
• Pyruvate: The end-product of glycolysis and glucose metabolism: Hyperglycemia, diabetes, and loss of ATP
• Pyruvate Kinase: Glycolysis/glucose metabolism: Hyperglycemia, diabetes and loss of ATP
• Pyruvate Dehydrogenase Kinase: Inactivate pyruvate dehydrogenase during glycolysis: Impaired energy production and loss of ATP
• Ribokinase: Production of ATP and D-ribose, glucose metabolism: Impaired energy production and glucose intolerance
• Branched-chain α-ketoacid dehydrogenase kinase: Catalyzation of the oxidative decarboxylation of branched, shortchain alphaketoacids: Iodine deficiency and impaired thyroid function
• Fructose 1,6-bisphosphatase: Converts fructose- 1,6-bisphosphate to fructose 6- phosphate in gluconeogenesis: Inadequate glucose production and energy shortage in certain glucose dependent orans
• Diol Dehydratase: Catalyze the B12- dependent conversion of 1,2-diols to the corresponding aldehydes, glycerol-lipid metabolism: Impaired alcohol and fatty acid metabolism
• Heat Shock Cognate Protein (Hsc70): Regulate proper protein folding, autophagy, apoptosis and cell stability: Cell senescence, DNA damage, carcinogenesis and neurodegeneration
• Pyridoxal Kinase: Vitamin B6 metabolism: Impaired serotonin, melatonin and dopamine production: Nerve dysfunction
• Histone Deacetylase (HDAC) Inhibition: DNA binding and DNA expression: Accelerated aging, cardiac defects and neurodegeneration
• IMP dehydrogenase or Inosine-5- monophosphate dehydrogenase (IMPDH): Guanine de novo biosynthesis, DNA/RNA synthesis, and energy transfer: Impaired cellular function and weaker immunity
• Serine Dehydratase (SDH): Gluconeogenesis, pyruvate production and release of ammonia: Hyperglycemia and impaired glucose tolerance
• Tryptophanase: Tryptophan and nitrogen metabolism and neurotransmitter production: Ammonia build-up and low melatonin and serotonin
• Tyrosine Phenol-Lyase: Tyrosine and nitrogen metabolism, protein synthesis, thyroid hormone production: Impaired neurotransmitter production, low thyroid

Because low potassium impairs calcium reabsorption by the kidneys, it can increase urinary calcium, which can cause kidney stones. Potassium citrate may prevent kidney stones from forming and it also helps to break down kidney stones. However, it is primarily citrate that seems to be responsible for this effect. Nevertheless, a low potassium intake is still a potential contributor to kidney stone formation.

You can ask your doctor to assess your kidney health and functioning using the below methods:

• Blood Pressure – hypertension damages small blood vessels in the kidneys. Most people are below 140/90. If you have kidney failure, most doctors will say that blood pressure should be lower than 130/80 but 120/80 is considered normal.
• Protein in Urine – traces of albumin protein in urine are an early sign of kidney disease. Optimally, you want to have less than 30 mg of albumin per gram of urinary creatinine.
• Serum Creatinine – poor kidney functioning leads to the accumulation of creatinine in the blood, typically a waste product. A normal serum creatinine is 0.7-1.3 mg/dL for men and 0.6-1.1 mg/dL for women. However, it can vary, depending on other variables, as having more muscle can increase serum creatinine.
• Glomerular Filtration Rate (GFR) – this is a calculation of kidney functioning based on creatinine levels, age, race, gender, etc. A score over 90 is good, 60-89 should be monitored, and less than 60 for three months indicates kidney damage.
• Cystatin C – is one of the best ways to estimate kidney function as muscle mass, exercise and creatinine levels will not affect the results, unlike GFR. A normal cystatin C is 0.6-1 mg/L.

To improve kidney health, you want to eat a healthy diet, maintain an active lifestyle, consume an adequate amount of salt, potassium and magnesium, consume bicarbonate or fruits/vegetables, stay hydrated and avoid refined carbs/sugars/omega-6 seed oils. You should also avoid smoking and excessive alcohol intake.

Getting Potassium from Food and Supplements

Malabsorption conditions, such as bariatric surgery, IBS and inflammatory bowel disease (ulcerative colitis and Crohn’s) can reduce potassium absorption.

In Nordic countries, fruit and vegetables contribute 17.5% of overall potassium intake, whereas in Greece they provide 39%. Vegetables and potatoes typically provide about 24.5% of the total potassium intake in the UK. In the U.S., potatoes contribute up to 19-20% of the total daily potassium intake. There is an inverse relationship between both raw, as well as cooked, vegetables and blood pressure, although the relationship is slightly greater with raw vegetables. Monocropping, and other non-regenerative farming methods, depletes the soil of potassium, reducing the potassium content of the food that is grown on it.

In 2019, it was decided that there was insufficient data to set an RDA for potassium and thus an adequate intake for potassium was decided on 3,400 mg/day for men and 2,600 mg for women. However, as you know adequate intakes and RDAs are not optimal intakes. For primary prevention of hypertension, it has been recommended to get over 3,500 mg/day of potassium, which is above the adequate intake for men and women.

Many “salt sensitive” people simply need more potassium, magnesium or calcium instead of sodium restriction. It’s very likely that the higher the magnesium intake, the less potassium is needed, as the former helps prevent potassium loss from the cell.

Hunter-gatherer tribes that eat only whole foods have been estimated to consume anywhere from 5,850-11,310 mg/day of potassium. Sodium intake was estimated at 1,131-2,500 mg/day but this did not take into account sodium consumed from blood, interstitial fluids, salt licks and salty/brackish water. Thus, the sodium intake is an underestimation. To be fair, the potassium to sodium ratio of our ancestors likely sits somewhere between 2-3:1. On the other hand, industrialized societies that consume a lot of processed foods get about 2,100-2,730 mg/day of potassium and about 3,400 mg/day of sodium or a K/Na ratio of 0.7:1. Potentially up to 10 in foragers.

• Estimates for ancestral sodium intake did not take into account the sodium content of aquatic vegetation/seafood, organs, blood, interstitial fluids, salt licks and salt/brackish water, which would have increased the estimated sodium intake that would have occurred during Paleolithic times. Indeed, blood contains 3,200 mg of sodium per liter and interstitial fluids can be even higher in salt.

Even fairly large daily doses of potassium do not seem to be an issue for those with normal kidney function. The ratio of dietary potassium to sodium also affects potassium concentrations.

Potatoes have even been shown to have beneficial effect on blood pressure, lipid profiles and glycemic control. This may have something to do with their high potassium content. Consider eating lightly cooked and cooled potatoes. Lightly cooking and cooling potatoes maintains the resistant starch, helping to reduce the spike in glucose and insulin that occurs after you eat it. Perhaps more importantly, eating a steak with your potato, will also reduce the glucose/insulin spike.

Using salt substitutes has its risks and benefits. On one hand, salt substitutes that have more potassium and less sodium can be great for increasing dietary potassium intake without the need for supplementation. However, it can also cause hyperkalemia and do harm in patients with chronic renal failure whose kidneys are working at near maximum capacity to excrete potassium. This effect is exacerbated further by sodium restriction.

Potassium Absorption and Excretion

Approximately 90% of the consumed potassium is lost in the urine and 10% of it is excreted in the stool. A small amount of potassium is lost through sweat. With zero potassium intake, serum potassium can reach deficient levels of 3.0-3.5 mmol/L in about a week. Potassium excretion is regulated by the kidneys in response to dietary potassium intake. Unless you are potassium deficient, excretion of potassium increases rapidly after consuming potassium.

The glomerulus of the kidneys freely filters potassium and 70-80% of it is reabsorbed in the proximal tubule and loop of Henle. The two major factors that contribute to potassium loss are the renal handling of sodium and mineralocorticoid activity. Reabsorption of potassium in the proximal tubule is mostly passive and happens in proportion to the reabsorption of solute and water. In the Henle’s loop of the kidney, a small amount of potassium is excreted in the descending limb, whereas reabsorption of potassium and sodium occurs in the thick ascending limb. A lot of the potassium excretion/regulation happens in the late distal convoluted tubule (DCT) and the early connecting tubule of the kidney. Dietary potassium intake inhibits the sodium-chloride transporter in the distal convoluted tubule, reducing the absorption of salt by the kidneys. In other words, potassium consumption promotes salt excretion and helps people handle higher salt loads. Low potassium, however, causes salt retention and contributes to hypertension through activation of the sympathetic nervous system.

Aldosterone is a major mineralocorticoid that increases the excretion of potassium out in the urine by increasing sodium reabsorption in the lumen. It stimulates epithelial sodium channels and Na + -K + ATPase activity. Primary aldosteronism is associated with an increased risk of cardiovascular disease. The diurnal rhythm of aldosterone expression can affect renal potassium excretion, which should be kept in mind when taking urine samples. Aldosterone tends to be highest in the morning between 6-9 AM together with cortisol and drops down in the afternoon. Salt restriction increases aldosterone, which promotes sodium reabsorption and potassium/magnesium excretion, creating the opposite desired effect. Normal or even excess sodium intake results in suppressed or delayed aldosterone activity. Thus, reducing sodium intake may not be the most effective long-term strategy for lowering blood pressure.

A normal serum potassium concentration is 3.6-5.0 mmol/L. Hypokalemia or low potassium levels occur below 3.6 mmol/L and hyperkalemia (elevated potassium) is above 5.0 mmol/L.

Hypokalemia and hyperkalemia are rare in healthy people with normal kidney function, but it can occur due to diarrhea, kidney failure or vomiting. Hypokalemia affects up to 1/5th of hospitalized patients because of the use of diuretics and other pharmaceuticals. Mild hypokalemia can cause constipation, muscle cramps, weakness and malaise. Moderate hypokalemia causes encephalopathy, glucose intolerance, paralysis, arrhythmias and dilute urine. Severe hypokalemia can be fatal due to the induction of arrythmias. Magnesium deficiency can promote hypokalemia by increasing excretion of potassium. Hypokalemia and magnesium deficiency are associated with each other. Thus, fixing potassium deficiency would also require improving magnesium deficiency. Hyperkalemia can result from the use of ACE inhibitors, such as benazepril, and ARBs, such as losartan because they reduce potassium excretion. Potassium-sparing diuretics can also increase the risk of hyperkalemia. The side-effects of hyperkalemia include arrhythmias, palpitations, muscle pain and weakness. In severe cases hyperkalemia can cause cardiac arrest and death.

Here are the things that increase potassium demand or excretion:

• Sodium overload
• Magnesium deficiency
• Metabolic acidosis
• Diabetes, insulin resistance
• A drop in extracellular pH levels
• A drop in extracellular bicarbonate
• Diarrhea, vomiting or extreme sweating
• Inflammatory bowel disease
• Diuretics or proton pump inhibitors (PPIs)
• Kidney damage or kidney injury

Here are the things that improve potassium status

• Sodium
• Magnesium
• Insulin
• Bicarbonate
• Citrate
• Potassium-sparing diuretics

Assessing potassium status is difficult because most of the body’s potassium is located in the cell. Blood potassium levels do not correlate accurately with tissue potassium stores. Muscle biopsies can be used to look at tissue potassium status but measuring net potassium retention and excretion can also be an indicator.

Ways to Optimize Potassium Intake without Causing Hyperkalemia:

• Assess your blood pressure and kidney health
• Include 4-5 cups of fruit and vegetables into your daily diet or consume land animal meat plus fish
• Include more high-potassium foods (Fish, greens, potatoes, tomatoes and beans) in the diet if tolerated
• Aim for a daily potassium intake of at least 4,000 mg and optimally 4,500 mg
• Aim for a daily sodium intake of 3,500-4,000 mg
• Increase sodium intake if you are sweating a lot and potassium intake if you have diarrhea or are suffering from some malabsorption diseases
• Minimize packaged foods and processed foods
• Salt to taste with natural salt sources like sea salt or rock salt
• Be careful with using salt substitutes. Especially, if they’re the only source of sodium in your diet.
• Add potassium or sodium bicarbonate if you suffer from metabolic acidosis
• Add potassium citrate if you suffer from kidney stones or kidney damage
• Drinking alkaline mineral waters can help to keep you hydrated and reduce chronic latent metabolic acidosis
• Before potassium supplementation, assess your potassium status
• Check potassium levels 1 week after increasing potassium intake to see if there is a baseline risk for hyperkalemia.
• Always work with your doctor before implementing any dietary change or adding a supplement.

In conclusion, potassium and sodium are important minerals for cardiovascular health and the prevention of hypertension and insulin resistance. Traditionally, all the blame has been put on sodium when really it is sugar that’s the problem. Insulin resistance and diabetes can cause sodium retention and accumulation and raise blood pressure. At the same time, salt restriction comes with an array of negative side-effects that perpetuate insulin resistance and cardiac complications. Thus, it is more important to fix the underlying cause of hypertension, i.e., metabolic syndrome and obesity, which is due to an overconsumption of refined carbohydrates and sugars. Keeping potassium intake high by eating more muscle meat, fish, potatoes, fruit and green leafy vegetables alongside other mineral-dense foods is a great way to prevent glucose intolerance and ensure a healthy sodium to potassium ratio. Reaching an intake of potassium of 4,000-4,500 mg/day may seem like a daunting task but it is possible if you replace the processed foods with whole animal foods and fresh produce.

Chapter 12: Boron and Other Possibly Essential Trace Minerals

Boron intake is associated with a reduced risk of cancer, improved brain function, bone mineralization and reduced inflammation. It also seems to have anti-inflammatory, anti-osteoporotic, anti-coagulating, anti-neoplastic and hypolipemic (blood lipid lowering) effects.

Boron is found in many foods, especially vegetation, as it is a structural component of plant cell walls, providing cell wall rigidity. In plants, boron also has important roles in nucleic acid, carbohydrate and protein metabolism.

Boron’s Effect on Health and Vitality

More than 90% of boron consumed is absorbed and distributed as boric acid with 98% getting excreted through urine within 120 hours. Nearly 96% of the boron in an organism is uncharged boric acid [B(OH) 3] and a small amount of it is the borate anion [B(OH) 4 -]. Boric acid or borate forms ester complexes with many important sugars in energy production and stabilizes them, such as ribose, helping to produce energy and combat fatigue. Because of that, boron can regulate ribose-containing enzymes and catalysts, such as S-adenosylmethionine (SAMe), diadenosine phosphate, NAD+, and the NAD+ metabolite cyclic ADP ribose (cADPR).

These enzymes are involved with energy production, neurological function, cardiovascular health and bone formation. S-adenosylmethionine (SAMe) and diadenosine phosphates have a high affinity for boron. S-adenosylmethionine is one of the most common enzymatic substrates in the body, used primarily in methylation reactions. Boron also binds to oxidized NAD+ and cyclic ADP ribose, which can prevent the release of intracellular calcium.

Turkish men with a boron intake of 6 mg/day have significantly smaller prostate glands than men who consume 0.64–0.88 mg/day. Physiological concentrations of boric acid have been shown to inhibit prostate cancer cell growth in a dose-dependent manner through controlled apoptosis. Tumor suppressor p53 function requires the activation of activating transcription factor 4 (ATF4) and binding immunoglobulin protein (BiP) also known as glucose regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5), which get increased by physiological doses of boric acid. Boric acid inhibits cADPR, reducing endoplasmic reticulum Ca 2+. This reduction in endoplasmic reticulum Ca 2+ activates ATF4 and nuclear factor erythroid 2 like 2 (Nrf2), which increases antioxidant response element genes.

Supplemental doses of boron likely act as an Nrf2 booster, which activates our body’s overall antioxidant defense enzymes. This is why boron has been suggested to protect against oxidative stress and DNA damage. Boron compounds (such as boric acid and borax) can increase total glutathione levels, total antioxidant capacity and numerous antioxidant enzyme activities in red blood cells, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase (GST) and glucose-6-phosphate dehydrogenase (G-6-PDH).

• Superoxide dismutase prevents tissue damage from superoxide anions and catalase can prevent lipid and protein oxidation in red blood cell membranes against peroxide radicals. G-6-PDH provides the NADPH for increasing reduced glutathione, which prevents hemoglobin denaturation, preserves red blood cell membrane sulfhydryl group integrity and detoxifies oxidants in red blood cells. Thus, maintaining adequate boron intake may help to preserve the integrity of red blood cells and increase oxygenation throughout the body.

Boron might be useful for reducing symptoms of osteoarthritis by reducing inflammation. By binding to 6-phosphogluconate, boron inhibits the 6-phosphogluconate dehydrogenase enzyme and reduces the inflammatory response and reactive oxygen species. Boron also inhibits other inflammatory enzymes like lipoxygenase that triggers the inflammatory responses of prostaglandins, leukotrienes and thromboxanes. Supplementing with calcium fructoborate at 112 mg/day reduces LDL, triglycerides, total cholesterol, interleukin-6, monocyte chemoattractant protein-1, c-reactive protein and the pro-inflammatory cytokine IL-1beta. Boron intake helps to regulate osteoblast and osteoclast proteins. Boron deprivation inhibits protein synthesis, which can result in delayed wound healing and soft tissue repair.

