Fasting Basics (In Progress)

Metabolic Autophagy Notes

How Does the Body Produce Energy While Fasting?

The body’s default fuel source is glucose, which exogenously (externally) comes in the form of sugar and carbohydrates and is stored endogenously (internally) as glycogen. The liver can deposit 100-150 grams of glycogen and muscles about 300-500 grams. They’re used for back-up. Liver glycogen stores will be depleted already within the first 18 to 24 hours of not eating – almost overnight. This decreases blood sugar and insulin levels significantly, as there are no exogenous nutrients to be found.

Glucagon gets released when the concentration of glucose in the bloodstream gets too low. The liver then starts to convert stored glycogen into glucose.

Fasting and Ketosis

As fasting continues, the liver starts to produce ketone bodies which are derived from our own fat cells. Lipolysis (breakdown of stored triglycerides in the adipose tissue) and ketogenesis increase significantly due to fatty acid mobilization and oxidation. Ketosis can occur after 2-3 days of fasting. Triglycerides (molecules of stored body fat) are broken down into glycerol, which is used for gluconeogenesis (creation of new glucose) and three fatty acid chains. Fatty acids can be used for energy by most of the tissue in the body, but not the brain. They need to be converted into ketone bodies first.

Ketosis is a metabolic state in which fat is the primary fuel source, instead of glucose, and can be achieved either through fasting or by following a ketogenic diet. Fasting induces ketosis rapidly and puts the body into its more efficient metabolic state. The more keto-adapted you become the more ketones you’ll successfully utilize. At first, the brain and muscles are quite glucose dependent. But eventually, they start to prefer fat for fuel. After several days of fasting, approximately 75% of the energy used by the brain is provided by ketones. Protein catabolism decreases significantly, as fat stores are mobilized and the use of ketones increases. Muscle glycogen gets used even less and the majority of our energy demands will be derived from the adipose tissue.

The Krebs cycle is a sequence of reactions taking place in our mitochondria that generate energy during aerobic respiration. When glucose enters this metabolic furnace it goes through glycolysis, which creates the molecule pyruvate. In the case of fatty acids, the outcome is a ketone body called acetoacetate, which then gets converted further into beta-hydroxybutyrate and acetone.

The difference between pyruvate and ketone bodies is that the latter can create 25% more energy. On top of that, the by-products of glycolysis are advanced glycation end-products (AGEs), which promote inflammation and oxidative stress, by binding a protein or lipid molecule with sugar. They speed up aging and can cause diabetes.

Fasting VS Caloric Restriction VS Starvation

Starvation is a severe deficiency in energy intake. The body doesn’t have access to essential nutrients and is slowly wasting away by cannibalizing its vital organs. It’s a gradual process of degradation that’s often characterized by the skinny-fat look or the bloated stomach called kwashiorkor, which is caused by insufficient protein even in the presence of sufficient caloric intake.

Caloric Restriction reduces calorie intake without causing malnutrition or starvation. You’re simply consuming fewer calories needed to maintain your body’s current energy demands. This will make you burn your stored fat and also lowers the body’s overall metabolic rate, down-regulated reproductive hormones, thyroid functioning and promotes gluconeogenesis. The difference between caloric restriction and starvation is that when calorically restricted, your body still gets access to the energy it needs to maintain its daily energy demands. It’s just that those energy demands have adapted to be lower and more efficient in terms of energy gained per calorie.

Fasting is a state of metabolic suspension in which you’re not consuming any calories. Despite that, your body is still nourished and gets the energy it needs. This happens by shifting into ketosis, in which you’ll be burning your body fat almost exclusively.

To prevent malnutrition and starvation, while restricting calories, you want to establish ketosis and autophagy as soon as possible. Even consuming small amounts of food will put you into a fed state. It doesn’t matter whether you eat 200 calories or 1000, you’ll still be shifted out of a fasted state.

Fasting and the Mitochondria

Time-controlled fasting prevents mitochondrial aging and deterioration. It can also promote the longevity of mitochondria by eliminating the production of reactive oxygen species and free radicals by dysfunctional organelles.

Mitochondrial biogenesis is the process of building new mitochondria through the activities of certain metabolic regulators such as PGC-1α and AMPK. AMPK produces new mitochondria and controls mitophagy as well. The key to growing new mitochondria is to signal the body to produce energy under energy depletion and in stressful environments. This causes cellular crises that need to be compensated for by building new power plants.