Boron also controls calcium and magnesium metabolism, which are vital for bone health. Boron supplementation reduces calcium excretion. In postmenopausal women, a low boron diet (0.25 mg boron/2,000 kcal) can raise urinary calcium and magnesium excretion. At the same time, a low boron diet promotes hyperabsorption of calcium for compensation. That can cause cardiovascular and bone health complications. Supplementing with 3 mg of boron a day for 10 months in sedentary female college students reduces serum phosphorus, increases serum magnesium and may slow the loss in bone mineral density.

Boron affects the function of many hormones, including vitamin D. Supplementing 3 mg/day of boron after 63 days of boron deprivation (0.25 mg/day) raises 25-OH-vitamin D (calcidiol) levels in older men and women. Boron also increases the half-life of active vitamin D likely through inhibition of 24-hydroxylase, which is the primary enzyme that inactivates calcitriol.

Boron affects sex hormones like estrogen and testosterone. By inhibiting sex hormone binding globulin (SHBG), boron prevents testosterone from being bound up, resulting in higher free testosterone. Instead of increasing estrogen directly, boron inhibits its breakdown and enhances estrogen receptor beta activity. Both estrogen and testosterone levels have been shown to double in women and men, respectively, after an increase in boron intake in individuals who were previously on a low boron diet. In healthy men, supplementing with boron at 10 mg/d for only a week can raise free testosterone from 11.83 pg/mL to 15.18 pg/mL and decrease estrogen from 42.33 pg/mL to 25.81 pg/mL (although in some studies boron increases both testosterone and estradiol levels in men).

• All inflammatory markers (high-sensitivity c-reactive protein, IL-6 and TNF-alpha) decreased. The increase in testosterone with boron supplementation may also be due to improved vitamin D status, which does have an effect on sex hormones.

Here are the boron-dependent enzymes, functions and consequences that may occur with deficient boron intake:

Boron-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Superoxide Dismutase: Removes superoxide anions: Increased tissue damage and oxidative stress
• Catalase: Removes hydrogen peroxide: Increased tissue damage and oxidative stress
• NAD+ (Nicotinamide Dinucleotide): Energy production and governs most enzymatic reactions: Accelerated aging and onset of disease
• D-Ribose: Component of ribonucleotides in RNA, energy production: Chronic fatigue and impaired gene expression
• S-adenosylmethionine (SAMe): Methylation donor, wide enzymatic substrate: High homocysteine, inflammation and depression
• Vitamin D: Hormone production, immune system function, bone density, physical growth: Increased risk of autoimmunity, weaker immune system, loss of bone density and mood disorders
• Cyclic ADP Ribose (cADPR): Calcium signaling, functions of ribose: Low blood calcium levels, intracellular calcium accumulation
• 6-Phosphogluconate: Regulates respiratory burst mechanisms and inflammation: Excess inflammation and reactive oxygen species
• Collagenase: Degrades calcified collagen barriers: Bed sores, arthritis and tissue calcifications
• Calcitonin: Reduces calcium levels and inhibits osteoclast activity: Excess calcification and reduced bone health
• Estradiol: Female reproduction and fertility, neuroprotection: Infertility, neurodegeneration and impaired cognition
• Gcn4: Transcription factor for gene expression and protein synthesis: Muscle mass and soft tissue deterioration
• Delta-aminolevulinic acid dehydratase (ALA-D): Heme synthesis, precursor to hemoproteins and cytochromes: Anemia, low heme and poor tissue oxygenation

Boron Food Sources

Boron is found the most in plant foods, such as legumes, vegetables, tubers and fruit. Alcoholic beverages like wine, beer and cider also have some boron. Personal-care products like toothpaste, lip balm, baby oil and deodorants also have trace amounts of boron. Prunes are an excellent source of boron, providing 1.5 to 3.0 mg of boron per 3 oz serving. A study found that eating 3 ounces of prunes a day for a year improved bone mineral density in postmenopausal women, but dried apples did not. Boron does not accumulate in fish or land animals, but it does in algae, seaweed and plants. Many people following an animal-based diet like to eat avocadoes to boost their boron intake (8 oz. provides ~ 2 mg of boron).

Brazil, Japan and most of the U.S. have low boron in the soil because of high rainfall. California, Chile, Russia, China, Argentina, Turkey and Peru, however, have higher boron levels. Excessive levels of boron in the soil also reduce crop yields. One estimate suggested that up to 17% of the barley loss in Southern Australia was caused by boron toxicity. Borate deposits form into the ground when boric acid reacts with steam, which is why areas with hot springs and geysers tend to have more boron.

Urine, blood and other bodily fluids primarily contain boric acid. The absorption of boron occurs in the intestine but not through the skin. Boron homeostasis is regulated primarily by the kidneys and urinary excretion similar to sodium. The excretion of boron happens mostly through urine, feces, bile or sweat. Up to 92-94% of boron gets excreted in the urine after 96 hours of consumption. If dietary intake of boron is high, excretion is also higher and vice versa.

Environmental boron exposure is not a threat to human health. However, accidental consumption of borax found in household chemicals and pesticides (at doses of 18 to 9,713 mg) causes nausea, gastrointestinal distress, vomiting, convulsions, diarrhea, rashes and vascular collapse. Oral doses of 88 grams of boric acid were not shown to be toxic. However, taking over 84 mg/kg of boron has caused gastrointestinal, cardiovascular and renal adverse effects, dermatitis and death.

In excess amounts, boron can also contribute to the development of goiter by competing with iodine absorption. High concentrations of boron are used to eliminate bacterial and fungal infections by causing mitochondrial dysfunction.

Supplemental boron usually comes in the form of sodium borate, sodium tetraborate, boron amino acid chelate, boron gluconate, boron glycinate, boron picolinate, boron ascorbate, boron aspartate, boron citrate and calcium fructoborate. Taking 10 mg of boron as sodium tetraborate for 7 days can reduce sex hormone binding globulin (SHBG), resulting in higher testosterone, lower high sensitivity CRP (hsCRP) and TNF-alpha 6 hours after supplementation. Boron supplementation does not seem to affect lean body mass or strength in young male bodybuilders already engaged in resistance training. Calcium fructoborate has been shown to reduce inflammation in osteoarthritis and cardiovascular disease.

When taking boron supplements, it might be worthwhile to consume away from foods that contain B-vitamins and/or consume more foods with B-vitamins like beef, fish, eggs, vegetables and beans. Boron has a high affinity for riboflavin and ingesting high doses of boron may lead to side effects due to riboflavin deficiency (dry skin, photosensitivity and inflammation of the mouth and tongue).

Other Possibly Essential Trace Minerals

Lithium – There is a lot of evidence to show that lithium benefits mental conditions like bipolar disorder, schizophrenia and depression. Lithium can also benefit cluster headaches. These benefits are partially due to increased serotonin transmission but also from enhanced folate and vitamin B12 transport.

• Areas with low lithium in drinking water have higher rates of crime, violence and suicides. Lithium deficiency can also promote aggression and rates of homicide. Supplemental lithium for 4 weeks in former drug users increases positive mood scores, happiness and friendliness steadily over the course of the treatment compared to placebo.
• In animals, lithium deficiency causes low birth weight, depressed fertility and weaning weight. However, women who take lithium during pregnancy increase the risk of their infants developing Ebstein’s cardiac anomaly.
• Lithium also has insulin mimetic properties, making it beneficial for blood sugar management. However, treating mental disorders with large doses of lithium can cause nephrogenic diabetes insipidus. Mild symptoms of lithium toxicity cause gastrointestinal problems, tremors and muscle weakness. Severe toxicity can result in coma, convulsions and death. This is why ingesting low doses of lithium contained naturally in mineral waters seems to be a better way to get lithium for the general population compared to large pharmaceutical doses.
• Grains and vegetables are the predominant food sources of lithium, but fish, eggs and meat also contain it. The RDA for lithium is suggested to be 1 mg/day. The minimum adult requirement for lithium is estimated to be less than 100 mcg/day. The daily need for lithium can typically be covered with food and water intake but this usually falls short of an optimal intake. Supplementation with lithium should only be done with the provision of a medical professional.

Vanadium is another trace metal with many biological functions. In animals, vanadium deficiency causes low thyroid, depressed fertility and lactation.

• Cell studies show that vanadium has insulin-mimetic properties and anti-diabetic effects in animals. Because of this potent insulin mimicry, excessive intakes of vanadium can cause hypertension and death. However, oral vanadyl sulfate at 100 mg/day for 3 weeks improves liver and peripheral insulin sensitivity in type 2 diabetic patients. Supplemental vanadyl sulfate (l00 mg/d) or sodium metavanadate (125 mg/d) has not been shown to improve glycemic control in type 1 diabetics but their daily insulin requirements did decrease.
• The threshold for vanadium toxicity in humans is around 10-20 mg/d or only 1/5th of the observed beneficial dosage for insulin reduction, causing mild gastrointestinal disturbance and green tongue. In mice, the lethal dose has been estimated to be 1000 mg/kg body weight. Vanadium deficiency is not considered common in humans and most diets provide 15-30 mcg/day. Foods with vanadium include shellfish, mushrooms, herbs and some seeds. Fruit and vegetables contain little vanadium.

Nickel is circumstantially essential for growth, reproduction and glucose regulation in animals. It also influences iron metabolism, increasing its concentrations in the liver. Vitamin B12 and folic acid are also connected to nickel status. These vitamins are important for regulating homocysteine and thus affecting cardiovascular disease risk.

• Estimated daily requirements for nickel have been thought to be 25-35 mcg/d. Doses of 0.6 mg from water can cause skin irritation and rashes. Food sources of nickel include chocolate, nuts, beans, peas and grains. Most diets provide less than 150 mcg/d.

Silicon is a mineral important for connective tissue, blood vessels and bones. Animals deprived of silicon show abnormal cartilage and collagen. Reports since the 1970s suggest deficient silicon intake contributes to hypertension, atherosclerosis, bone disorders, arthritis and Alzheimer’s disease. Silicon might have anti-atheroma activity, reducing the accumulation of plaque in the inner wall of arteries.

• There is no RDA for silicon because of limited data. Athletes are recommended to get 30-35 mg/d and non-athletes 5-10 mg/d. Thus, the more physically active you are or the older you are, the more silicon you might need to compensate for the damage to the joints and tendons. On average, people get around 20- 50 mg of silicon a day. Foods that contain silicon include vegetables, high bran grains, oats, fruit and beans. However, you may want to couple that with foods that contain collagen, such as animal meat tendons and ligaments. The vitamin C from plant foods will also help with collagen synthesis.

Cobalt – It is a key component of cobalamin or vitamin B12, which is an essential vitamin. Vitamin B12 deficiency can cause hyper-homocysteinemia, which is associated with cardiovascular disease and Alzheimer’s. Ruminants convert cobalt into vitamin B12 in their stomachs.

• Grazing animals in areas with low cobalt in the soil experience “bush sickness” and other wasting diseases. Cobalamin neuropathy causes nervous system abnormalities. In experimental acrylamide neuropathy, ultra-high doses of vitamin B12 (500 mcg/kg of body weight, intraperitoneally) promotes nerve regeneration in rats.
• Cobalt deficiency can lead to pernicious anemia, which is disease wherein not enough red blood cells are produced due to a vitamin B12 deficiency. It can be treated with oral B12 replacement at doses of 1,000 mcg/d or with injections.
• There is no established RDA for cobalt, but adults are suggested to get 10-20 mcg/d. The upper limit is 250 mcg and therapeutic range 50-100 mcg/d. You can get cobalt from liver, buckwheat, cereal grains, meat, seafood and vegetables.
• The RDA for vitamin B12 is 2.4 mcg. You can get vitamin B12 only from animal foods. Clams and liver are the richest source of vitamin B12 with a dose of 70-84 mcg/3oz serving. Fish like salmon and trout provide 4.8-5.4 mcg/3oz. Nutritional yeast provides around 2.4 mcg of B12 per serving.
• The median lethal dose for soluble cobalt salts is estimated to be 150-500 mg/kg. Soluble cobalt salts are considered possibly carcinogenic to humans. Addition of cobalt compounds to stabilize beer foam in 1966 Canada caused a type of cardiomyopathy called drinker’s cardiomyopathy.

In addition to the ones already mentioned, there are many other trace minerals that play some biological role in the body (bad or good), such as bromine, germanium, rubidium, tin and others. Their requirements, however, are just so small that there is no need to specifically try to increase intake. The toxic heavy metals aluminum, cadmium, arsenic and lead should be avoided, as many of us are getting too much due to environmental contamination. In regard to cadmium toxicity, oysters and scallops are the most contaminated, thus, their intakes should be kept to a minimum.

Chapter 13: Sulfur, Glutathione, and Organosulfur Compounds

Sulfur, after calcium and phosphorus, is the 3rd most abundant mineral in the human body. Elemental sulfur is non-toxic and soluble sulfate salts come packaged in things like Epsom salts, which are typically used in baths for helping with muscle recovery and muscle soreness. Burning sulfur (power plants) creates sulfur dioxide (SO2), which can be harmful to the eyes and lungs in large concentrations. When SO2 reacts with atmospheric water and oxygen, it produces sulfuric acid (H2SO4) and sulfurous acid (H2SO3), which make up acid rain. Sulfuric acid is also a powerful dehydrant that can be used to dehydrate sugar or organic tissue. Sulfuric acid can also be produced in the body by eating sulfur-rich amino acids found in animal protein.

• Sulfur (S) is the chemical element with an atomic number of 16 and a neutral charge.
• Sulfate (SO42-) and sulfite (SO32-) are oxyanions (an oxygen-containing negative ion) of sulfur with a negative charge. Sulfate is a salt found in some foods as well as cleaning products, but sulfite is used for food preservation and processing.
• Sulfur oxide is the smelly substance found in volcanoes and thermal springs, whereas organic sulfur is used by the body to carry out a wide range of processes, especially antioxidant defense.

Historically, sulfur has been used to treat skin conditions, dandruff, improve wound healing and protect against acute radiation. Today, organic sulfur has been seen to improve rosacea and psoriasis. Sulfur springs and water have been known to have therapeutic effects for centuries. Studies show that spa therapy with sulfur water improves osteoarthritis and inhaling aerosolized sulfur containing water improves respiratory conditions. Sulfur-containing foods like broccoli may protect against inflammatory conditions like vascular complications from diabetes and heart disease.

Effects of Sulfur on the Body

Next to hydrogen, CO2 (carbon dioxide) and nitrogen, sulfur was probably one of the first nutrients organisms used as a building block of life and for energy production. These organisms can be divided into sulfur reducing or sulfur oxidizing. Sulfur-reducing anaerobic bacteria are believed to trace back to 3.5 billion years ago, making them one of the oldest living microorganisms on Earth. They obtain energy through a process called sulfate respiration, during which the oxidation of organic compounds or molecular hydrogen gets coupled to the reduction of sulfate.

• Sulfur-oxidizing microorganisms oxidize hydrogen sulfide (H 2 S) into elemental sulfur or sulfate to generate reducing power. Sulfur acts as a signaling nutrient for hydrogen sulfide, which is a colorless gas that has many therapeutic effects when generated in the body. Many invertebrates need sulfur to grow and to avoid some of the potential harmful effects of hydrogen sulfide. At low concentrations, hydrogen sulfide stimulates the electron transport chain increasing energy production.

One of the most important roles of sulfur is serving as a precursor in glutathione synthesis and promoting detoxification. The sulfur amino acids (SAA) methionine and cysteine promote protein synthesis as well as glutathione synthesis. In plants, sulfur partitioning between glutathione and protein synthesis determines growth. Eating a sulfur-rich diet in humans increases glutathione levels and reduces oxidative stress.

• Glutathione regulates prostaglandin biosynthesis and thus has anti-inflammatory effects. It also has detoxifying properties that support liver health. Sulfur baths and sulfur mineral water consumption have been shown to increase antioxidant defense status, lower oxidative stress and improve lipids. Most of the sulfur in our bodies is stored as glutathione in the liver and because inflammation depletes glutathione it will also deplete sulfur.
• Cysteine is the rate-limiting factor in glutathione synthesis and a cysteine deficiency will result in low glutathione levels. Thus, suboptimal cysteine levels can lead to low glutathione and increased oxidative stress. The increased oxidative stress seen in aging is even thought to be the result of cysteine deficiency. Eating more sulfur in the diet can help spare the losses of glutathione.

Defects in Fe-S cluster biogenesis cause numerous mitochondrial issues, anemia and problems with fatty acid and/or glucose metabolism. Mammalian target of rapamycin (mTOR), the body’s master growth pathway responsible for growth, regulates iron metabolism through iron-sulfur cluster assembly. Prolonged elevation of iron-sulfur cluster assembly enzyme (ISCU) protein levels enhanced by mTOR can inhibit iron-responsive element and iron-regulatory protein binding activities that are involved in iron uptake. Thus, sulfur is important for keeping iron levels in check and preventing iron overload. Protein and amino acids that contain sulfur (which also tend to contain the most leucine) are the most mTOR-stimulating food sources that promote growth.

• Under low sulfur amino acid intake, protein synthesis is maintained at the expense of sulfate and glutathione synthesis. Low serum levels of cysteine and glutathione are associated with muscle wasting diseases and mitochondrial damage.

Alzheimer’s disease patients have low levels of sulfur and selenium. These reductions are implicated in the lower glutathione levels seen in these patients and the increased oxidative stress and neuroinflammation, which promote neurodegeneration. Sulfur is also a potent aluminum antagonist that can reduce aluminum accumulation. Aluminum is a neurotoxin and considered a causative factor in Alzheimer’s disease. High amounts of aluminum in the brain tissue are associated with familial Alzheimer’s disease and other neurological disorders.

Connective tissue, the skin, ligaments and tendons require sulfur for proper cross-linking and extracellular matrix proteins like glycosaminoglycans (chondroitin sulfate, dermatan sulfate, keratan sulfate and heparan sulfate). Extracellular matrix proteins are highly sulfonated. They strengthen the bone structure and retain moisturization. Sulfur is needed to make bile acid for fat digestion and is a constituent of bone, teeth and collagen. The hair and nails are made of a sulfur-rich protein called keratin. Sulfur is also a component of insulin and hence is needed for blood glucose regulation.

Vitamin D3 sulfate is a water-soluble form of vitamin D3, unlike un-sulfated vitamin D3, and as a result of that, it can travel the bloodstream more freely without needing to be carried in LDL lipoproteins. Vitamin D3 sulfate has less than 5% of the ability of vitamin D to mobilize calcium from bones and about 1% of the ability to stimulate calcium transport, raise serum phosphorus or cause bone calcification. The form of vitamin D in human milk and raw cow’s milk is vitamin D3 sulfate but pasteurization destroys it.

• The origins of vitamin D3 sulfate are not clear, but a sulphated precursor may be needed for its synthesis. Cholesterol sulfate is considered a potential precursor as it’s widely distributed throughout the body. Instead of being just a metabolic end-product, cholesterol sulfate is found in all cell membranes and epidermal barriers, but mostly in skin tissue. Sunlight hitting the skin also appears to be a source of vitamin D3 sulfate. Regardless, adequate sulfur status is required to make vitamin D3 sulfate.
• Cholesterol sulfate helps to create a barrier against harmful bacteria and fungi in the skin as well as support platelet adhesion. It regulates the gene for a protein called profilaggrin, which is a precursor to filaggrin that protects the skin. By interacting with phospholipids, cholesterol sulfate can stabilize biological membranes. Perhaps it is plausible that for optimal protection against the UV radiation from the sun you need adequate cholesterol sulfate and sulfur from diet.
• During sperm maturation, cholesterol sulfate stabilizes sperm cell membranes. In cultured skin fibroblasts, cholesterol sulfate inhibits sterol synthesis at the level of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting step in cholesterol synthesis. This affects epidermal lipid metabolism. Atherosclerosis may develop because of a cholesterol sulfate deficiency. Cholesterol sulfate is also a substrate for the synthesis of sulfonated steroid hormones, such as pregnenolone sulfate and DHEA sulfate. Vitamin D induces sulfotransferase enzyme SULT2B1b activity, which governs cholesterol sulfurylation.

Sunlight exposure triggering eNOS sulfate production increasing sulfate availability for heparan sulfate proteoglycan (HSPG) synthesis, which buffers against glycation damage and coagulation. Hyperinsulinemia reduces cholesterol sulfurylation into cholesterol sulfate by lowering calcitriol bioavailability, thus contributing to thrombosis seen in COVID-19. Platelets will respond to cholesterol sulfate but not other forms of cholesterol or steroid sulfates under the same conditions. Like vitamin D3 sulfate, cholesterol sulfate is also water-soluble and doesn’t have to be packed in LDL particles to be delivered to tissues. It has been shown that cholesterol sulfate inhibits enzymes involved in blood clotting, such as thrombin and plasmin, which may prevent coagulation in the arteries. Additionally, sulfate promotes oxygen delivery to oxidative phosphorylation dependent cells. Thus, a lack of sulfur in the diet may worsen COVID-19 outcomes by increasing protein glycation and coagulation and reducing tissue oxygenation.

Sulfur is needed for transporting free fatty acids from chylomicrons/VLDL/LDL into the capillary endothelium. Lipoprotein lipase (LPL), which is an enzyme that governs the uptake of free fatty acids from lipoproteins into cells, works with heparan sulfate proteoglycans (HSPGs). Abnormal or dysfunctional LPL expression is associated with various conditions like atherosclerosis, hypertriglyceridemia, obesity, diabetes, heart disease, stroke, Alzheimer’s and chronic lymphocytic leukemia. A low sulfur intake could lead to a decrease of free fatty acids into tissues that express LPL, such as the heart, skeletal muscle and brown adipose tissue, leading to an increase in free fatty acids in the blood and reduced supply to these tissues for energy.

Glucose can enter the cells through specific cholesterol-rich sites in the cell wall called lipid rafts that also control GLUT-4’s actions. GLUT4 is a receptor that sits on our cellular membranes to bring glucose into muscle cells. Cholesterol sulfate in the cell membrane reduces the risk of oxidation. Overconsuming refined glucose and fructose can promote the formation of advanced glycation end products (AGEs) that are associated with cardiovascular disease, diabetes and aging.

• Hyperglycemia increases AGEs and the production of reactive oxygen species. The conversion of glucose into fat storage also glycates the fat cells and damages them. As a result of that, cholesterol can’t be transported to the membrane and it accumulates in the cell, leading to macrophage accumulation that contributes to atherosclerosis and thrombosis.
• Sulfur can be in oxidation states ranging from -2 to +6. If glucose gets reduced by sulfur +6, it will prevent glycating the muscle cells and protect against AGEs.
• Sulfate ions attached to oxidized cholesterol have been shown to be protective against atherosclerosis. Glutathione, the sulfur antioxidant, also eliminates AGEs and AGEs are more dangerous when glutathione levels are low.

Here are the sulfur-dependent enzymes, functions and consequences that may occur with deficient sulfur intake:

Sulfur-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Glutathione: Protects against oxidative stress and inflammation: Increased oxidative stress and reduced immunity
• Nrf2/ARE: Promotes glutathione synthesis and other antioxidants: Increased oxidative stress and reduced immunity
• Heparan Sulfate Proteoglycans (HSPGs): Anticoagulation and protection against glycation damage: Increased risk of thrombosis and atherosclerosis
• Lipoprotein Lipase: Promotes the uptake of cholesterol and free fatty acids into tissues: Hyperlipidemia, atherosclerosis, and decreased skeletal, muscle/heart function
• S-adenosylmethionine (SAMe): Methylation donor, wide enzymatic substrate: High homocysteine, inflammation and depression
• Vitamin D3 Sulfate: Hormone production, immune system function, Anticoagulation: Increased risk of autoimmunity, weaker immune system, blood clots
• Cholesterol Sulfate: Stabilizes cell membranes, protects the skin, promotes vitamin D3 sulfate synthesis, platelet adherence, anticoagulation: Increased risk of coagulation, thrombosis and platelet aggregation. Cell membranes more vulnerable to oxidation.
• Hydrogen Sulfide: Cell signaling, antioxidant defense, glutathione: Increased oxidative stress, cardiovascular complications, inflammation
• Methylation: Moves methyl groups around, prevents high homocysteine: High homocysteine, neuronal complications and inflammation
• Endothelial NO Synthase (eNOS): Promotes nitric oxide and endothelial function: Atherosclerosis and hypertension
• Trans-sulfuration Pathway: Mediates glutathione pathways and hydrogen sulfide production: Increased oxidative stress and reduced glutathione

Sulfur-Containing Compounds and Organosulfur Compounds

Sulfur exists in all cells and extracellular compartments as part of the amino acids cysteine and methionine. Covalent bonds of sulfhydryl groups between molecules form disulfide bridges that are required for the structure of proteins that govern the function of enzymes, insulin and other proteins.

Sulfur is also a component of chondroitin in bones and cartilage, thiamine (vitamin B1), biotin (vitamin B7), pantothenic acid (vitamin B5) and S-adenosyl methionine (SAM-e), methionine, cysteine, homocysteine, cystathione (an intermediate in the formation of cysteine), coenzyme A, glutathione, chondroitin sulfate, glucosamine sulfate, fibrinogen, heparin, methallotheionein and inorganic sulfate.

With the exception of thiamine and biotin, all of these substances are synthesized utilizing methionine or cysteine. The vast majority of the sulfur demands of the body are met with methionine and cysteine consumption. Glutathione, taurine, Nacetylcysteine, MSM (methylsulfonylmethane) and inorganic sulfate can spare the dietary need for methionine and cysteine.

Here is an overview of the effects of sulfur containing compounds:

• Glucosamine Sulfate – Glucosamine sulfate is an amino-monosaccharide (a combination of glutamine and glucose). It is required for cartilage glycosaminoglycan (GAG) synthesis. Glucosamine has many trials showing efficacy for osteoarthritis. It has been found that glucosamine supplementation was associated with a 39% reduction in overall mortality among 16,686 U.S. subjects. Among 466,039 participants without cardiovascular disease in the UK, habitual glucosamine use was linked to a lower risk of cardiovascular disease events.
• Chondroitin Sulfate – Chondroitin sulfate is found in human cartilage, bone, skin, cornea and the arterial wall. It is believed to increase water retention and elasticity in cartilage. Sulfur in the diet provides sulfates for glycosaminoglycan synthesis and glutathione in cartilage.
• Glutathione – Glutathione is the main antioxidant that regulates free radicals, immunity and redox homeostasis. A low protein diet with inadequate sulfur amino acids can induce a glutathione deficiency. Cysteine and Nacetylcysteine are glutathione precursors.
• Cysteine – Oral cysteine supplementation increases glutathione levels. It can also chelate certain trace minerals and alleviate potential heavy metal toxicity.
• N – acetylcysteine (NAC) – Oral NAC increases intracellular cysteine and glutathione levels. Administration of the glutathione precursor Nacetylcysteine increases glutathione synthesis and improves hydrogen sulfide clearance. NAC can increase the release of histamine from mast cells and peripheral mononuclear blood cells and lower nitric oxide levels. In certain susceptible individuals this may increase the contraction of the pulmonary vascular bed leading to what’s commonly referred to as “wheezing in the lungs”. Thus, NAC is not for everyone, and supplementation may need to be cycled on and off or necessitate the administration of nitric oxide boosters (beetroot powder, dietary nitrates, citrulline/arginine) and/or antihistamines.
• Taurine – Taurine regulates detoxification, bile acid conjugation, membrane stabilization and cellular calcium modulation. It is important for muscle contractions, energy production, hydrogen sulfide synthesis and more.
• Alpha – Lipoic Acid (ALA) – ALA regulates antioxidant activity and oxidative stress. It has also been shown to increase CoQ10 and glutathione levels. ALA also activates Nrf2.
• Dimethyl Sulfoxide (DMSO) – DMSO can scavenge free radicals and pass-through membranes easily. It can also protect against the breakdown of joint tissue in inflammatory arthritic conditions.
• Methyl-sulfonyl-methane (MSM) – In humans, MSM is used to treat arthritic conditions, muscle pains, allergies and for immunomodulation, although its effectiveness is not considered clinically significant. MSM inhibits inflammation through suppressing NLRP3 inflammasome activation. It has been found to be safe and effective for hemorrhoids. In mice, MSM can be therapeutic against obesity-induced metabolic disorders, such as hyperglycemia, hyperinsulinemia and insulin resistance.
• S-adenosylmethionine (SAMe) – SAMe is a metabolite of methionine and an important methyl donor that can lower homocysteine. The body can make all the SAMe it needs from methionine, but defective methylation or inadequate consumption of SAMe cofactors (methionine, choline, folate) would reduce SAMe production. SAMe also increases the production of hydrogen sulfide.
• Methionine – Methionine is one of the main protein-creating amino acids needed for methylation and protein synthesis. As a methyl donor, it helps to prevent fatty liver. AIDS patients have low methionine, and it can be effective for treating Parkinson’s disease and acute pancreatitis.

Eating a half of an onion or more per day may lower the incidence of stomach cancer. In Northeast China, consumption of fresh cabbage and onions is inversely associated with brain cancer risk. More than one serving of garlic per week is inversely associated with the risk of colon cancer in postmenopausal women. Onion and garlic also possess antidiabetic, antibiotic, cholesterol-lowering and fibrinolytic effects. Garlic can lower mild hypertension and blood lipids, potentially reducing the risk of cardiovascular disease. Allium-containing vegetables like garlic, shallots and onions can raise glutathione levels via their organosulfur compounds.

• To activate the beneficial compounds of garlic, you have to first crush it and let it sit for a few minutes. Heat inactivates the enzyme alliinase (which catalyzes the synthesis of allicin), reducing the beneficial effects of garlic. An in vitro study found that heating or boiling inhibited the anti-platelet aggregation properties of crushed and uncrushed garlic, but the crushed garlic maintained more of its anti-aggregatory activity compared to uncrushed garlic. Microwaving uncrushed garlic for 60 seconds or for 45 minutes in a regular oven blocks the DNA damage protective effects against a carcinogen in rats. Some of garlic’s beneficial compounds can be retained if you crush it and leave it out in the open for 10 minutes before heating.

Sulforaphane (SFN) is another sulfur-containing compound that has a long record of health benefits. Research has shown sulforaphane to be beneficial in managing Type-2 diabetes, improving blood pressure, Alzheimer’s disease, liver detoxification, LDL cholesterol, the immune system, bacterial and fungal infections, inflammation, liver functioning, brain derived neurotrophic factor (BDNF) and may reduce cancer risk. A lot of these effects are mediated by increased glutathione production as SFN promotes glutathione synthesis through the activation of the Nrf2/ARE antioxidant defense system. Sulforaphane is produced when we eat cruciferous vegetables like broccoli, cauliflower, cabbage and Brussels sprouts. Eating cruciferous vegetables have been shown to raise glutathione S-transferase activity (a family of phase II detoxification enzymes), which binds glutathione to a wide variety of toxic compounds for their elimination.

• Sulforaphane primarily inhibits Histone Deacetylase (HDAC), which is a group of enzymes that interact with DNA. HDAC deacetylases or unravels DNA proteins called histones that keep it compact. Sulforaphane inhibits HDAC enzymes, which increases the activity of another pathway called Nrf2. This stimulates the production of important antioxidants like glutathione, thioredoxin, and NQO-1. The same HDAC inhibition leads to the activation of autophagy as well. Sulforaphane promotes energetic stress, autophagy, and cell death. It will kill both cancerous cells but may scavenge some weaker healthy cells in the process.
• SFN causes mild oxidative stress, lipid peroxidation, and generates ROS, which are considered to be a part of its chemo-protective properties by up-regulating glutathione and autophagy. Excessive sulforaphane can cause some genome instability and over-activation of white blood cells. In mice, sulforaphane increases the susceptibility to seizures and other symptoms of toxicity. However, that was done with a dose at 200 mg/kg, which is pretty hard to reach by eating just vegetables or broccoli. The optimal intake of sulforaphane is around 20-40 mg/day in humans.
• When certain plants get damaged from either chewing or cutting, they produce myrosinase that transforms glucoraphanin into sulforaphane. After this process, SFN starts to degrade quite rapidly. Cooking at temperatures below 284˚F (140˚C) also produces sulforaphane but higher temperatures start to destroy it. Adding mustard seeds to cooked broccoli increases the bioavailability of sulforaphane.
• Sprouting cruciferous vegetables increases their glucoraphanin content by 10-100 times. Broccoli sprouts are the highest in glucoraphanin and sulforaphane. Raw cruciferous vegetables, if overconsumed, can inhibit iodine absorption because of the goitrogens. Uncooked Brussels sprout juice in rats causes DNA damage and apoptosis or programmed cell death. Thus, it is better to cook or steam your vegetables slightly to get the best benefits but not overcook them.

A small amount of sulfur can be obtained from the organosulfur compounds found in foods like broccoli, garlic and onions. However, the actual content of sulfur in a food depends on the soil quality.

Whole foods appear to be a more bioavailable source of sulfur than supplements. A study found that sulfur-methyl-L-methionine (SMM) from kimchi was more bioavailable than SMM by itself and it led to better digestion. Fresh vegetables and plants also contain more organosulfur compounds than processed foods. Taurine, which spares cysteine and hence the utilization of sulfur in the body for other functions, is found in animal foods but not in plants.

Benefits of Hydrogen Sulfide (H2S)

Overproduction of H 2 S is implicated in cancer, whereas deficiency can cause vascular disease. Hydrogen sulfide is involved in multiple cell signaling processes, such as the regulation of reactive oxygen species, reactive nitrogen species, glutathione and nitric oxide:

Hydrogen sulfide has cardioprotective effects that prevent atherosclerosis and hypertension. Hydrogen sulfide has vasorelaxant effects and acts as an endogenous potassium-ATP channel opener. H 2 S stimulates endothelial cells to facilitate smooth muscle relaxation. Disrupted H2S production has been suggested to promote endothelial dysfunction.