Fasting increases AMPK which promotes fatty acid oxidation which produces ketone bodies. The mitochondria run a lot better on ketone bodies because they can get into the mitochondria faster via the electron transport chain and they’ll yield more ATP than glucose.
Fasting increases FOXO proteins, which regulate longevity through the insulin/IGF-1 pathway and mitohormesis. FOXO1 and FOXO3 promote mitophagy.
Fasting increases sirtuins. Sirtuins regulate fat and glucose metabolism in response to physiological changes in energy levels, thus they’re crucial determinants of energy homeostasis and health span of the cell. SIRT1 regulates mitochondrial biogenesis and PGC-1α. Suppressing SIRT2 restricts fatty acid metabolism, reduces mitochondrial activity, and promotes obesity. SIRT3 is the major mitochondrial deacetylase and it protects against oxidative stress through its anti-oxidant properties.

Fasting and Mitochondrial Density

Mitochondrial density refers to the cells’ ability to produce more energy from fewer resources and become more efficient at it.

Fasting increases NAD+ levels, which is an enzyme that helps with energy production and promotes longevity.

NAD+ supports mitochondrial functioning during youth and restore it in later life.
NAD+ protects the cells against oxidative stress with the help of sirtuins. NAD+ activates sirtuins which then help to grow blood vessels and muscle.
NAD+ replenishment improves lifespan and health span through mitophagy and DNA repair. NAD+ supplementation can promote DNA repair in mice.

Burning fatty acids and ketones causes less damage to the mitochondria as well. Glycolysis, which is the process by which mitochondria burn glucose, causes more oxidative stress and the creation of free radicals, which in turn will speed up aging.

Reactive oxygen species and oxidative stress activate FOXO pathway to adapt to the stress. Fasting causes mild stress that makes the body adapt to it through hormesis. Inactivity of FOXO factors accelerates atherosclerosis and compromises stem cell proliferation.

Fasting and the Brain

Fasting boosts brain power by increasing brain-derived neurotrophic factor (BDNF), which helps to grow new brain cells and synapses. It also promotes serotonin, which regulates synaptic plasticity with BDNF.
Fasting can boost BDNF by 50-400%. Even 16:8 style intermittent fasting promotes neuroplasticity and stimulates the production of new brain cells. BDNF also has anti-depressant benefits and it protects against stroke.
Fasting protects the brain against neurodegeneration. During autophagy, fasting helps to clear out beta-amyloid plaques and lowers oxidative stress on neuronal tissues. Fasting and the ketogenic diet are very commonly used to treat epilepsy.
Fasting boosts growth hormone that provides neuroprotection and regeneration. Growth hormone not only protects against muscle catabolism but also prevents brain cells from dying.
Fasting gives the brain ketones which lower inflammation and maintain stable energy levels. The ketogenic diet has BDNF increasing properties.
Fasting increases mitochondrial biogenesis, which helps to produce more energy. There’s a lot of mitochondria in the brain and other vital organs.
Fasting helps to lose weight, which can improve brain function. Studies link a higher BMI with decreased blood flow to regions in the brain that are associated with attention span, reasoning, and higher executive functioning.

The brain can use about 120 grams of glucose a day and if glucose levels fall below 40mg/dl its functioning begins to suffer. However, during fasting, the brain can get more than enough energy from other sources:

Ketone bodies are derived from fatty acid metabolism and after ketoadaptation, they can cover 50-75% of the brain’s energy demands.
Astrocytes in the brain and spinal cord can produce ketones that can be for neuronal metabolism and they have neuroprotective properties.
Fatty acids from your body fat can also be converted into glucose through a process called gluconeogenesis which breaks fat molecules into 3 fatty acid chains and glycerol. Glycerol can contribute up to 21.6% of daily glucose production.
Lactate can also give the brain energy during intense exercise. The brain prefers lactate over glucose when both are available. Lactate gets produced during anaerobic metabolism.
Recent research in vitro has shown that fuel alternatives to glucose improve neuronal efficiency and oxidative metabolism.

Alzheimer’s disease is now being referred to as type-3 diabetes, as it’s caused by an energy crisis in the brain. Insulin resistance in the brain contributes to the development of cognitive decline and people with type-2 diabetes have an increased risk of Alzheimer’s of 50-65% and higher. Fortunately, fasting may help your brain with cognitive decline as well.