• Hydrogen sulfide enhances the effects of nitric oxide by increasing endothelial NO synthase (eNOS). H 2 S and nitric oxide are mutually dependent in regulating angiogenesis and endothelium-dependent vasorelaxation. Formation of NO and H 2 S creates a novel compound called nitrosothiol that has vasodilating effects. The cytoprotective effects of hydrogen sulfide are dependent of nitric oxide. Thus, you need sufficient NO and the minerals required for its synthesis to gain the benefits of H 2 S. Next to carbon monoxide and nitric oxide, hydrogen sulfide is thought to be the third biological gas. The benefits on vasoactivity of garlic are also mediated by H2S, which is a food relatively high in sulfur.
• Hydrogen sulfide is an endogenous stimulator of angiogenesis or the growth of new blood vessels. Patients with coronary artery occlusion or multi-vessel lesions have lower H 2 S levels. In mice and human umbilical vein endothelial cells, H 2 S exerts antiatherogenic effects. It also protects against endoplasmic reticulum stress. Some of the cardioprotection is also mediated through Nrf2 signaling. Hydrogen sulfide alleviates myocardial ischemia-reperfusion injury by maintaining mitochondrial function.
• Hydrogen sulfide plays a role in kidney homeostasis and may provide kidney protection. It affects glomerular filtration and sodium reabsorption. H₂S regulates blood pressure and vascular tone through activating the renin angiotensin aldosterone system (RAAS). During renal hypoxia, H₂S can help to restore oxygen balance by increasing blood flow to the medulla. Tubulointerstitial hypoxia has been recognized as the final pathway from chronic kidney disease (CKD) to end stage renal disease (ESRD). Sodium hydrogen sulfide (NaHS) has been shown to attenuate fibrosis and inflammation in obstructive kidney disease at doses starting at 5.6 mcg/kg/d and optimally at 56 mcg/kg/d.

H2S may have neuroprotective effects by increasing glutathione and suppressing oxidative stress. There is a high level of hydrogen sulfide in the brain and it may act as an endogenous neurotransmitter. H 2 S might be able to scavenge peroxynitrite and prevent oxidative stress, especially in the brain where there is low extracellular glutathione. In mice and rats, H 2 S is released from bound sulfur in neurons and astrocytes. Alzheimer’s patients have lower hydrogen sulfide levels in the brain.

Hydrogen sulfide is involved in cell-death and inflammatory signaling as an endogenous mediator. Elevation of H 2 S accompanies inflammation, infection and septic shock. Inhibiting H 2 S production contributes to the gastric injury caused by nonsteroidal anti-inflammatory drugs (NSAIDS).

• Endogenous gases (CO, NO, H2S) regulate mitochondrial biogenesis during inflammation and oxidative stress. Hydrosulfide anions HS – (80% of H 2 S dissociates to HS – in the extracellular space but are essentially equal in the cell) are strong reducing agents of reactive oxygen species. In cardiomyocytes, hydrogen sulfide activates Mn-SOD and Cu,Zn-SOD and decreases ROS during ischemia/reperfusion. However, in the presence of oxygen (O 2), H 2 S can generate free radicals.
• Nitric oxide and hydrogen sulfide protect gastrointestinal integrity and promote ulcer healing. However, H₂S produced by gut microbes is associated with ulcerative colitis, Crohn’s disease and irritable bowel syndrome. Thus, having an overabundance of bacteria that produce H2S in the gut could be detrimental.

Hydrogen sulfide has a beneficial effect on longevity and lifespan. Nematodes that live in an environment of 50 ppm H 2 S exhibit higher thermotolerance and a 70% longer lifespan. They also have higher antioxidant and stress response gene activity. In bacteria, endogenous hydrogen sulfide and nitric oxide protects against antibiotic-induced oxidative stress and death. In mice, H 2 S exposure inhibits cytochrome c oxidase, lowers metabolic rate and body temperature, putting them in a suspended hibernation state. Calorie restriction is one of the few known ways of reliably extending lifespan in virtually all species. Endogenous production of hydrogen sulfide appears to be essential for the benefits of restricting calories by mediating the enhanced stress resistance. However, humans who are chronically exposed to exogenous sources of hydrogen sulfide from working in an industrial setting show signs of accelerated aging.

Hydrogen sulfide gets synthesized by three enzymes: cystathionine γ-lyase (CSE), cystathionine β- synthetase (CBS) and 3-mercaptopyruvate sulfur-transferase (3-MST). CSE and CBS go through the trans-sulfuration pathway during which a sulfur atom gets transferred from methionine to serine, forming a cysteine molecule. Thus, dietary amino acids like methionine and cysteine are the main substrates in the production of hydrogen sulfide. They are also needed for glutathione and taurine synthesis.

After consumption, methionine reacts with adenosine triphosphate (ATP) with the help of methionine adenosyltransferase to produce S-adenosylmethionine (AdoMet), a universal transmethylation methyl donor. The transfer of AdoMet creates Sadenosylhomocysteine (AdoHcy), which gets rapidly hydrolyzed into adenosine and homocysteine by AdoHcy hydrolase. Homocysteine can be either methylated into methionine or used to synthesize cysteine and hydrogen sulfide. About 50% of the methionine taken up by hepatocytes gets regenerated. The remaining 50% is metabolized by the trans-sulfuration pathway.

• In the first step of the trans-sulfuration pathway, homocysteine is condensed with serine to form cystathionine by cystathionine β-synthase (CBS). Then, cystathionine is cleaved into α-ketobutyrate, ammonia and cysteine by cystathionine γ-lyase (CSE). Cysteine cannot be converted back into methionine by mammals, making methionine an essential amino acid. However, cysteine can be created from methionine via the trans-sulfuration pathway.

The trans-sulfuration pathway is present in many tissues, such as the kidney, liver and pancreas. It does not appear to take place in the spleen, testes, heart and skeletal muscle. Inhibition of the trans-sulfuration pathway results in a 50% decrease in glutathione levels in cultured cells and tissues. Oxidative stress can activate the trans-sulfuration pathway and antioxidants downregulate it. The synthesis of glutathione from cysteine depends on ATP and thus magnesium.

Sulfates and Sulfites

Sulfites are food preservatives derived from sulfur added to packaged foods, hair colors, topical medications, eye drops, bleach and corticosteroids to prevent spoilage. They can also develop naturally during fermentation, such as in sauerkraut, kimchi, beer or wine. Thus, alcohol can be a significant source of sulfites, which in excess can promote inflammation and gastrointestinal problems. About 1% of people, and 3-10% of asthmatics, are sulfite sensitive and they experience swelling, rashes, nausea and possibly seizures or anaphylactic shock when consuming large amounts of sulfites. Some people are allergic to sulfur and sulfur-containing foods like garlic or eggs, causing them to experience swelling, rashes and low blood pressure.

Sulfate is a source of sulfur for amino acid synthesis. Sulfate-reducing bacteria in the gut can promote ulcerative colitis through hydrogen sulfide. Patients of ulcerative colitis have elevated levels of fecal sulfide and sulfate-reducing bacteria. Sodium sulfate supplementation has been shown to stimulate the growth of sulfate-reducing bacteria. Excess sulfide can overburden the detoxification systems, impairing butyrate oxidation and causing colonic epithelial inflammation.

Gastrointestinal absorption of sulfate happens in the stomach, small intestine and colon. The absorption process is sodium-dependent. Heat and cooking reduce the digestibility of cysteine because heating oxidizes cysteine into cystine, which is absorbed more poorly. More than 80% of oral sulfate taken as soluble sulfate salts like sodium sulfate or potassium sulfate gets absorbed. Insoluble sulfate salts like barium sulfate barley get absorbed. The sulfate that does not get absorbed in the upper gastrointestinal tract will be passed to the large intestine and colon where it is either excreted in the feces, reabsorbed or reduced to hydrogen sulfide.

Getting Enough Sulfur-Containing Amino-Acids from the Diet

About 89% of sulfur amino acids are obtained as cystine, which is the oxidized disulfide of cysteine. Ingesting ample amounts of cysteine will also have a sparing effect on methionine. Safe minimum methionine requirements in the presence of excess dietary cysteine have been found to be 5.8-7.3 mg/kg/d compared to the 12.9-17.2 mg/kg/d in the absence of dietary cysteine (a 55-58% sparing effect).

Sulfur amino acids are not maintained in the body for the long-term. They either get excreted through urine, oxidized into sulfate or stored as glutathione. Sulfur is excreted primarily as sulfate with urinary sulfate reflecting the overall intake of sulfur from inorganic sources or amino acids. The 24-hour urinary excretion of urea, the final end-product of protein metabolism, reflects the 24-hour urinary excretion of sulfate because methionine and cysteine are the primary sources of body sulfate stores. Urinary sulfate excretion is inversely associated with all-cause mortality in the general population with higher excretion rates linked with mortality.

Many drugs used in the treatment of joint diseases and pain like acetaminophen require a lot of sulfate for their excretion. Up to 35% of acetaminophen is excreted conjugated with sulfate and 3% is conjugated with cysteine. The rest is conjugated with glucuronic acid, which is a major component of glycosaminoglycans that is essential for the integrity of cartilage. Thus, acetaminophen depletes the body of sulfur. Added methionine or cysteine can overcome methionine deficiency induced by acetaminophen.

Current research has seen that the maximum effects of protein on muscle growth appears to be around 0.8-1.0 grams of protein per pound of lean body mass, which would be roughly 1.0-1.2 grams per pound of total body weight.

Glutathione status is compromised in various disease states and an increased supply of sulfur amino acids can reverse many of these changes. A restriction in dietary sulfur amino acids slows down the rate of glutathione synthesis and diminishes its turnover. Fruit and vegetables contribute up to 50% of dietary glutathione, whereas meat contributes 25% for an average diet. Direct food sources high in glutathione are freshly prepared meat, fruit and vegetables are moderate sources and dairy and cereal are low in glutathione. Freezing foods maintains relatively the same amount of glutathione as fresh food, but other preservation methods, such as fermentation or canning, lead to extensive losses. Whey protein is also a good source of cysteine and hence glutathione and has been shown to lower oxidative stress. Milk thistle can raise glutathione levels and has antioxidant properties. Turmeric and curcumin can also promote glutathione synthesis and inhibit inflammation.

Excess methionine intake may lead to harmful side-effects, such as brain lesions and retinal degeneration, especially if not balanced with glycine intake. High dietary methionine intake (5-6 g/d compared to the 1-1,2 g RDA) can also raise homocysteine levels, even on top of adequate B-vitamin intake.

Methionine restriction (MR) is thought to increase lifespan and slow down aging. Additionally, it’s possible that those effects can happen without caloric restriction, which so far is the only known way of lengthening life in many species. Restricting methionine in Baker’s yeast extends their lifespan, which was accompanied by an increase in autophagy. However, when autophagy genes were deleted, the extension in lifespan was also prevented. It’s thought that restricting just protein can give the same effect on life-extension than caloric restriction without needing to restrict calories.

• Compared to caloric restriction, protein restriction does not contribute to the benefits of caloric restriction. The benefits of reduced protein intake are caused primarily by decreased caloric consumption. Restricting protein and methionine may actually cause other problems related to poor detoxification, methylation and glutathione synthesis. Improper methylation is linked with autoimmune conditions.
• Loss of methionine promotes the greying of hair. Methionine and cysteine are also important for alleviating oxidative stress.
• Furthermore, glycine supplementation has been found to have the same effects on life-extension as methionine restriction. Glycine is found in organ meats, ligaments, drumsticks, skin and collagen supplements. Bone broth or chicken soup (especially ones that contain collagenous meats), rich in glycine, glucosamine and sulfur, has been found to lower inflammation, infections and reduce joint pain.

Methionine and cysteine are the most widespread sulfur amino acids that support glutathione and protein synthesis. A low intake of them can promote muscle wasting and inflammation.

• The minimal optimal intake of sulfur amino acids per day is roughly 3.0 grams, but this demand increases up to 5.0 grams during disease states and/or injury. Generally, you can obtain that amount from eating 0.6-1.0 grams of protein per pound of body weight every day. To prevent the negative side-effects of excess methionine, ensure an adequate intake of B vitamins and glycine (3-5 grams per meal) or get your protein from glycine-rich organ meats/tendons/ligaments.
• Organosulfur compounds in allium vegetables like garlic and onions are also beneficial for the body’s antioxidant systems. They may have protective effects on cardiovascular disease and cancer. Eating only a half of an onion per day and a single serving of garlic per week may be enough to provide the benefits.
• Sulforaphane-containing vegetables like broccoli and cabbage give an additional boost in glutathione and anti-cancer defenses. To activate the beneficial compounds, you have to cut and slightly cook the vegetables at temperatures below 284˚F (140˚C). Eating cruciferous raw will begin to inhibit iodine absorption and promote hypothyroidism. How many vegetables you need to eat is hard to know but the general recommendation of 3-5 cups of vegetables a day should be more than enough. You also have to pay attention to how you individually react because sulforaphane may cause digestive problems for some people.

In conclusion, sulfur is a central mineral for the body’s detoxification and antioxidant defense systems. It is needed for preventing oxidative stress-related conditions like atherosclerosis, cardiovascular disease, neurodegeneration, arthritis and aging in general.

Chapter 14: Chromium and Blood Sugar Management

Type-1 diabetes is an autoimmune disorder with a genetic basis wherein the pancreas produces almost no insulin. Without treatment, blood sugar can stay continuously elevated in Type 1 diabetics. Type 2 diabetes is where the body becomes resistant to the effects of insulin. In other words, the body can make insulin, but it doesn’t respond to it as well.

Diabetes increases the risk of cardiovascular disease and stroke by up to 1.8 to 6-fold. Nearly 50% of diabetics die due to cardiovascular disease. Diabetes is also the leading cause of kidney disease and kidney failure.

Diabetic retinopathy can cause blindness and impaired vision, whereas diabetic neuropathy in the limbs can lead to a lack of feeling in the extremities resulting in untreated wounds, which can lead to amputation. Furthermore, diabetes is associated with impaired cognition and neurodegenerative diseases like Alzheimer’s disease.

The first sign of Type 2 diabetes is hyperinsulinemia. However, this can only be picked up by measuring insulin levels after an oral glucose tolerance test, which most doctors do not order. Thus, by the time someone is diagnosed with having impaired glucose tolerance and/or impaired fasting glucose, they have already lost ~ 50% of their beta-cells that are needed to produce insulin. Both Type 1 and Type 2 diabetes are diagnosed as a fasting blood glucose ≥ 7.0 mmol/l (126 mg/dl) or when plasma glucose after a glucose challenge is ≥ 11.1 mmol/l (200 mg/dl) two hours later. Glycated hemoglobin (HbA1c) of ≥ 48 mmol/mol (6.5%) is another diagnosis method. Symptoms of diabetes include dry mouth, increased thirst, fatigue, hair loss, blurred vision, peripheral neuropathy and frequent urination.

Magnesium deficiency has been implicated in pancreatic beta-cell function, reduced DNA repair capacity, insulin resistance, cardiovascular disease, type-2 diabetes, osteoporosis, hyperglycemia and hyperinsulinemia. Copper, zinc, potassium and sodium are also needed for proper glucose metabolism.

Here are the main causes of Type 2 diabetes and/or impaired glucose intolerance:

• Overconsumption of added sugars and sugar-sweetened beverages
• Overconsumption of omega-6 seed oils
• Overconsumption of hydrogenated fats
• Overconsumption of refined carbohydrates
• Physical inactivity
• Obesity and excess body fat
• Visceral fat accumulation
• Low magnesium
• Low chromium
• Smoking and tobacco
• Persistent organic pollutants and plastics
• Lack of sleep and sleep deprivation
• Testosterone deficiency
• Low vitamin D levels

Chromium Benefits

Chromium 3+, or trivalent chromium, was found to be the main active component of the ‘glucose tolerance factor’ in rats that alleviated their glucose intolerance caused by high sucrose consumption. In diabetic patients, chromium-enriched yeast can decrease fasting blood glucose and insulin. Chromium is required for the binding of insulin to the cell surface so it can exert its effects. However, chromium appears to require the synergy with nicotinic acid to work in lowering blood sugar through the glucose tolerance factor. GTF enhances the activity of insulin.

The most recent adequate intake (AI) for chromium in the U.S. has been set at 25-35 mcg/d for adults. To reach the 1 mcg/d recommendation you would have to ingest about 33-100 mcg/d. In 1980, the Estimated Safe and Adequate Daily Dietary Intake (ESADDI) for chromium was set at 50-200 mcg/d for adults. According to the World Health Organization, an approximate chromium intake of 33 mcg/d is likely to meet normal requirements. In Australia and New Zealand, the AI for chromium is 35 mcg/d for men, 25 mcg/d for women, 30 mcg/d for pregnant women and 45 mcg/d for lactating women.

Chromium supplementation does not appear to improve insulin sensitivity in healthy non-obese people.

The current understanding is that chromium binds to an oligopeptide to form chromodulin that activates the insulin receptor to mediate the actions of insulin. Chromodulin stimulates insulin-dependent tyrosine kinase activity that activates the insulin receptor. Thus, chromodulin functions as an amplifier of insulin signaling. Another oligopeptide called low-molecular-weight chromium-binding substance (LMWCr) carries chromium around the body as a second messenger for insulin signaling.

Because of its effects on insulin and glucose metabolism, chromium is thought to help with polycystic ovary syndrome (PCOS), which is characterized by insulin resistance and dyslipidemia. Chromium supplementation of 200-1,000 mcg/d for 8-24 weeks has not been found to have a significant effect on fasting glucose, but it did lower fasting insulin and bodyweight. Among diabetic PCOS patients, chromium supplementation improved HOMA-IR scores (a marker of insulin resistance). However, due to mixed results, more studies are needed.