Autophagy clears out the beta-amyloid plaques that begin to accumulate with cognitive decline and Alzheimer’s progression. Alzheimer’s is also linked to obesity and insulin resistance.
β-hydroxybutyrate, actually blocks part of the immune system that regulates inflammatory diseases like arthritis and Alzheimer’s.
Ketone bodies also raise BDNF and lower oxidative stress. Ketones can also reduce too much excitement in the brain caused by excess glutamate and not enough GABA.

If a person experiences hypoglycemia and gets the symptoms of such, then their brain is simply unable to use the other fuel alternatives. Ergo, when the body is keto-adapted enough, it’s going to prevent any energy crises in the first place.

Fasting and the Immune System

Fasts that last for 48-120 hours reduce pro-growth signaling and enhance cellular resistance to toxins. They also trigger stem cells, which help to reinvigorate old cells and promote their youthfulness.

Valter Longo says:

When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged.
We noticed in both our human work and animal work that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back.

Longo found that in order for the stem cells to be turned on, an enzyme called cAMP-dependent protein kinase A (PKA) needs to be shut down. Prolonged fasting has also been shown to lower blood sugar, insulin levels, and other hormones such as mTOR and IGF-1, which are all growth factors that prevent the body from healing itself using its internal resources.

Fasting can weaken your immune system only if it becomes an overbearing stressor on your body. It’s like any other physiological stressor your immune system has to deal with. If you’re fasting for five days, having mad CrossFit workouts, not sleeping enough, controlling three screaming kids in the mini-van, and being stressed out, then, of course, you’re more prone to getting sick.

Fasting and Gut Health

Dietary restriction has been shown to prevent gut pathologies and extend lifespan in fruit flies:

Short-term intermittent fasting improves gut health and extends lifespan in fruit flies independent of the TOR pathway.
Intermittent fasting promotes clearance of pathogens and infectious bacteria and helps to heal the gut in mice infected with salmonella.
Fasting protects the gut against the negative effects of stress, such as inflammation. Fasting activates cAMP, which further activates genes that promote intestinal lining integrity and strength. The cognitive benefits of fasting on the brain will also improve your mood and improve stress resiliency which protects against leaky gut again.
Intermittent fasting promotes white adipose tissue browning and reduces obesity by shaping the gut microbiome. The gut microbiota influences adipose tissue browning and insulin sensitivity by signaling the browning of white fat into brown fat.
Caloric restriction and weight loss increase the number of beneficial bacteria in the gut called Bacteroidetes. Obese people have less of these bacteria than lean people. Caloric restriction enriches phylotypes in the gut that are positively correlated with increased lifespan.

Fasting and time restricted feeding heal the gut by giving your intestines rest from breaking down food. Digestion requires about 25% of the calories from each meal. Being in a fasted state promotes anti-inflammatory cytokines and cellular autophagy that instigate healing.

Fasting also increases the activity of the migrating motor complex (MMC), which is a mechanism that controls stomach contractions in a cyclical manner over 2-hour periods. The MMC cleans out the GI tract and helps to eliminate undigested food particles. It’s regulated by feeding/fasting hormones such as ghrelin, serotonin, cortisol, and somatostatin. Eating inhibits MMC and not eating increases it.

However, fasting may cause some gut issues if done wrong:

Fasting and eating at night may lower your sleep quality. Some species of bacteria like Enterobacter aerogenes are sensitive to melatonin (the sleep hormone), which influence circadian rhythms. A disruption in circadian rhythms can disrupt the microbiome and thus negatively affect metabolic health. That’s why it’s important to not overeat at night.
Prolonged restrictive diets may cause a lack of microbial diversity. The gut microbiome can respond to changes in diet very fast and thus restructure the microbiome according to that. Short-term consumption of either fully animal or plant-based diets alter the gut microbial status, which can cause trade-offs in carbohydrate or protein metabolism.
Fasting decreases the size of some digestion organs like the small intestine and liver, which can lower the capacity to consume food. That’s why you may find it more difficult to eat as much as you did before when breaking your fast. However, these organs will regrow themselves quite rapidly and they’ll become more functional afterward.

Fasting promotes the diversity and dynamics of the microbiome, which is determined by feeding and fasting cycles of the host. At the same time, it will still starve off some of the pathogens, viruses, and bad bacteria.

The Microbe-Gut-Brain (MGB) Axis is this network of biochemical signaling between the gastrointestinal tract (GI) and the central nervous system (CNS). It includes the enteric nervous system (ENS), the endocrine system, the hypothalamic-pituitary axis (HPA), the autonomic nervous system, the vagus nerve, the endocrine system, and the gut microbiome.

Your immune cells, muscle cells, cells of the gastrointestinal tract are all mediators of the neuro-immuno-endocrine system that are influenced by both the brain and the gut microbiome. In fact, it’s been thought that the microbiome plays a much more influential role in the state of your being than the brain.

Fasting and Fat Loss

Contrary to popular belief, intermittent fasting doesn’t slow down the metabolism but actually increases it by 3.6% after the first 48 hours. 4 days in, resting energy expenditure increases up to 14%. Instead of slowing down the metabolism, the body revs it up and puts it into higher gear. This is probably caused by increased adrenaline so that we would have more energy to go out into the savannah and find some food.

There’s no reason to be concerned about malnutrition during fasting because our fat stores can deposit almost an infinite number of calories. The main issue is rather micronutrient deficiencies. Potassium levels may drop slightly, but even 2 months of fasting won’t decrease it below a safe margin. Magnesium, calcium, and phosphorus remain stable because 99% of them are stored in our bones.

Fasting and Growth Hormone

After 20-24 hours of fasting, GH increases by 1300-2000%. It not only promotes tissue repair, body composition, and metabolism but also preserves youthfulness.

What goes hand in hand with HGH is insulin-like growth factor (IGF-1). It’s one of the major growth factors in mammals which together with insulin is associated with accelerated aging and cancer. Just 5 days of fasting can decrease IGF-1 by 60% and a 5-fold increase in one of its principal IGF-1-inhibiting proteins: IGFBP1.

Potential Side Effects

Headaches, dizziness, lightheadedness, fatigue, low blood pressure and abnormal heart rhythms are all short-term. Some people may experience impaired motor control or forgetfulness. But these are all symptoms of withdrawal from glucose dependence, not fasting.

Fasting may cause some flare-ups of certain medical conditions, such as gout, gallstones or other diseases. This is yet again not because of fasting directly but because of the overall high amounts of toxins in the body. The adipose tissue also stores poisons and infections that we digest. Once you start breaking down triglycerides, those same toxins will be released into your bloodstream again and need to get flushed out. There may also be some nervous stomach, irritable bowel of diarrhea.

Autophagy is a metabolic process during which cells disassemble and remove their dysfunctional components. There are many benefits to autophagy, such as reduced inflammation, improved immunity, prevention of genotoxic stress, antiaging, suppression of cancerous tumor cells, and elimination of pathogens. Compromised autophagy pathways will lower the body’s ability to eliminate and heal the organism from inflammation, accumulation of toxins, and parasitic infections. Inability to cause autophagy makes rats fatter, less active, have higher cholesterol and impaired brain function.

When autophagy gets activated, the organelles of your healthy cells start to hunt out dead or diseased cells and then consume them.

Autophagy gets triggered mostly by nutrient starvation:

In yeast, starvation of nitrogen and other essential factors like carbon, nucleic acid, auxotrophic amino acids, and even sulfate can activate autophagy to some degree.
In plant cells, nitrogen and carbon starvation can also trigger autophagy. These were the points of interest for Dr. Ohsumi in yeast as well.
In mammals, autophagy happens in various tissues in different degrees. There’s macro autophagy in the liver, brain, muscle, mitophagy in the mitochondria and Chaperone-Mediated Autophagy (CMA). Depletion of amino acids is a strong signal for triggering autophagy but that depends on the type of cell and amino acids because amino acid metabolism differs among tissues.
In vivo, it’s thought that autophagy is regulated mostly by the endocrine system, particularly by insulin. Insulin suppresses liver autophagy by raising blood sugar and signaling the presence of nutrients. Glucagon, which is the counterpart of insulin, releases liver glycogen to be burnt for energy, and that increases autophagy.

The main inhibitor of autophagy in muscles is a kinase called Akt. It can regulate autophagy mainly in two ways: (1) a rapid regulation of mTOR activation, and (2) a slower response of gene transcription via FoxO3. FoxO3 controls the transcription of autophagy-related genes, such as LC3 and Bnip3, which mediate the effect of FoxO3 on autophagy. Akt activation blocks FoxO3 and autophagy.

With poor autophagy functioning, your body wouldn’t be able to maintain lean tissue. It improves your body’s ability to deal with catabolism and atrophy by promoting protein sparingness. A weakened or inadequate state of autophagy may contribute to aging, and muscle wasting through sarcopenia.