By increasing insulin sensitivity, chromium supplementation has also been promoted as a way to increase muscle mass and athletic performance. With higher insulin action, nutrients would be stored and utilized faster, which is why bodybuilders use injectable insulin. The potential benefits of chromium on muscle anabolism are thought to be marginal, however, many athletes are thought to be deficient in this nutrient. If not deficient, the effects appear negligible.

Athletes who train at an intense level and sweat for around 60 minutes per training session, should consider supplementing with an extra 600 mcg of chromium picolinate (which has a 1.2% bioavailability, providing 7.2 mcg of chromium) or another chromium supplement with a similar bioavailability (such as Brewer’s yeast chromium) on exercise days.

• Diets high in simple sugars increase urinary chromium excretion by 300%. Athletes tend to consume more simple sugars to fuel their workouts and for post-exercise glycogen replacement. This would lead to further chromium losses out the urine and increase the risk of chromium deficiency.
• Caffeine or coffee may increase urinary chromium losses. Thus, it may not be a bad idea for those consuming caffeine/coffee to get extra chromium in their diet.

A prospective study involving 3,648 subjects found an inverse association between the occurrence of metabolic syndrome and toenail chromium concentrations. Low toenail chromium concentration has also been associated with an increased risk of a heart attack. In Korean males, insulin resistance is associated with lower chromium hair concentrations and higher Ca/Mg ratio. Type 1 and Type 2 diabetes are correlated with blood chromium deficiency.

Here are the chromium-dependent enzymes, functions and consequences that may occur with deficient chromium intake

Chromium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Glucose Tolerance Factor (GTF): Enhances insulin activity: High blood sugar, reduced muscle gains
• Chromodulin: Activates the insulin receptor: High blood sugar, insulin resistance & reduced muscle gains
• Tyrosine Kinase: Activates the insulin receptor: High blood sugar, insulin resistance & reduced muscle gains
• Low-Molecular-Weight Chromium- Binding Substance (LMWCr): Carry chromium around the blood, mediate insulin signaling: Elevated blood sugar, insulin resistance and reduced muscle gains
• Glycolytic Flux: Conversion of glucose into pyruvate and ATP: Glucose intolerance, metabolic inflexibility, lactic acid accumulation and lack of energy
• Superoxide Dismutase: Removes superoxide anions: Increased tissue damage & oxidative stress
• Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
• DNAzymes: RNA cleavage, catalyst of enzymes: Inadequate enzymatic reactions

Chromium Foods

Chromium is found in many foods, starting with meat and ending with vegetables. Many medicinal plants like sand immortelle, foxglove, Alexandrian laurel, Greek valerian, marsh cudweed, adenostilis and lobelia have high amounts of chromium. However, not all chromium in foods has glucose tolerance factor (GTF) and thus total chromium content may not be a valid indicator of the insulin sensitizing benefits of a given food.

Foods with the highest amount of chromium as GTF are brewer’s yeast, black pepper, liver, cheese, bread and beef, whereas the lowest ones are skim milk, chicken breast, flour and haddock. Supplementation with 9 grams of Brewer’s yeast per day for 8 weeks can improve impaired glucose tolerance, reduce serum cholesterol and lower the insulin response to a glucose load in humans. Polyphenolic herbs and spices like cinnamon have also been shown to improve insulin sensitivity together with chromium.

The richest sources of chromium are mussels and oysters, probably because of environmental contact. Fresh water fish living in areas of stainless-steel manufacturing, chrome plating or rubber processing have nearly 5 times more chromium than normal. They also get more of the toxic hexavalent chromium, which causes mutagenic gene damage.

Refining grains and wheat reduces the amount of chromium by up to 8-fold. Peeling apples and eating them without the skin reduces their chromium content by 70% (from 1.4 mcg to 0.4 mcg per apple).

Human milk also contains small amounts chromium, which ranges from 0.25-60 mcg/L, depending on the nutrient and lactation status of the mother. Infants of less than 6 months of age need less than 0.5 mcg/d of chromium. Finnish infants who are exclusively breast-fed and get 0.27 mcg/d of chromium do not show any abnormalities. Exposure to excess environmental chromium during pregnancy increases the risk of delivering low birth weight babies. Chromium levels in the body are higher at birth than later in life, which might explain why infants need much less chromium.

In deficiency the body tends to shut down urinary/fecal losses and increase mineral absorption. Thus, it may appear that someone is in positive mineral balance (less urinary/fecal losses than what is being absorbed) but this may actually indicate mineral deficiency. This is why you typically need to give an oral or IV loading dose of a mineral to see how much gets excreted out in the urine (at least for minerals that are regulated by the kidney) to determine deficiency. This is because if the body does not excrete much of a high loading dose of a mineral, this suggests a deficiency, as the body is trying to hold onto the mineral.

Chromium can also be obtained from the use of stainless-steel cookware during cooking. Cooking acidic foods like tomato sauce for several hours promotes the leaching of nickel and chromium from the cookware into the food. Preparing fresh meat in a food processor equipped with stainless-steel blades nearly doubles its chromium content and it does so 10-fold for liver after 3 minutes of blending. Canned and processed foods may be higher in chromium than fresh foodstuff because of this reason. The exception is refined white sugar that is incredibly low in chromium, whereas brown sugar and molasses are high in chromium. Consuming refined sugar as it comes in candies, pastries or other processed foods will thus contribute to excretion of chromium, especially if it is not being replaced.

Vitamin C (ascorbic acid) and prostaglandin inhibitors, such as aspirin, increase chromium absorption, whereas antacids and oxalates decrease it. Taking 100 mg of vitamin C together with 1,000 mcg of chromium raises plasma chromium levels more than taking 1,000 mcg of chromium alone. High sugar and fructose intake increases chromium excretion. Simple sugars excrete more chromium than complex carbohydrates. Thus, hyperglycemia and insulin resistance will also promote chromium elevation in blood and its excretion. Diabetics show a 3-fold increase in urinary chromium excretion. Physical exercise, sweating and injury will also promote chromium losses. Infections such as viruses promote the excretion of chromium.

Vitamin C (ascorbic acid) and prostaglandin inhibitors, such as aspirin, increase chromium absorption, whereas antacids and oxalates decrease it. Taking 100 mg of vitamin C together with 1,000 mcg of chromium raises plasma chromium levels more than taking 1,000 mcg of chromium alone. High sugar and fructose intake increases chromium excretion. Simple sugars excrete more chromium than complex carbohydrates. Thus, hyperglycemia and insulin resistance will also promote chromium elevation in blood and its excretion. Diabetics show a 3-fold increase in urinary chromium excretion. Physical exercise, sweating and injury will also promote chromium losses. Infections such as viruses promote the excretion of chromium.

Taking chromium together with insulin can trigger hypoglycemia because of the increased insulin sensitivity. The same applies to metformin or other blood sugar lowering medication.

It is recommended to not take levothyroxine of other thyroid medications with food or together with a chromium supplement. Instead, it would be best to take levothyroxine before eating and chromium at least 2 hours after levothyroxine. Chromium supplementation has been shown to reverse corticosteroid-induced diabetes.

In conclusion, chromium is considered an essential nutrient, especially because of its effects on insulin, glucose and lipid metabolism. However, healthy individuals do not need to deliberately be eating a high chromium diet to prevent metabolic syndrome as there are other more important variables, such as overall energy intake and body composition. Chromium has a more beneficial effect in people who have diabetes, insulin resistance or prediabetes. For them, chromium picolinate supplementation of 200-1,000 mcg/d may improve glycemic control and fasting insulin levels. An adequate consumption of 25-35 mcg/d from whole foods would probably be enough to prevent prediabetes in already healthy subjects but optimally most people would benefit from 33-100 mcg/d. To obtain that amount, you can get the most chromium from animal foods, especially mussels, oysters and lobster, but nutritional yeast and potatoes also have quite a lot. The demand for chromium increases with diabetic comorbidities, exercise and sweating.

Chapter 15: Manganese and Molybdenum: Hidden Players of the Body’s Antioxidant Defense

Manganese has its own superoxide dismutase –manganese superoxide dismutase (MnSOD) – which functions to protect our mitochondria and endothelium from oxidative stress.

Molybdenum is also an interesting mineral that plays a part in a lot of enzymatic reactions in the body, involving detoxification of sulfites, purines and alcohol.

Manganese, MnSOD and the Body’s Antioxidant Defense

Manganese (Mn) is an essential mineral involved in the function of many enzymes, the immune system, blood clotting, bone formation and metabolism. In nature, it is found in combination with iron. Deficiencies in manganese impair growth, lead to skeletal defects, reduce fertility and alter glucose tolerance. Manganese metalloenzymes include arginase, glutamine synthetase, phos-phoenolpyruvate decarboxylase and MnSOD, all of which have an important role in antioxidant defense and metabolic reactions. Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect, which may promote cancer and metastasis.

Manganese deficiency reduces bone mineral density, whereas supplementation improves bone health. Women with osteoporosis have been observed to have lower serum manganese levels than those without osteoporosis.

One of primary functions of manganese is that it makes up Mn superoxide dismutase (MnSOD), which scavenges free radicals and reactive oxygen species (ROS) in the mitochondria, endothelium and even in atherosclerotic plaque.

Atherosclerosis is a disease of chronic inflammation that damages the blood vessel wall and oxidizes LDL cholesterol. Superoxide dismutase protects against the oxidation of lipids. Manganese protects against heart mitochondria lipid peroxidation in rats through MnSOD. MnSOD can reduce oxLDL-induced cell death of macrophages, inhibit LDL oxidation and protect against endothelial dysfunction. There is an association between decreased MnSOD and atherogenesis.

Insulin resistance can be thought of as a cellular antioxidant defense mechanism against oxidative stress in the absence of other antioxidant defense systems, such as manganese superoxide dismutase or glutathione. In other words, a lack of manganese may be a direct cause of insulin resistance.

Manganese is required for creating oxaloacetate from pyruvate via pyruvate carboxylase. In mammals, oxaloacetate is needed for gluconeogenesis, the urea cycle, neurotransmitter synthesis, lipogenesis and insulin secretion.

Oxaloacetate also synthesizes aspartate, which then gets converted into other amino acids, asparagine, methionine, lysine and threonine. During gluconeogenesis, pyruvate is converted first into oxaloacetate by pyruvate carboxylase, which is then simultaneously decarboxylated and phosphorylated into phosphoenolpyruvate (PEP). This is the rate-limiting step in gluconeogenesis. Pyruvate carboxylase is expressed the most in gluconeogenic tissues, such as the liver, kidneys, pancreatic islets and lactating mammary glands.

Arginase is another manganese-containing enzyme and the final enzyme in the urea cycle, during which the body gets rid of ammonia. Arginase converts L-arginine into L-ornithine and urea. Manganese ions are required for stabilizing water and hydrolyzing L-arginine into L-ornithine and urea. Arginase is also involved with nitric oxide synthase. Disorders in arginase metabolism are implicated with neurological impairment, dementia and hyperammonemia. Excess ammonia is not acutely harmful to humans as it will either be converted into amino acids or excreted through urine. However, high ammonia is associated with upper gastrointestinal bleeding in cirrhosis and kidney damage. Urea cycle disorders cause delirium, lethargy and even strokes in adults.

Manganese is a co-factor for glutamine synthetase (GS), which is an enzyme that forms glutamine from ammonia and glutamate. Glutamine is used by activated immune cells. It supports lymphocyte proliferation and helps to produce cytokines by lymphocytes and macrophages. Additionally, glutamine may help people with food hypersensitivities by reducing inflammation on the gut surface. It can thus protect against and repair leaky gut, hence improving immunity. Getting enough glutamine from the diet or by using a supplement may help to protect intestinal epithelial cell tight junctions, which prevents intestinal permeability. Glutamine synthetase is most predominantly found in the brain, astrocytes, kidneys and liver. In the brain, glutamine synthetase regulates ammonia detoxification and glutamate the excitatory neuro-transmitter. Manganese gets in the brain with the help of the iron-carrying protein transferrin, but manganese doesn’t seem to compete with iron absorption.

Acute manganese toxicity causes manganism, characterized by neurological symptoms, mood swings, compulsive behavior and decreased response speed. Manganese overexposure can also impair cardiovascular function and heartbeat. Chronic exposure leads to a more permanent dysfunction that resembles Parkinson’s disease. Unlike Parkinson’s, manganism does not appear to cause a loss of sense of smell and patients do not respond to LDOPA treatment. The neurotoxic effects appear to be caused by disturbed iron and aluminum metabolism and iron overload that causes oxidative stress. Oxidative stress is one of the main factors of manganese-induced neurotoxicity. It is important to note that a lack copper in the body leads to iron overload, which can lead to manganese overload in tissues. Thus, a lack of one mineral, such as copper, can lead to the harmful accumulation and dysregulation of other minerals in the body.

Manganese accumulation in the mitochondria can also cause mitochondrial dysfunction by inhibiting complex I and II. The highest accumulation rate is observed in the mitochondria of astrocytes and neurons compared to other organelles after chronic manganese exposure. Excessive manganese gets excreted out of the mitochondrial lumen through sodium-independent mechanisms, but it gets imported mainly by the calcium uniporter. Manganese inhibits calcium efflux, which increases the probability of mitochondrial permeability transition associated with brain injury and stroke.

Manganese poisoning can occur due to drinking contaminated water or when exposed to the fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) and the pesticide manganese ethylene-bisdithiocarbamate (Maneb). Permanganate (Mn 7+) is much more toxic than Mn 2+ with potassium permanganate having a lethal dose of 10 grams. Mining and processing manganese causes air and water pollution, which threatens the health of workers and local residence, especially in South Africa, China and Australia where most of the world’s manganese is mined from.

The olfactory tract is the most direct pathway for manganese to get into the brain. By using two zinc transporters ZIP8 and ZIP14, it can bypass the blood-brain barrier. Infants have an immature blood-brain barrier, making them more vulnerable to manganese toxicity. MRI studies show that manganese accumulates predominantly in the globus pallidus located in the basal ganglia. Dopamine oxidation by manganese causes oxidative stress. Chronic manganese exposure has been seen to reduce choline levels in the hypothalamus and thalamus.

Here are the manganese-dependent enzymes, functions and consequences that may occur with deficient manganese intake:

Manganese-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Superoxide Dismutase: Removes superoxide anions: Increased tissue and mitochondrial damage and oxidative stress
• Arginase: Participates in the urea cycle to remove harmful ammonia: Ammonia accumulation, kidney damage
• Pyruvate Carboxylase: Converts glucose into oxaloacetate, gluconeogenesis, lipogenesis, neurotransmitter biosynthesis, insulin secretion: Impaired insulin production, low-carb intolerance, ammonia accumulation
• Glutamine Synthetase: Glutamine formation, nitrogen metabolism, ammonia detoxification: Weaker immunity, intestinal permeability, ammonia accumulation, neurotoxicity
• Divalent Metal Transporter 1 (DMT1): Transports ferrous iron, regulates iron homeostasis, absorption and transportation of manganese, binds to divalent metals: Poor iron homeostasis, manganese deficiency
• Transferrin Receptor (TfR): Imports iron into the cell, manganese influx and efflux: Poor iron homeostasis, manganese overload or deficiency

Manganese Food Sources

There is no established RDA for manganese. The estimated safe and adequate daily intake for manganese has been set at 2-5 mg/d. Adequate intakes for adult males are 2.3 mg/d and 1.8 mg/d for females. Men on experimentally manganese-deficient diets (< 0.74 mg/d) have been shown to develop erythematous rashes. Women consuming < 1 mg of manganese per day experience altered mood and increased pain during their premenstrual phase of the estrous cycle. During pregnancy or lactation, the demand for manganese increases to 2.0-2.6 mg/d. Children that are 1-3 years old should get 1.2 mg/d, 4-8 years old 1.5 mg/d and boys 9-13 years old should get 1.9 mg/d and girls 1.6 mg/d. Newborns that are 6 months old or younger should get 0.003 mg/d and 7– 12-month-olds should obtain 0.6 mg/d. The tolerable upper intake levels for manganese have been set at 9-11 mg for adults and 2-9 mg for children 12 months of age or older.

Manganese is found in many foods, including grains, clams, oysters, legumes, vegetables, tea and spices. One of the most commonly consumed sources of dietary manganese are rice, nuts and tea. Dietary and non-experimental manganese deficiency is quite rare, and toxicity occurs mostly due to environmental exposure. Some supplements are also fortified with manganese, ranging from 5 to 20 mg. The amount of manganese in human breast milk ranges from 3-10 mcg/L. Cow’s milk-based infant formulas contain 30-100 mcg/L. Soy-based formulas have the highest concentration of manganese (200-300 mcg/L), which might lead to manganese accumulation. The absorption of manganese from human milk is the highest (8.2%) compared to soy formulas (0.7%) and cow’s milk formula (3.1%).

• Intravenous absorption of manganese, however, is close to 100%, which can cause manganese toxicity. Infants have a much higher absorption and retention of manganese than adults, making them more susceptible to manganism. They also have a higher total amount of manganese in the body than older children and adults. The amount of manganese in the hair of newborn babies increases from 0.19 mcg/g at birth to 0.965 mcg/g at 6 weeks of age and 0.685 mcg/g at 4 months when they’re fed infant formulas. Normal children at age 8 have a hair manganese concentration of 0.268 mcg/g and those with learning disability (hyperactive) have 0.434 mcg/g.