A constant supply of nutrients and access to energy inhibits the body’s ability to induce autophagy and protect against catabolism. In fact, a continuous circulation of both macro and micronutrients all the time inhibits their usage and uptake by making the cells less responsive. It means that to actually absorb the nutrients you’re feeding yourself, you need to go through periods of mild deprivation as you’ll be more sensitive to those nutrients afterwards again.

Exercise performed in a fasted state shows a higher increase in LC3BII level compared with a fed state, which suggests exercise done while fasting to have a better autophagic response.

To really gain the benefits of autophagy, you’d have to be fasting for over 48 hours to allow the stem cells and immune system to do their work. That’s why it’s recommended for everyone to fast for at least 3-5 days 2-3 times per year.

The Negative Side Effects of Autophagy

Autophagy controls inflammation and immunity by eliminating inflammasome activators. Removal of pathogens by autophagy is called xenophagy, which has many immune strengthening benefits. However, some bacteria like Brucella use autophagy to replicate themselves. That may cause some bacterial overgrowth or at least prevent its death.

The essential autophagy gene ATG6/BECN1 encoding the Beclin1 protein has been found to suppress tumors in cancer. However, it’s not been found to be that big of a tumor-suppressor as previously thought and sometimes it can even promote cancer due to the self-replicative process. Self-eating can enhance tumor cell fitness against environmental stressors, which makes them more resilient against starvation and chemotherapy. It may be that autophagy is better for cancer prevention rather than treatment.

It’s not clear whether autophagy prevents or promotes apoptosis or programmed cell death. The outcome turns out to depend on the stimulus and cell type. Blocking autophagy enhances the proapoptotic effect of bufalin on human gastric cancer cells, which is a Chinese medical toxin used for tumor suppression, through endoplasmic reticulum stress. In this example, less autophagy led to more cancer cell death because the cancer cells were weaker whereas with autophagy, they became stronger.

How to Measure Autophagy

To accurately estimate autophagic activity, it is essential to determine autophagic flux, which is defined as the amount of autophagic degradation. To trigger autophagic cell death you need a catabolic catalyst that would increase AMPK and cause cellular stress. Being anabolic and growing will inhibit autophagy by raising mTOR through the insulin/IGF-1 signaling pathway.

To know whether or not you’re more anabolic or catabolic or more mTOR or AMPK activated, you can measure your insulin to glucagon ratio (IGR). In general, an increase in IGR is associated with more anabolism – weight gain, muscle growth, fat storage, hyperinsulinemia, and higher risk of hypoglycemia. A reduction in IGR promotes catabolism, fat loss, and prevents hypoglycemia.

To know your insulin to glucagon ratio you can take blood tests for insulin as well as glucagon from your medical doctor. Here’s what research has found to influence your IGR:

A 1:1 insulin to glucagon ratio: 1.0
While fasting you have lower insulin and more glucagon. Fasting + No Food: ~0.8
While eating the Western Diet with higher carbs there’s more insulin. Carbs + Eating: ~4.0
On a Low Carb Diet, there’s fewer carbs and less insulin. Low Carb + Eating: ~1.3
Consuming protein while fasting causes a drop in insulin by raising glucagon-induced gluconeogenesis. Fasting + Protein: ~0.5
Consuming protein on a low carb diet doesn’t raise insulin and doesn’t significantly affect glucagon. Low Carb + Protein: ~1.3
Consuming protein with high amounts of carbohydrates spikes insulin 20x more than normally because of the anabolic effects. Carbs + Protein: ~70
Amino acids combined with carbohydrates produce a much larger anabolic effect and insulin response than just carbs or protein alone. That’s a significant difference between macronutrients and their anabolic response.

The Glucose Ketone Index

Here’s the Glucose Ketone Index Formula: (Your Glucose Level / 18) / Your Ketones Level = Your Glucose Ketone Index

Measure your blood glucose by pricking your finger. Write down the number you got.
Measure your blood ketones by pricking your finger again. Write down the number you got.
Divide your blood glucose number by 18.
- If your device is using mg/dl, then dividing that with 18 converts it over to mmol/l
- If your device is already showing mmol/l, then you don’t need to divide anything and can skip this step
Divide your result from the previous step by your ketone numbers.
The end result is your GKI.

In general, having a GKI below 3.0 indicates high levels of ketosis in relation to low levels of glucose; 3-6 shows moderate ketosis, and 6-9 is mild ketosis. Anything above 9 and 10 is no ketosis. Therefore, a lower GKI will reflect an estimated insulin-glucagon ratio by virtue of how glucose and ketones affect that relationship.