Manganese absorption and influx is mostly mediated by the divalent metal transporter 1 (DMT1) and transferrin receptor (TfR) on the cell surface that also transport other divalent cations, such as iron and calcium. Iron deficiency can increase the risk of manganese poisoning because manganese absorption will increase under low iron states.

• About 75% of the manganese in human milk is bound to lactoferrin. Excess ferric lactoferrin could inhibit the absorption of this manganese complex. The addition of calcium to human milk significantly decreases manganese absorption, while addition of phytates, phosphate and ascorbic acid to infant formulas, as well as iron and magnesium to wheat bread has no significant effect. High manganese intake leads to adaptive changes that include reduced gastrointestinal absorption of manganese, enhanced liver metabolism and increased manganese excretion.
• In adults, 3-5% of manganese is absorbed through the gastrointestinal (GI) tract with women absorbing slightly more than men, possibly due to poorer iron status. After GI absorption, manganese enters the bloodstream and is distributed throughout different tissues. Intravenous administration of manganese bypasses GI regulation and results in 100% of absorption. Aging decreases manganese absorption and retention. Thus, we need more manganese as we get older.
• The primary manganese excretion pathway is biliary secretion. More than 95% of manganese is excreted through bile so the threshold for dietary manganese toxicity is quite high.

Liver damage impairs manganese excretion, causing high levels of manganese in the blood. Patients with portosystemic shunts (also known as liver shunts) and biliary atresia (narrowed or blocked bile ducts) exhibit hypermanganesemia, even without increasing dietary manganese intake.

Lymphocyte manganese is thought to be better than whole blood manganese for measuring manganese deficiency.

Most of blood manganese gets distributed in soft tissue (~60%), with the remainder being in the liver (30%), kidney (5%), pancreas (5%), colon (1%), bone (0.5.%), urinary system (0.2.%), brain (0.1.%) and erythrocytes (0.0.2%). Divalent Mn 2+ is the predominant form of blood manganese and it is complexed with different molecules, such as albumin (84% of total Mn 2+), hexahydrated ion (6%), bicarbonate (6%), citrate (2%), and transferrin (Tf) (1%), whereas almost all trivalent Mn 3+ is bound to transferrin. Mn 3+ is more reactive and gets reduced to Mn 2+ and Mn 2+ can be oxidized to Mn 3+ by ceruloplasmin the active form of copper. Mn 3+, typically coming in the form of manganese (III) fluoride, manganese (III) oxide and manganese (III) acetate, is more effective at inhibiting the mitochondrial complex I. The reduction of Mn 3+ to Mn2 + is mediated by ferrireductase, which helps to avoid oxidative stress.

Tissues with a high energy demand like the brain and liver as well as high pigment regions such as the retina and skin have the highest concentrations of manganese. Approximately 40% of total body manganese is stored in the bones (1 mg/kg). It has been found that the hand bone manganese levels of welders exposed to high manganese environments are significantly higher compared to non-occupationally exposed individuals.

Molybdenum for Fixing Nitrogen and Detoxifying Toxins

Molybdenum cofactors (Moco) are complexed to a pterin, forming molybdopterin, which is a cofactor for many important enzymes in the body including sulfite oxidase, xanthine oxidase, dimethyl sulfoxide (DMSO) reductase, aldehyde oxidase, carbon monoxide dehydrogenase (CODH), nitrate reductase and mitochondrial amidoxime reducing component (mARC). They metabolize sulfur-containing amino acids and heterocyclic compounds, including purines and pyrimidines. Xanthine oxidase, aldehyde oxidase, and mARC also help to metabolize drugs, alcohol and toxins. The only molybdenum enzyme that does not contain molybdopterin is nitrogenases that fix nitrogen (protein) in all life forms. The cofactor for nitrogenase is called FeMoco (iron-molybdenum cofactor) that converts atmospheric nitrogen into ammonia.

Genetic mutations of a molybdenum cofactor deficiency cause an absence of molybdopterin, which leads to the accumulation of sulfite and neurological damage due to lack of sulfite oxidase. Some people with blatant molybdenum deficiency may also have troubles dealing with sulfites in food because of a poorly functioning sulfite oxidase. Molybdenum cofactor deficiency is not the same as molybdenum deficiency.

Molybdenum cofactors cannot be obtained as a nutrient from dietary sources and need to be synthesized by the body (de novo biosynthesis). One of the enzymes that catalyzes this process is radical SAM (an enzyme that uses iron-sulfur clusters to cleave Sadenosyl-L-methionine (SAM) to generate a radical. The other option for molybdopterin, besides molybdenum-sulfur pairing, is to complex with tungsten(wolfram)-using enzymes, which requires selenium for its action.

Here are the molybdenum-dependent enzymes, functions and consequences that may occur with deficient molybdenum intake:

Molybdenum-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Molybdopterin: Molybdenum cofactor used in molybdenum and tungsten containing enzymes: Sulfite accumulation and toxin buildup
• Sulfite Oxidase: Oxidize sulfite and sulfate via cytochrome C, transfer electrons to the electron transport chain and allow the generation of ATP: Sulfite and sulfate accumulation, poor energy production
• Xanthine Oxidase: Break down xanthine and purines into uric acid, generate reactive oxygen species and superoxide: Insufficient ROS signaling, in excess promotes gout
• Dimethyl Sulfoxide (DMSO) Reductase: Catalyze the reduction of dimethyl sulfoxide (DMSO) to dimethyl sulfide (DMS): Excess sulfoxide accumulation
• Aldehyde Oxidase: Oxidize aldehydes into carboxylic acid, eliminate alcohol toxicity: Alcohol toxicity, liver damage
• Carbon Monoxide Dehydrogenase (CODH): Partake in the carbon cycle as a source of energy and fixate CO2: Poor energy metabolism and growth
• Nicotinate Dehydrogenase: Partake in nicotinate and nicotinamide (NAM) metabolism. NAM and nicotoniate are forms of vitamin B3, like niacin and NAD+: Poor energy production, lack of enzymatic reactions.
• Nitrate Reductase: Reduce nitrate to nitrite, which is critical for producing protein in plants: Poor nutritional quality and low protein crops
• Nitrogenase: Fixate nitrogen, facilitate growth, biosynthesis of nucleotides and amino acids: Poor growth, physical deterioration
• Mitochondrial Amidoxime Reducing Component (mARC): Reduce amidoximes to amidines, help with cholesterol metabolism: Poor lipid profile, liver damage

Molybdenum Food Sources

The RDA for molybdenum is 45 mcg/d for adults 19 years of age and older and 43 mcg/d for teenagers 14-18 years of age. During pregnancy and lactation, it is recommended to get 50 mcg/d of molybdenum and for children 9-13 years old 34 mcg/d. Infants from birth to 6 months of age should get 2 mcg/day and from 6 to 12 months of age 3 mcg/d. Children aged 1-3 years of age should get 17 mcg/day and children 4-8 years of age should get 22 mcg/day. The tolerable upper intake level (UL) for adults 19 years of age and older is 2,000 mcg/d. The UL for children 1-3 years old is 300 mcg/d, 4-8 years old is 600 mcg/d, 9-13 years old is 1,100 mcg/d and 14-18 years old is 1,700 mcg/d. Consuming a reasonably high molybdenum diet does not pose a threat to health because it gets rapidly excreted through urine. The minimum requirement for molybdenum for adults is deemed to be 22-25 mcg/d and estimated average requirement is 34 mcg/d.

Low soil concentrations of molybdenum, ranging from Iran to Northern China cause a dietary molybdenum deficiency, which is associated with an increased rate of esophageal cancer. There is no evidence that excess molybdenum causes cancer in humans or animals.

Exposure to prolonged high intakes of molybdenum can raise uric acid levels because xanthine oxidase breaks down purines into uric acid.

Exposure to molybdenum in molybdenum-copper plants can raise serum bilirubin and decrease blood albumin/globulin ratios, which is interpreted to indicate liver dysfunction.

Foods high in molybdenum include legumes, beans, whole grains, nuts and liver. They are also the top sources of molybdenum in the U.S. diet. For teenagers and children, the top sources are milk and cheese. Molybdenum deficiency is quite rare because it can be found in a lot of different foods.

Molybdenum is absorbed at a rate of 40-100% from dietary sources in adults. Soy contains relatively high amounts of molybdenum but is a less bioavailable source (56.7% absorption rate), whereas foods like kale are as bioavailable as other foods (86.1%). Dietary tungsten reduces the amount of molybdenum in tissues and sodium tungsten is a competitive inhibitor of molybdenum.

The human body contains roughly 0.07 mg of molybdenum per kilogram of bodyweight. Molybdenum is stored in the liver, kidneys, adrenal glands and bones in the form of molybdopterin. It is also found in tooth enamel, helping to prevent tooth decay. The ability to synthesize molybdopterin, which is an iron-sulfur and selenium-dependent process, seems to be necessary for retaining molybdenum in tissues.

The kidneys are the main organs regulating molybdenum levels in the body and promote its excretion through urine. Urinary excretion of molybdenum directly reflects dietary molybdenum intake. During low molybdenum intake, about 60% of consumed molybdenum gets excreted through urine and 90% is excreted when molybdenum intake is high. The average U.S. urinary molybdenum concentration is 69 mcg/L. In molybdenum cofactor deficiency and in that single case of molybdenum deficiency, urinary sulfate and serum uric acid were low, but urinary xanthine, hypoxanthine and plasma methionine increased. However, these indicators have not been associated with molybdenum intake in normal healthy people.

Getting Enough Manganese and Molybdenum

Here is a brief overview of the daily requirements:

• The optimal intake of manganese is 2-5 mg/d with a tolerable upper limit of 11 mg/d for adults. Average Western diets may not provide an optimal intake of manganese but eating mussels and oysters once a week can help you reach those levels. Other manganese-rich foods include beans, vegetables, unrefined whole grains, nuts and spices.
• The tolerable upper limit of manganese for children is 3-9 mg/d, which they are not likely to hit eating an average diet, unless they eat a lot of mussels daily. Children 7-12 months old should consume around 0.6 mg/d, which can be obtained from breast milk. Be cautious with manganese-fortified baby formulas.
• The RDA for molybdenum in adults 19 years of age and older is 45-50 mcg/d with a tolerable upper limit of 2,000 mcg/d. Infants should get 2-3 mcg/d, which can be easily obtained from 0.5-0.8 liters of breast milk.
• The highest sources of molybdenum are beans, legumes and liver. Getting enough copper from these foods also prevents copper deficiency that may happen due to excess molybdenum intake. Other minerals needed for molybdenum to work are iron, sulfur and selenium.
• Molybdenum and manganese toxicity and frank deficiency are rare with the former usually occurring because of industrial exposure. Excess manganese and molybdenum are rapidly excreted from the body.

In conclusion, manganese and molybdenum are hidden players in the body’s antioxidant defense system that provide protection against free radicals, oxidative stress and inflammation. It is hard to become deficient in them, but many people are not getting optimal intakes, especially for manganese.

Chapter 16: Eating for the Minerals and Preventing Deficiencies

Optimal Daily Intake of Minerals

Both EPA and DHA can be created by the body by converting the essential omega-3 fatty acid alpha-linoleic acid (ALA) into EPA and DHA. So technically, EPA and DHA are not essential nutrients. However, the conversion of ALA to EPA and DHA in the body is low and taking preformed EPA and DHA has numerous health benefits. Hence, despite the fact that EPA and DHA are not considered ‘essential’, a lack of these nutrients in the diet can lead to poor health, especially during pregnancy, malnourishment, childhood growth and during some diseases. And this is likely to be the case for numerous ‘non-essential’ minerals. In fact, the situation is likely grimmer as there isn’t a mechanism in the body to produce non-essential minerals. Thus, both essential and non-essential minerals must be obtained through diet on a regular basis to maintain optimal nutrient status and health.

7 Macrominerals

Mineral: Health Function: Risk of Deficiency/Excess

• Calcium: Improves bone mineral density. Promotes fat breakdown: Deficiency: osteoporosis, weight gain. Excess: calcification, atherosclerosis
• Chloride: Creates stomach acid, fights infections, maintains electrolyte balance: Deficiency: lack of nutrient absorption, illness. Excess: hypertension, vascular damage, and metabolic acidosis.
• Magnesium: Improves bone mineral density, regulates blood pressure, maintains insulin sensitivity: Deficiency: atherosclerosis, hypertension, insulin resistance, osteoporosis. Excess: diarrhea
• Phosphorus: Improves bone mineral density, glycolysis, gluconeogenesis: Deficiency: osteoporosis, anorexia, rickets. Excess: atherosclerosis, cardiovascular disease
• Potassium: Regulates blood pressure, maintains insulin sensitivity, reduces atherosclerotic lesions: Deficiency: hypertension, atherosclerosis, insulin resistance. Excess: Impaired kidney function, electrolyte imbalance, arrhythmia
• Sodium: Regulates blood pressure, electrolyte balance, transports iodine into the thyroid, transports nutrients into the cell: Deficiency: hypotension, insulin resistance, cramping, hypothyroidism. Excess: hypertension
• Sulfur: Promotes antioxidant systems, cholesterol and vitamin D sulfate, manages inflammation, detoxification, methylation: Deficiency: low glutathione, low protein synthesis, weaker immunity, hypercholesterolemia, atherosclerosis, vascular damage. Excess: gut disturbance, rashes, inflammation, high methionine levels

10 Trace Minerals

Mineral: Health Function: Risk of Deficiency/Excess

• Chromium: Enhances insulin action, improves glycemic control, supports lipid metabolism, lowers blood sugar, supports antioxidant defense: Deficiency: insulin resistance, hyperglycemia, hyperlipidemia, hyperinsulinemia, diabetes. Excess: hypoglycemia, low birth weight in infants, anemia, iron deficiency
• Cobalt: Vitamin B12 function, nerve function and regeneration, myelination and cognition: Deficiency: neuropathy, anemia, muscle wasting, cognitive impairment: Excess: cardiomyopathy, lethal toxicity
• Copper: Regulates iron status, improves lipid profile, maintains glycemic control, supports antioxidant defense, helps with energy production, collagen and soft tissue synthesis, thyroid function, immune system function, reproductive system, kidney health: Deficiency: anemia, cardiovascular disease, atherosclerosis, vascular damage, hyperglycemia, hypothyroidism, iron overload, collagen damage. Excess: Angiogenesis/survival of malignant cells and tumors, inflammation
• Fluoride: Prevents tooth decay, dental mineralization, fights infections: Deficiency: tooth decay, bacterial infections, bone demineralization, weight gain, impaired growth. Excess: cognitive impairment, nausea, abdominal pain, gastrointestinal distress, dental fluorosis
• Iodine: Maintains thyroid function, produces thyroid hormones, supports metabolic health, mental development, immune system function, protects against lipid peroxidation: Deficiency: hypothyroidism, hypogonadism, low energy, frailty, osteoporosis, goiter, hypercholesterolemia, obesity. Excess: autoimmunity, thyroiditis, muscle wasting
• Iron: Tissue oxygenation, regulates oxidative stress, nitrogen fixation, electron transfer: Deficiency: anemia, fatigue, low energy, infection risk, physical deterioration. Excess: atherosclerosis, inflammation, infection risk, organ damage, oxidative stress
• Manganese: Antioxidant defense, MnSOD activity, immune system function, glycolysis, gluconeogenesis, nitrogen metabolism, removes excess ammonia, bone mineral density: Deficiency: atherosclerosis, endothelial dysfunction, insulin resistance, diabetes, kidney damage, cirrhosis. Excess: neurological complications, mitochondrial dysfunction, metabolic syndrome, atherosclerosis
• Molybdenum: Nitrogen fixation, removes excess sulfites, metabolizes toxins and alcohol, metabolizes purines and sulfur: Deficiency: neurological damage, poor physical development, toxin accumulation. Excess: reduces copper absorption, increases urea levels, promotes gout, liver dysfunction
• Selenium: Supports thyroid function, produces thyroid hormones, immune system function, protects against oxidative stress, prevents lipid peroxidation, detoxifies heavy metals: Deficiency: hypothyroidism, weaker immune system, atherosclerosis, oncogenesis, low glutathione, hyperlipidemia. Excess: hyperglycemia insulin resistance, nausea
• Zinc: Immune system function, antioxidant defense, calcification of bone, wound healing, produces thyroid hormones, insulin production glucose metabolism, brain development and plasticity, sex hormone production, melatonin/serotonin production, glutathione synthesis, DNA damage repair: Deficiency: hypothyroidism, hypogonadism, hyperglycemia, atherosclerosis, osteoporosis, mental impairment, weak immunity. Excess: decreased HDL cholesterol, reduced immunity, altered iron metabolism, nausea, diarrhea, cramping

5 Possibly Essential Trace Minerals

Mineral: Health Function: Risk of Deficiency/Excess

• Boron: Brain function, tumor suppression, antioxidant defense, improves vitamin D status, better testosterone/estrogen status, elastase/collagenase activity, anti-osteoarthritic effects: Deficiency: vitamin D deficiency, osteoarthritis, hypogonadism, inflammation, impaired brain function. Excess: gastrointestinal distress, kidney damage, goiter, reduced iodine absorption
• Lithium: Neurotransmitter balance, brain function, mimics the effects of insulin, improves glucose metabolism: Deficiency: depression, increased suicide rate, mental impairment, aggression. Excess: inhibits iodine absorption, gastrointestinal stress, nausea, convulsions, coma, death
• Nickel: Regulates glucose metabolism, regulates homocysteine metabolism, supports reproduction and growth: Deficiency: hyperglycemia, hyper-homocysteinemia, impaired growth, infertility. Excess: rashes and skin irritation
• Silicon: Support connective tissue, blood vessels and arteries, reduces plaque formation, protects against atherosclerosis: Deficiency: atherosclerosis, osteoarthritis, plaque formation, hypertension. Excess: calcification, impaired tissue mobility
• Vanadium: Mimics the effects of insulin, improves glucose metabolism, supports metabolic health: Deficiency: hypothyroidism, depressed fertility and growth, hyperglycemia, insulin resistance. Excess: hypertension, gastrointestinal stress, death

Here is an overview of these same minerals, their recommended dietary sources and recommended daily intakes for adults

7 Macrominerals

Mineral: Recommended Dietary Sources: Optimal/Deficiency/Excess Intake

• Calcium: Milk, cottage cheese, curd, cheese, yogurt, pumpkin seeds, nuts, spinach, sardines with bones, salmon, cartilage, soft ribs: Optimal: 1,000-1,200 mg/d. Deficiency:< 550 mg/d. Excess Intake: >1,500-2,000 mg/d
• Chloride: Sea salt, rock salt, mineral waters, celery, tomatoes, lettuce, meat, olives, fish, seaweeds, kelp, whole grains, beans, legumes: Optimal: 5,200 mg/d. Deficiency: < 1,000 mg/d. Excess Intake: > 7,500 mg/d
• Magnesium: Pumpkin seeds, nuts, legumes, beans, lentils, spinach, chia seeds, salmon, halibut, avocado, dark chocolate, coffee: Optimal: 400-600 mg/d. Deficiency: < 180 mg/d. Excess Intake: > 1,000 mg/d (however some people may benefit from high amounts, i.e., 1,800 mg/day for high blood pressure for example)
• Phosphorus: Sardines with bones, salmon with bones, liver, yogurt, fish, meat, cheese, seafood, beans: Optimal: 750-1,250 mg/d. Deficiency: < 580 mg/d. Excess Intake: > 2,000 mg/d
• Potassium: Potatoes, carrots, apricots, Swiss chard, bok choy, broccoli, cauliflower, collard greens, squash, beans, legumes, strawberries, cherries, blueberries, oranges, apples, seafood, fish: Optimal: 4,000-6,000 mg/d. Deficiency: < 2,400 mg/d. Excess Intake: > 15,000 mg/d
• Sodium: Sea salt, rock salt, mineral waters, celery, tomatoes, lettuce, meat, olives, fish, seaweeds, kelp, whole grains, beans, legumes: Optimal: 3,500 mg/d. Deficiency: < 1,000 mg/d. Excess Intake: > 5-6,000 mg/d (intake will depend on needs and losses, some people will need more than 5,000 mg/d)
• Sulfur: Seafood, fish, eggs, meat, cruciferous vegetables, garlic, shallots, leaks, onions, organ meats: Sulfur-containing amino acids RDA: 13-15 mg/kg body weight. Optimal: 3-4X higher than the RDA. Taking 1 gram of MSM 3X/d for extra sulfur has shown numerous benefits on joint health and allergies

10 Trace Minerals

Mineral: Recommended Dietary Sources: RDA/Deficiency/Excess Intake

• Chromium: Mussels, clams, oysters, brewer’s yeast, broccoli, meat, fish, shrimp, oats, barley, maple syrup, apples with the skin: RDA: 33-50 mcg/d. Optimal: 200-1,000 mcg/d. Deficiency: < 24 mcg/d. Excess Intake: > 1,000 mcg/d
• Cobalt: Liver, seafood, clams, oysters, buckwheat, meat, beef, vegetables: Optimal: 10-20mcg/d. Deficiency: <2.4 mcg/d. Excess Intake: >1g/d
• Copper: Liver, kidneys, mollusks, oysters, beans, lentils, seaweeds, buckwheat, dark chocolate, cocoa powder, potatoes: Optimal: 2.6-3.0 mg/d. Deficiency: < 0.8 mg/d Excess Intake: > 10 mg/d
• Fluoride: Toothpaste, fluorinated drinking water, bottled water, tea, coffee, shrimp, seafood: Optimal: 3-4 mg/d. Deficiency: < 2 mg/d. Excess Intake: > 5 mg/d
• Iodine: Seaweeds, kelp, nori, spirulina, salmon, fish, oysters, clams, whole milk, cheese, yogurt, iodized salt, fortified bread, eggs: Optimal: 150-200 mcg/d. Deficiency: <100 mcg/d. Excess Intake: > 300-1,000 mcg/d
• Iron: Red meat, beef, pork, oysters, clams, dark chocolate, beans, lentils, beetroot, spinach: Optimal: 8-18 mg/d. Deficiency: < 8 mg/d. Excess Intake: > 45 mg/d
• Manganese: Mussels, oysters, hazelnuts, pecans, rice, beans, legumes, chickpeas, clams, spinach, pineapple: Optimal: 2-5 mg/d. Deficiency: < 2 mg/d. Excess Intake: > 11 mg/d
• Molybdenum: Beans, liver, peas, legumes, yogurt, chickpeas, eggs, potatoes: Optimal: 45-50 mcg/d. Deficiency: < 22 mcg/d. Excess Intake: > 2,000 mcg/d
• Selenium: Brazil nuts, kidney, clams, oysters, sardines, shrimp, salmon, beef, eggs, liver, beans: Optimal: 300-400 mcg/d. Deficiency: < 50 mcg/d. Excess Intake: > 800 mg/d
• Zinc: Oysters, mollusks, clams, eggs, meat, beef, lamb, mutton, pork, wheat, germ, buckwheat: Optimal: 20-80 mg/d. Deficiency: <8 mg/d. Excess Intake: > 80 mg/d (technically safe upper limit is set at 40 mg based on 60 mg/day causing some side effects but this also included supplemental zinc)

5 Possibly Essential Trace Minerals

Mineral: Recommended Dietary Sources: RDA/Deficiency/Excess Intake

• Boron: Legumes, beans, lentils, vegetables, dried prunes, raisins, avocado, black currants, plums, almonds: Optimal: 3-11 mg/d. Deficiency: < 1 mg/d. Excess Intake: > 28 mg/d
• Lithium: Mineral water, grains, vegetables, mustard, kelp, pistachios, dairy, fish and meat: Optimal: 1 mg/d. Deficiency: <100 mcg/d. Excess Intake: >2 mg/d
• Nickel: Black tea, nuts and seeds, cacao, chocolate, meat, fish and grains: Optimal: 25-150 mcg/d. Deficiency: < 25 mcg/d. Excess Intake: 500mcg/d or higher
• Silicon: Whole grains, fruits, vegetables: Optimal: 5-35 mg/d. Deficiency: <5 mg/d. Excess Intake: > 35 mg/d
• Vanadium: Mushrooms, shellfish, black pepper, beer, wine, grains and certain unrefined salts: Optimal: 10-15 mcg/d. Deficiency: <10 mcg/d. Excess Intake: > 10-20 mg/d

Guidelines for Eating Superfoods

Not all foods are created equal in terms of their nutrient values, especially their mineral content. Some of them, like beef liver and pastured eggs, contain virtually all the nutrients your body needs while others, like prunes are an excellent source of primarily one thing – boron. Then there are a bunch of foods that are moderately good for getting a wide range of minerals, such as beans or potatoes. Regardless, there are specific “superfoods” that you may want to keep in your diet on a regular basis to cover your bases for some of the more common deficiencies. However, you shouldn’t be eating things like liver, cruciferous vegetables, dairy or legumes in excess either because they can cause imbalances with other minerals or reduce their absorption.

Here is a list of the more frequently referred to superfoods that you should know in what amounts and how often to eat:

Liver – Arguably the most nutrient-dense food on the planet is liver, whether from beef, lamb, pork, chicken or game. It is an excellent source of the commonly deficient minerals, especially copper, iron, chromium, molybdenum, selenium and zinc. However, because liver is so packed with vitamins and minerals, eating it in excess will lead to increased urinary excretion and overload of certain nutrients.

• You can either eat 0.5-1 oz. per day or 1-3 oz. two to three times per week. Theoretically, more frequent smaller intakes throughout the week are more beneficial and will result in greater absorption compared to large boluses in a single sitting.
• There is the concern that the liver of conventionally raised animals is full of toxins and chemicals. Liver can store dioxins and kidneys tend to store cadmium. However, if you source quality organs from reputable companies consuming organs in the above amounts should not pose any problems. In fact, the fat tissue can have more toxins because the adipose tissue is the primary storage site for calories as well as toxins. So, eating liver, even from conventionally raised animals, should have less toxins, unlike the fatty marbled meat. Kidneys do taste funny and weird because of their filtration role. You can soak both the liver and kidneys in water or milk to draw out their gnarly taste. Buying ground blends of meat that contain muscle meat, liver, heart and kidney will help mask the taste. You can cook the ground meats on the stove top and add taco spices to further mask the taste.

Heart – Although not as nutrient-dense as liver, heart is still packed with a lot vitamins and minerals, in comparison to regular muscle meat. The most noticeable nutrient in heart is CoQ10, which is a coenzyme involved with many mitochondrial processes as well as participates in the electron transport chain and ATP generation. It also has antioxidant properties and is has been used in cardiovascular diseases including those with heart failure. Heart also contains high amounts of protein and amino acids, zinc, selenium and elastin. However, it is slightly higher in iron than regular red meat. Consuming about 0.5-1 oz. of heart daily or 2-3 oz. of heart two to three times per week would suffice.

Oysters/Clams/Mollusks – Just a single 3 oz. serving of oysters or mollusks can cover your entire weekly zinc demand (75-150 mg vs the 8-11 mg RDA). However, it is likely your body doesn’t absorb all of it in a single sitting and responds by increasing urinary excretion. Regardless, eating oysters/clams/mollusks every day is probably not a good idea as it could lead to zinc overload, which reduces copper absorption. Thus, eating seafood like oysters once a week is sufficient enough to help boost your zinc RDA.

• Remember, it is beneficial to include 1 mg of copper for every 20-40 mg of zinc. So, if you do eat large amounts of zinc in a given meal, have more copper-rich foods, like liver.

Red Meat/Beef/Pork/Chicken/Game – Meat is also an excellent source of many minerals, especially zinc, iron and sulfur. It is the best way to get all the sulfur amino acids, like methionine and cysteine, but because of that same reason can lead to a high methionine to glycine ratio.

• Too much zinc and iron can inhibit copper absorption, elevating cholesterol levels and causing symptoms of anemia. That is why a diet high in muscle meat should be balanced with liver or other sources of copper such as Ezekiel bread.
• Eating excessive amounts of processed meat has been linked with an increased risk of colon cancer but the evidence isn’t definitive and does not apply to pastured meat. Cooking meat and protein at high temperatures does create carcinogenic compounds like heterocyclic amines and polycyclic aromatic hydrocarbons. Consuming cooked meat with certain spices, coffee and other plant compounds seems to offset these harms. In fact, drinking coffee is associated with a lower risk of numerous cancers including liver cancer.
• The tendons, ligaments and cartilage from ribs, drumsticks and wings is also a better way to get some glycine, which would balance the methionine, while still getting a high amount of sulfur amino acids. Eating pastured meat every day is actually important for optimal health, however you want to make sure that overall dietary acid load is balanced. This means that the diet should include some berries, dates, dark greens and/or bicarbonate-containing mineral waters.

Beans/Legumes/Lentils – Beans, legumes and lentils are one of the top nutrient-dense foods in developing countries that don’t have as much access to meat. They are the highest sources of plant-based protein, making them essential for any vegetarian/vegan diet.

• Beans and lentils are also relatively high in copper, boron, molybdenum, magnesium and potassium. However, because of their phytate content, they will also chelate things like zinc, iron and calcium. That can either be a good or bad thing, depending on the person’s nutrient status. Excess iron, zinc and calcium can all be harmful to your health by causing calcification, oxidative stress and by inhibiting copper absorption. In that case, the phytates in beans and legumes will improve your health. On the other hand, if you are deficient in zinc (hypothyroid, hypogonadism) or deficient in calcium (osteoporosis), the antinutrients are exacerbating the deficiency of these minerals. Regardless, if you tolerate them, adding some beans and legumes to your iron/zinc-rich meals is an excellent way to prevent their excess intake.
• You will likely realize whether or not you are eating too many beans and legumes by paying attention to your digestion and gastrointestinal condition. Cooking, soaking and sprouting beans/legumes/lentils greatly reduces their antinutrient content.

Broccoli/Cauliflower/Cabbage – Cruciferous vegetables are great for increasing glutathione through sulforaphane and Nrf2. They are also good for getting more potassium, boron, chromium, calcium and magnesium. Compared to beans, broccoli and cauliflower do not contain phytates or phytonutrients that chelate iron or zinc. However, their goitrogenic content does reduce iodine absorption if high amounts are consumed raw, which may cause goiter and hypothyroidism. To prevent that, you should not eat a high amount of these vegetables raw or in smoothies. Instead, cooking, heating, frying and steaming them reduces their goitrogenic properties without losing a lot of micronutrients.

Kale/Spinach/Collard Greens – All kinds of greens like kale and spinach can have some health properties, especially in terms of their magnesium, potassium and calcium content. However, they can also harm the thyroid when eaten raw. That is why you should cook them beforehand. They are also high in oxalates that can promote kidney stones and gastrointestinal distress in those who are susceptible, however, their high calcium content tends to make them fairly low in bioavailable oxalates. Citric acid (lemon juice) and increased calcium intake helps to break down oxalates. So, if you are making a salad, adding some lemon juice, vinegar and eating it with some dairy can prevent potential negative effects.

Eggs – Similar to liver, eggs contain nearly all the vitamins and minerals your body needs. Eggs have all the amino acids both essential and non-essential. Because of that, eating 2-4 pastured eggs a day is an easy way to meet your daily sulfur requirements, while simultaneously hitting a lot of the other minerals, such as iodine, magnesium, molybdenum, selenium, zinc and phosphorus. You should avoid eating conventional eggs as they will have less omega-3s and other health promoting nutrients. To avoid a high methionine/glycine ratio, either stick to eating around 4 eggs a day or ensure you are consuming additional sources of glycine such as hydrolyzed collagen peptides.

• The egg itself doesn’t contain calcium but the eggshells do. Eating eggshells isn’t necessary, but they can be a more natural and moderate-dose calcium supplement for those at a higher risk of osteoporosis or when overall calcium intake is low. You can wash the eggshells carefully, dry them and then grind them up into a powder and take around 1 tsp/d. However, it may be easier to consume calcium from natural mineral waters, which will also have a better bioavailability versus eggshells.

Dairy/Cheese/Milk – One of the most bioavailable and common sources of calcium is dairy. Milk is probably more bioavailable than cheese and curds because it’s a liquid and, similar to mineral waters, minerals get absorbed better when consumed in a liquid form. It is hard to get excess calcium (>1,500 mg/d) by eating dietary calcium. Regardless, you may want to add a little bit of dairy/calcium to your larger meals because it also reduces the total absorption of fat, helping with body composition. Consuming more calcium from sardines (with the bones) or a glass of pastured milk with salads will also protect against oxalates. On a daily basis, you can meet your calcium requirements by drinking either 1 glass of milk per meal or having 3 oz of fish with the bones next to 1.5-3 oz of cheese. Many people do not tolerate dairy, thus dairy consumption should be individualized.

Fish/Salmon/Sardines – Omega-3s are greatly beneficial for reducing inflammation and improving lipid profile. Fish itself is also a great source of other minerals, such as magnesium, iodine, selenium, zinc, manganese and potassium. You can also get calcium from the bones of small fish, like sardines or sprats.

• Wild fish are more exposed to heavy metals and environmental pollution than farmed fish. However, they also have a higher selenium content that detoxifies some of these toxins. So, unless you are eating high-mercury fish like tuna or swordfish every day, you don’t have a lot to worry about in terms of heavy metal toxicity. The increased iodine content in open water fish also protects against lipid peroxidation, which can occur during cooking and damage the healthy fats.
• Overheating farmed fish turns the omega-3s inflammatory and more harmful than good because it has fewer protective minerals and antioxidants. Getting enough copper will also provide enough protection through superoxide dismutase. Both caffeine and coffee melanoidins inhibit lipid peroxidation and reduce the absorption of secondary lipoxidation products.
• Fish consumption has been linked with reduced risk of cardiovascular disease and better metabolic health for a long time. People who eat fish once or twice a week have 50% fewer strokes, 50% lower cardiovascular (CVD) risk and a 34% lower CVD mortality risk compared to those eating no fish. Wild salmon is an excellent source of omega-3s and the antioxidant astaxanthin.

Coffee/Tea – The most consumed beverages in the world after water are coffee and tea. They have a long history of culinary and recreational use. However, research also finds these drinks have some health benefits. There’s evidence that habitual tea drinking has positive effects on brain efficiency and slows down neurodegeneration. The polyphenols in coffee have also shown to reduce the risk of diabetes, Alzheimer’s, dementia, and even liver cancer.