Thomas Seyfried (Cancer as a Metabolic Disease) says that the optimal glucose ketone index range for cancer treatment and prevention is between 0.7-2.0, preferably around 1.0.

If you combine a lower insulin to glucagon ratio with a lower glucose ketone index while you’re in a fasted state with depleted liver glycogen, then you can predict the degree of autophagy you’re in. It wouldn’t tell you about autophagy if you’d been eating because calories will suppress autophagy and you can be anabolic with higher mTOR while still maintaining a low insulin to glucagon ratio and vice versa. You can only predict it if you’re in a fasted state because that’s the surest way we know to increase autophagy.

You don’t want to be autophagic all the time either because it would prevent growth and repair of your body. Too much autophagy may lead to muscle wasting and dysfunctional cell death, which is why you want to balance catabolism with anabolism. Maintaining lean muscle is incredibly important for longevity and increased health span.

Balancing Autophagy and mTOR

The main idea of this entire book is that by regulating and controlling the expression of certain nutritional factors you can get drastic results in your body composition as well as expected lifespan. Let’s take a look at the Protein Kinase Triad once again:

mTORC1 (mammalian/mechanistic target of rapamycin complex 1) – it’s the main regulator of cell growth and anabolism through upregulating protein synthesis
mTORC2 (mammalian target of rapamycin complex 2) – it’s a multiprotein complex of TOR that regulates the actin cytoskeleton, which is a network of filaments and fibers, extending throughout the cytoplasm of cells
AMPK (AMP-activated protein kinase) – it’s the main fuel sensor that helps to mobilize the body’s internal energy stores in situations of energy deprivation
ULK1 (Unc-51-like kinase 1) – it’s a protein that’s involved with activating autophagy and other catabolic reactions to amino acid deficiencies

These 3 pathways (mTOR/Autophagy/AMPK) sense the energy status of the body and determine whether your cells will be favoring anabolic processes of growth or catabolic processes of self-devouring and preservation.

There’s always an evolutionary trade-off between anabolism and catabolism as well as growth and repair.

Being too anabolic may speed up your biological clock by causing oxidative stress to the mitochondria and making your other organs work harder. If you grow fast, you’ll inevitably age faster as well.
Being too catabolic and degrading at a quicker rate than you can repair will also damage vital cells and other processes in the body. In this case, you’ll die sooner just by virtue of physical deterioration.