• There is not a high amount of minerals in teas but there can be a fair amount of manganese in tea and some potassium and chromium in coffee. However, coffee, and teas, are potent chelators of other minerals, such as calcium, iron and zinc. Thus, their intake must be individualized.
• Chelation of iron and zinc can be a good thing, depending on the context. For example, chelating iron can protect against the oxidation of fats when we eat cooked meat. If you are eating a low calcium diet, you may want to consume some calcium, like cheese or milk, with coffee to prevent calcium deficiency or better yet natural mineral waters that contain calcium.
• Contrary to popular belief, coffee does not make you lose magnesium directly, unless you overdose and induce diarrhea or over-activate the sympathetic nervous system, both of which can promote magnesium excretion.
• The biggest minerals that get excreted due to coffee and caffeine are sodium and chloride. So, drinking mineral waters or consuming a bit more salt while drinking coffee can help prevent sodium and chloride deficiency.
• On a daily basis, 1-2 cups of coffee or tea a day is a good moderate dose. It should prevent the caffeine dependency and anxiety a lot of people are suffering from. The upper limit should be 3 cups a day. Any more than that may start to interfere with sleep quality. If you feel like you need caffeine to wake up and start the day, you should look into improving the quality of your sleep. Learning to function on less caffeine, such as ½ cup of coffee twice daily, is a great option for preventing the caffeine blues and other side effects.

Chocolate/Cacao – One of the best-known superfoods of South America is cacao found in chocolate. It is true that chocolate actually has a significant amount of some minerals, such as magnesium, copper, iron and chromium.

• Chocolate and cacao do contain some oxalates, but they do not contain phytates that chelate minerals. However, most conventional chocolates are high in sugars and fats that actually promote the excretion of minerals, especially magnesium. If you become insulin resistant or obese because of overindulging on chocolate and candy, then you will also increase the overall demand for these minerals. Thus, you should stick to dark chocolate (>70%) and/or raw cacao powders. Eating 1 oz. of 80% cacao dark chocolate can be a great savory treat for dessert.

Fruit/Berries/Juices – Fruits and berries are naturally high in potassium, which is hard to come by in other foods. You can also get citrate, which helps to buffer against the dietary acid load from meat and eggs. However, added fructose as a sweetener tends to promote the excretion of minerals. Added fructose can also induce insulin resistance, which places an additional demand for certain minerals, such as magnesium and chromium.

• Fructose-sweetened beverages are linked with insulin resistance. Drinking juices from natural fruit is also not the best idea because you are getting a very large dose of fructose in one sitting, which overburdens the liver. Thus, it is best to stick to whole food sources of fructose from lower sugar fruit and berries, such as strawberries, blueberries and raspberries.
• Vitamin C enhances the absorption of iron and chromium from the diet.

Shilajit (mumie, moomiyo or mummiyo) also called mineral pitch is a black-colored substance, consisting of paleohumus and vegetation fossils, that’s high in fulvic acid and has been used in Ayurvedic medicine for thousands of years. It is collected from steep rock faces at altitudes 1000- 5000 meters. Shilajit is not an actual food per se but instead an herb that can be taken as a supplement. Typical doses range from 200-2,000 mg/d.

• Research has shown that shilajit improves mitochondrial respiration and oxidative phosphorylation, which promotes ATP production. Animal and human studies show it enhances spermatogenesis, testosterone levels and physical performance. It also has a beneficial effect on lipid profile, cholesterol levels, cognition and antioxidant status.
• Shilajit has anti-inflammatory and antiulcerogenic properties. In obese patients, shilajit improves the function and regeneration of skeletal muscle.
• Shilajit has been shown to have anti-addictive effects with fewer side-effects than alpha2- adrenergic or opioid agonists. By interacting with GABA levels in the brain, shilajit can also reduce the sensation of pain. In mice, ashwagandha and shilajit prevents ethanol withdrawal and alcohol addiction.
• Shilajit powder contains some iron, calcium, magnesium, selenium, zinc and other minerals. The predominant fulvic acid makes the minerals more bioavailable. Humic acids in shilajit also acts as a heavy metal chelator.

If you can’t tolerate organ meats by themselves, you can grind or mince them together with ground beef and make patties or pate.

Generally, cooking and overheating destroys some nutrients, which for goitrogens, lectins or phytates may actually be a good thing.

• Lightly cooking broccoli and cabbage triples their sulforaphane content vs. fully cooked. Steaming cruciferous vegetables leads to the highest nutrient content versus other cooking methods.
• Other foods like meat can become more hazardous from high heat cooking through the formation of carcinogens and oxidized lipids/cholesterol. For that, vinegars, plant polyphenols and spices and chelators like phytate can help offset any harms. Fortunately, marinating meat before cooking reduces the formation of these carcinogens by up to 90%. Regardless, animal foods are more adversely affected by cooking than plant foods.
• Vegetables and legumes actually need to be cooked to a reasonable degree to make them safer to eat, while the fats and protein in meat or fish can become oxidized.
• As a rule of thumb, cook your animal foods on light to moderate or sear them shortly and boil/roast the plants for longer. The other alternative to make meat healthier is to cut off the char.

Lightly cooking and cooling starch like potatoes and rice also increases their resistant starch content. There are many studies showing that resistant starch can improve insulin sensitivity, lower blood sugar, reduces appetite and help with digestion. Resistant starch also stimulates the bacteria in your gut to produce short-chain fatty acids (SCFAs) like acetic acid, propionic acid, and butyric acid. The SCFAs can feed the cells that line the colon and help with nutrient absorption. Some studies show that 15-30 grams of resistant starch/day for 4 weeks can improve insulin sensitivity by 33-50%.

• One medium cooked and cooled potato contains about 3 grams of resistant starch while 100 grams of cooked and cooled rice has 5 grams. To keep the resistant starch intact, you can reheat the food at low temperatures under less than 130 degrees. You don’t have to eat them cold but too high heat will convert it into regular starch.

Fresh foods tend to have more nutrients as storage can reduce nutrient content. Freezing, however, can help reduce the loss of the nutrients if the food is frozen right after harvest. Unfortunately, frozen veggies deactivate myrosinase, which is an enzyme that creates sulforaphane. Regardless, you would still get plenty of potassium, vitamin C and sulfur from vegetables. Organic foods also have more bioavailable nutrients, as pesticides and glyphosate can bind to minerals reducing their presence in the food and their bioavailability once consumed.

The US Department of Agriculture’s Pesticide Data Program publishes an annual report on the most pesticide-rich foods. They divide it into The Dirty Dozen and The Clean 15. Here’s a list for the year 2018:

• The Dirty Dozen (Buy Organic and avoid conventional) – strawberries, spinach, nectarines, apples, grapes, peaches, cherries, pears, tomatoes, celery, potatoes, sweet bell peppers.
• The Clean 15 (Safer to buy but still aim for organic) – avocados, sweet corn, pineapples, cabbages, onions, sweet peas, papayas, asparagus, mangoes, eggplants, honeydews, kiwis, cantaloupes, cauliflower and broccoli.

Fixing Mineral Deficiencies

About a third of the U.S. population is likely to be deficient in the below 10 minerals (estimated % not hitting RDA/AI or estimated % deficient):

1. Boron (> 75%)
2. Manganese (~ 75%)
3. Magnesium (52.2-68%)
4. Chromium (56%)
5. Calcium (44.1-73%)
6. Zinc (42-47%)
7. Iron (25-34%)
8. Copper (25-31%)
9. Selenium (15-40%)
10. Molybdenum (15%)

Here is how to prevent your body from becoming deficient of essential minerals by protecting against their excretion or improving their absorption:

Limit Added Sugar and Refined Food Intake – Hyperglycemia and high sugar consumption places an additional burden on the liver and kidneys, which also makes the body increase excretion of certain minerals, namely magnesium, chromium and copper.

• Added sugars drive coronary heart disease by inducing insulin resistance and hyperinsulinemia. Sugar, especially fructose, is worse than starch or other whole foods carbohydrate sources. The overconsumption of fructose-sweetened beverages is linked with insulin resistance.
• Animal and human studies have shown that replacing starch and glucose with sucrose or fructose, despite isocaloric eating, raises fasting insulin, reduces insulin sensitivity and increases fasting blood sugar. Compared to a diet containing less than 10% of calories from added sugars, a diet that consists of 25% calories or more from added sugars triples the risk of cardiovascular disease mortality.
• Overconsuming added sugars can promote copper deficiency, which contributes to fatty liver and insulin resistance. Most refined foods are also virtually non-existent of vitamins and minerals because the processing methods removes them. The more refined foods and sugar you consume the more minerals you need, especially magnesium, chromium and copper.

Fix Insulin Resistance and Improve Glycemic Control – During insulin resistance, the body either is not producing enough insulin (like in type-1 diabetes), keeping the blood sugar elevated for longer, or the cells are not responsive to the actions of insulin and don’t allow the entry of nutrients into the cell. In either case, hyperglycemia ensues that makes you burn through minerals while increasing their excretion.

• Abdominal visceral fat is strongly correlated with insulin resistance and type 2 diabetes. Thus, reducing the intake of added fructose, especially when combined with fat bombs such as heavy cream and butter, which can lead to visceral fat accumulation, is advised. Reducing the intake of calories shouldn’t happen at the expense of decreased nutrient intake, which means you have to focus more on eating nutrient dense foods as mentioned earlier.
• Physical activity is one of the biggest predictors of overall insulin sensitivity and glucose tolerance. Resistance training and having more muscle mass are the best things for improving glucose tolerance. Skeletal muscle acts like a sponge for glucose and the more muscle you have the higher your carbohydrate tolerance is.
• A lack of sleep impairs glucose tolerance, raises blood sugar and cortisol and promotes insulin resistance. Even one single night of bad sleep has been shown to induce the biomarkers of a pre-diabetic in the short term.
• Trans fats and vegetable oils like margarine, corn, soybean, safflower, cottonseed and canola oil promote oxidative stress, inflammation and insulin resistance. People who consume high amounts of omega-6 seed oils have a worse lipid profile and markers of insulin resistance. Chronic inflammation also promotes insulin resistance.
• Minerals that support glycemic control and insulin production are chromium, magnesium, potassium, sodium, copper and zinc. Insulin mimetics are lithium, nickel and vanadium although their supplementation requires consultation with your medical professional.

Improve Gut Health and Fix Malabsorption Conditions – Your gut is where most of the absorption of minerals from food occurs. Having a healthy gut is vital for assimilating and retaining nutrients. Many malabsorption conditions, such as intestinal permeability (leaky gut), IBS, Crohn’s and ulcerative colitis can reduce the absorption of certain minerals. If you have any gut condition, you will need to hit at least the RDA for magnesium, potassium, zinc, copper and selenium. If you already show signs of deficiencies in these minerals, you may need to increase your intake further in the short term.

• Chloride is used by our body to make hydrochloric acid, helping to form stomach acid for killing pathogens and absorbing nutrients. Acid-suppressing drugs decrease how much stomach acid gets produced and, as a result, fewer minerals are absorbed. Thus, a low salt intake can reduce stomach acid production and inhibit the absorption of nutrients from food because of inadequate digestion.
• Drinking mineral waters improves mineral absorption by 40-50% compared to food.
• Zinc supplementation improves intestinal barrier function and may even help to resolve intestinal permeability in patients with Crohn’s disease. Sufficient amino acid intake from protein is also required for repairing the gut lining. Certain allergenic foods like gluten or eggs may damage the intestinal lining and lead to intestinal permeability.

Improve Liver and Kidney Health – Most of the metabolic processes are regulated by the liver and kidneys. They also determine the homeostatic balance and excretion of all minerals. Poor kidney function tends to promote the urinary loss of magnesium, chromium, manganese, zinc, copper and many others.

• Excess iron damages the liver through oxidative stress and promotes fatty liver (visceral fat). Production of ROS during iron metabolism causes lipid peroxidation. Too much ferritin also supports lipofuscin formation, which is an age-related pigment that slows down cellular processes and promotes fatty liver. Replacing some of your muscle meat with organ meats or beans/legumes will help to lower iron overload and prevent liver damage.
• Studies find that coffee can reduce risk of liver cirhhosis by 25-70%. It can also reduce risk of non-alcoholic fatty liver disease (NAFLD) by 30-60%. NAFLD results primarily from metabolic syndrome. Losing some weight and improving insulin resistance can help improve NAFLD.
• Liver detoxification pathways require zinc, selenium, magnesium and molybdenum. Sulfur- and glutathione-rich foods like cruciferous vegetables, garlic, onions, eggs, and leeks support phase 2 detoxification.
• The kidneys affect electrolyte balance the most. Kidney damage increases the demand for potassium, copper, zinc and chromium. Excess ammonia, resulting from deficient manganese and potassium, can overburden the kidneys. Proper hydration and drinking adequate amounts of water are also important for filtrating out waste products that would otherwise accumulate in the body.

Avoid Heavy Metal Exposure – Environmental pollutants, especially heavy metals, also increase the excretion of some minerals and compete with their absorption. What’s more, mineral deficiencies like iron deficiency can increase the absorption of heavy metals, such as cadmium, lead and aluminum.

• Zinc deficiency has been shown to promote the accumulation of cadmium in the liver whereas iron and copper deficiency raise cadmium intake by the kidneys. Cadmium is a toxic metal with a half-life of 10-30 years that antagonizes zinc. Animal studies show that cadmium promotes the urinary excretion of copper, zinc and iron. Supplementation with copper and zinc has helped to prevent against the adverse effects of cadmium.
• Sauna therapy also helps to eliminate heavy metals like arsenic, cadmium, lead and mercury as well as persistent organic pollutants (POPs). Sauna use in combination with niacin and exercise can result in a 25-30% decrease in POP levels in fat tissue and blood by heat-induced sweating. Sweating alone has actually been used to improve uremia, or the accumulation of toxins in the blood of patients with kidney disease. You can’t avoid all heavy metal exposure in an industrialized world. However, you can support your body with additional detoxification methods, such as exercise and sauna. Getting enough selenium, zinc and copper are also important for the body’s antioxidant defense systems.

Avoid Drugs/Medications That Promote Mineral Loss – Pharmaceuticals tend to reduce the absorption of minerals and promote their excretion. Antacids and diuretics affect magnesium and potassium the most. When taking a prescription drug for a certain medical condition that cannot be avoided, look up to see what nutrients they may deplete and make sure you obtain enough of them in the diet or through supplementation.

Eat Mineral-Dense Foods Regularly – You should be eating things like liver, oysters and/or clams on a fairly regular basis, at least once a week. This way your requirement for supplements will greatly reduce as you’ll be getting the nutrients from your food. It is not necessary to be eating “superfoods” daily with every meal. However, you could also “microdose” (1 oz/d) foods like liver to spread your intake across the entire week. Large acute doses of minerals tend to make the body increase urinary excretion or reduce their absorption. It is also harder to catch up on deficiencies compared to having a consistent intake of minerals from foods.

Add Some Mineral Waters to Your Diet – One of the best ways to get more magnesium and calcium into your diet is to drink mineral waters. Mineral waters have a better bioavailability while providing other health benefits. Because they lack calories, mineral water is one of the healthiest ways to simultaneously improve your mineral status and metabolic health. Consuming about 1/3-2/3rds of your daily water intake as mineral water would contribute greatly to your daily mineral requirements.

Supplement Your Deficiencies – Taking supplements is a quick way to overcome severe nutrient deficiencies that are causing health problems. However, they may also have negative side-effects. For example, taking an iron or zinc supplement will impair copper absorption. Likewise, a chromium supplement for someone who is already metabolically healthy may be just a waste of money. Thus, you should supplement only those minerals you are deficient or suboptimal in. First, test your mineral status and then consult with a medical professional about the appropriate course of action in terms of supplementation. Minor deficiencies can easily be fixed by improving diet or metabolic health.

People who exercise or sweat a lot due to either being physically more active, sunbathing, or taking saunas frequently are more prone to electrolyte imbalances. When you sweat you lose water, sodium, chloride, copper, chromium, selenium and iodine. Because sweating is an essential way for humans to regulate their body temperature, we can’t avoid it and thus may be prone to becoming deficient or at least suboptimal in different minerals.

• It’s estimated that sweat contains on average 920-1,380 mg of sodium per liter. However, that would depend on your own electrolyte status and how hydrated you are. The RDA for sodium is 2300 mg, which is 6 grams or 1 teaspoon of salt. Vigorous exercise in hot weather for a prolonged period of time such as an endurance race or marathon may make you lose up to 4-10 liters and 3500-7000 mg of sodium through sweat.
• If you are going for a long run, you do burn calories and fat, but you also lose sodium and other minerals through sweat. To keep the weight off, maintain insulin sensitivity and ensure optimal nutrient intakes. If you’re vigorously exercising or sweating without replacing minerals you may find yourself in a vicious cycle of nutrient deficiencies, mild insulin resistance, increased stress and enhanced cravings for salty/sugary junk foods.
• Compared to oral rehydration fluids known to be effective in cholera, coconut water was found to have adequate potassium and glucose content, however, was relatively deficient in sodium, chloride and bicarbonate. The addition of salt to the coconut water is suggested to compensate for the sodium and chloride deficiency.