Principles of Metabolic Autophagy

Time-Restricted Feeding as Long as You Can Every Day – This is probably the most cost-effective thing you can do to improve your health and longevity. I mean, by simply not eating and fasting instead is one of the easiest ways to promote longevity and health. There isn’t a real physiological reason to be eating any more than twice a day. Hell, most people will do perfectly fine with a single meal, unless they’re under some special requirements. Whatever the case is, the minimum for daily time-restricted feeding is the 16/8-hour window, even when trying to build muscle. Instead of eating for distraction, you should leverage the fasted state as long as you can and then eat to support your physical conditioning.
Lift Heavy Things and Do Resistance Training – The goal of your exercise should be to promote muscle growth and maintenance. As it turns out, having more lean tissue is one of the best things for healthy aging and longevity. That’s why you want to predominantly resistance training instead of cardio. At minimum 2-3 and up to 4-6 times per week. If you’re working out more intensely more frequently, then you may have to adjust your fasting window to make sure you’re not getting weaker or losing muscle. Some days should still be kept for cardiovascular training and full-on recovery but they aren’t the main focus.
Get a Sweat on Daily – It’s incredibly important to keep your lymph system flowing and more active. Modern life is already quite sedentary and that can cause stagnation within the body. A lot of digestion issues and toxicities occur because of not clearing out the lymph fluids. Exercising and moving around are one of the best lymph node stimulators but any form of sweating whether by going to a sauna, doing yoga or running is great.
Maximize Nutrient Density – This means eating high-quality foods that have an abundance of micronutrients, minerals, and other cofactors. Your purpose isn’t to eat as many calories as you can get away with but to get more nutrition out of fewer calories. Mild caloric restriction and eating around maintenance is beneficial for longevity. Eat nose to tail, get adequate electrolytes, cover your essential nutrients, supplement your deficiencies, incorporate some superfoods into your diet, and cycle between different food groups. You shouldn’t deprive yourself of nutrients either. Doing intermittent fasting doesn’t mean you’re starving yourself. Quite the opposite. You’ll be getting more than enough nutrition. Just in a time-restricted manner.
Eat Whole Foods (A Lot of Plants) – In terms of nutrient density, you’d have to focus on eating a lot of vegetables that have many vitamins and other beneficial compounds but not a lot of calories. Animal foods have their place but you shouldn’t overconsume them. Most of what you eat in terms of volume should still be plant-based. Meat, eggs, fish, and fats simply have more calories. The antioxidants and polyphenols from cruciferous, veggies, berries, and other plants are pro-longevity because of being nTOR as well.
Control Blood Sugar and Insulin – This is one of the best ways to ensure stable energy levels, avoid health problems, and maintain a more effective state of nutrient partitioning. It’s just not a good idea to have high levels of blood sugar or insulin all the time and the research supports that. Instead, your goal should be to keep them relatively low the vast majority of time and only raise them where the body is more sensitive.
Don’t Combine High Carb High Fat Foods – Avoid processed inflammatory foods that are low protein, high carb, and high fat because it’s a recipe for insulin resistance, diabetes, and over-eating. This change will drastically enable you to avoid most metabolic disorders. The short dopamine rush may feel good but it’s not optimal in the long run. You can apply the 80/20 rule but do it at your own responsibility.
Limit Evolutionary Trade-Offs – Avoid the “natural diet” fallacy both in the context of eating too much protein and animal fat as well as the plant-based approach. It’s not a wise idea to go into the extremes and think that you’re somehow immune to all disease. Who knows how your body individually will react to different foods. Maybe you’re not as insulin sensitive as you think you are to justify that carb-up. Likewise, don’t roll the dice with eating things that will potentially yield negative results but come with zero benefits. I’m talking about lectins, fruit, dairy, grains, vegetable oils, too much saturated fat, and carcinogenic meat…
Stimulate mTOR and Anabolism Only When It’s Useful – You don’t want to be spiking insulin or mTOR just for nothing. To avoid any trade-offs in longevity, you want to eat ModTOR foods only after resistance training to support muscle homeostasis. At other times it’s better to stick to nTOR and autophagy-like compounds. This is relevant mostly when you’re eating more than twice a day. In the case of 2 meals a day, you’d want to make the first meal very low in anabolism and smaller in calories. The second one should be post-workout wherein you’re more sensitive to mTOR and insulin. If you’re not working out, then you’d be better off by limiting your protein intake and focusing on autophagy. You also don’t want to be eating a lot of meat, eggs, and fish every day. Most of your food should still be plant-based because of their nTOR qualities and polyphenols. Eat meat only after heavier resistance training workouts and not in excess. This way you’ll stimulate mTOR and anabolism only when it’s useful and without consequences on longevity.
Cycle Between Anabolism and Catabolism – Don’t stay in either state for too long. If you’re anabolic too long, you may accelerate aging. If you’re catabolic too long, you may lose your muscle. Both aren’t optimal for longevity nor performance. That’s why you’d want to cycle between periods of being at a small surplus with staying around your maintenance and even dropping into a deficit. The human body evolved under constant energy stress and it’s what we thrive under. Never be stagnant or dysfunctional.
Expose Yourself to Hormetic Stressors – Nutrition and exercise aren’t the only components of longevity. You also want to trigger hormetic adaptation outside of the gym. To live a longer and healthier life you have to become more resilient against stress and adaptable to the ever-changing conditions of the natural environment. Of course, modern life allows us to maintain homeostasis in everything we do whether that be our core temperature, daily routines, food consumption, or physical challenges but they’re elusive. To not be swept away by some unexpected circumstances, you want to follow a lifestyle that involves voluntary hormesis. Take cold showers, swim in icy lakes, turn off the central heating, burn some fat at the sauna, practice stress management, fast for 5 days a few times per year, and do something tough.

The biggest beneficial effects of fasting come from 3 things: autophagy, ketosis, and hormesis. IF promotes all of them to a certain degree, depending on how long you’ve been in a fasted state. The key trigger is energy deficit and glycogen depletion.

Fat doesn’t raise insulin significantly and it keeps mTOR suppressed in small amounts. Endogenous ketone bodies from your own body fat will stimulate autophagy, which can promote brain macro-autophagy as well. However, high amounts of ketones and fatty acids in the blood can still make you raise insulin. If there’s too much energy circulating the body, then that’s a signal to stop autophagy and trigger mTOR. Exogenous ketones can also be insulinogenic.

Huberman

The Ideal Fasting Protocol

You do not want to ingest food at least 60 minutes after waking up.

No food 2-3 hours prior to bed time.

8 hours in bed.

8 hour feeding window. Shorter windows tend to lead to overeating. OMAD if you can control yourself.

Most don’t adhere perfectly, so if your goal is 10 hours, make it 8.

Keep your daily window consistent. Don’t shift it daily as this is like traveling and messing with your circadian rhythm.

Place the window between 10am-6pm give or take an hour or two on either side. Weight training may make you hungrier so it’s better to place training later or bring your window earlier.

Use of glucose disposal agents or exercise. Berberine, metformin, cinnamon, lemon and lime juice, post prandial walk, HIIT, chromium.

Ingest enough fluids and electrolytes.

Artificial sweeteners or plant-based sweeteners maybe.

Evaluate your own system and regulate your light viewing behaviors.

Biohacker’s handbook (need ref)

Intermittent fasting (e.g. 16 hours). Grazing is often promoted by the food industry and rationalized with claims of activating the metabolism (no scientific basis). In fact, the basal metabolic rate increases slightly after a 36 hour fast. It is only after a 72 hour fast that it decreases.

From an evolutionary perspective, humans evolved to eat when there was food available (usually in the evening). The rest of the time was spent acquiring it (morning and day).

In practice IF works well as it allows for the consumption of satisfying meals during the eating window while maintaining a moderate overall energy intake. Consumption of food (particularly carbohydrates) in the evening significantly reduces the levels of stress hormones and promotes sleep as well as stabilizing the secretion of leptin, ghrelin, and adiponectin (burning fat). Consuming meals later in the evening also activates the PNS.

IF may also be used to balance the function of the suprachiasmatic nucleus.

Not recommended for people under 18, pregnant, breastfeeding, fatigued, or suffering from CFS.

Water, tea, and coffee are often consumed to maintain fluid balance when fasting. Low energy green juices are useful as they contain essential micronutrients. Highly active people may also consume EAAs or BCAAs in tablet or powder form.

Health benefits of fasting/IF:

May extend lifespan by slowing down the aging process
May reduce the risk of developing metabolic and chronic diseases such as cancer, diabetes, metabolic syndrome, arthritis, and neurodegenerative diseases.
May improve insulin sensitivity and lower blood pressure
May reduce oxidative stress in the body
May improve the hormonal balance

A simple guide:

Fast overnight and delay the first meal as much as possible (usually until 3-6pm)
While fasting, drink plenty of fluids such as mineral water (rich in minerals, delays hunger)
Hunger can be delayed by eating a fiber rich apple, low in calories or a cucumber
The first meal should consist of protein, fibrous vegetables, and fat.
The second (and last) meal, consumed between 8-11pm, should include plenty of carbohydrates as well as fat and protein.
Physical exercise is often timed either at the end of the fast in the afternoon or after the first meal

Boundless (ref)

Caloric restriction is an intentional reduction of your weekly or daily caloric intake. Fasting, especially intermittent fasting, does not require caloric restriction. You don’t eat less; you eat less often.

Many people attempt fasting and encounter thyroid downregulation, hormone depletion, low energy, and poor sleep because they try to marry caloric restriction-based fasting with an extremely active, calorie-decimating lifestyle with bodies that have few stores available (low body fat).

Fasting can be good for losing fat and improving brain health without restricting calories. It can also encourage metabolic autophagy. Abnormal or restricted autophagic activity is associated with neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. Frequent feeding, particularly sugars and proteins, cause elevated insulin, which reduces neuronal autophagy, resulting in metabolic dysregulation and neurodegeneration.

Fasting triggers autophagy, which is a programmed response cell turnover and recycling. Autophagy is particularly important for nervous system recovery, clearing away old neurons to make way for the growth of new ones. Improving cognition, muscle function, and movement pattern recognition. A 2009 study found that participants that lifted weights fasted had a greater anabolic response to a post-workout meal. Levels of p70S6 kinase, a signaling mechanism for muscle-protein synthesis that acts as an indicator of muscle growth, were twice as high in the fasted group. Constantly training in a fed state makes things too easy for the body.

Extremely lean individuals, people prone to eating disorders, and women who are dealing with adrenal or hormonal imbalances, suffer risk and stress that would outweigh any benefits. Fasting has been shown to reduce glucose tolerance in women. Even in overweight women, intermittent fasting has been shown to reduce lean body mass and muscle rather than pure adipose tissue.

Fasting Basics (In Progress)

Metabolic Autophagy Notes

Huberman

Biohacker’s handbook (need ref)

Boundless (ref)

HOM

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