Author: Peter Attia, MD

Topics: Health, medicine, longevity, exercise, nutrition, mental health

All information is attributed to the author. Except in the case where we may have misunderstood a concept and summarized incorrectly. These notes are only for reference and we always suggest reading from the original source.

Contents

Part I
CHAPTER 1: The Long Game: From Fast Death to Slow Death
CHAPTER 2: Medicine 3.0: Rethinking Medicine for the Age of Chronic Disease
CHAPTER 3: Objective, Strategy, Tactics: A Road Map for Reading This Book
Part II
CHAPTER 4: Centenarians: The Older You Get, the Healthier You Have Been
CHAPTER 5: Eat Less, Live Longer: The Science of Hunger and Health
CHAPTER 6: The Crisis of Abundance: Can Our Ancient Genes Cope with Our Modern Diet?
CHAPTER 7: The Ticker: Confronting—and Preventing—Heart Disease, the Deadliest Killer on the Planet
CHAPTER 8: The Runaway Cell: New Ways to Address the Killer That Is Cancer
CHAPTER 9: Chasing Memory: Understanding Alzheimer’s Disease and Other Neurodegenerative Diseases
Part III
CHAPTER 10: Thinking Tactically: Building a Framework of Principles That Work for You
CHAPTER 11: Exercise: The Most Powerful Longevity Drug
CHAPTER 12: Training 101: How to Prepare for the Centenarian Decathlon
CHAPTER 13: The Gospel of Stability: Relearning How to Move to Prevent Injury
CHAPTER 14: Nutrition 3.0: You Say Potato, I Say “Nutritional Biochemistry”
CHAPTER 15: Putting Nutritional Biochemistry into Practice: How to Find the Right Eating Pattern for You
CHAPTER 16: The Awakening: How to Learn to Love Sleep, the Best Medicine for Your Brain
CHAPTER 17: Work in Progress: The High Price of Ignoring Emotional Health

Part I

CHAPTER 1: The Long Game: From Fast Death to Slow Death

The Four Horsemen (slow deaths): heart disease, cancer, neurodegenerative disease, or type 2 diabetes and related metabolic dysfunction.

Longevity has two components: How long you live (chronological lifespan) and the quality of your years (health-span).

Cardiovascular disease has had its mortality rates cut by two-thirds but modern medicine has struggled to handle much more than that.

• Death rates from cancer have barely moved in the more than fifty years since the War on Cancer was declared.
• Type 2 diabetes remains a public health crisis.
• Alzheimer’s disease and related neurodegenerative diseases have virtually no effective treatments on the horizon.

The treatment guidelines of the American Diabetes Association specify that a patient can be diagnosed with diabetes mellitus when they return a hemoglobin A1c (HbA1c) test result of 6.5% or higher, corresponding to an average blood glucose level of 140 mg/dL (normal is more like 100 mg/dL, or an HbA1c of 5.1%).

• If their HbA1c test comes back at 6.4%, implying an average blood glucose of 137 mg/dL they have prediabetes, where the standard-of-care guidelines recommend mild amounts of exercise, vaguely defined dietary changes, possible use of a glucose control medication called metformin, and “annual monitoring”.
• HbA1c measures the amount of glycosylated hemoglobin in the blood, which allows us to estimate the patient’s average level of blood glucose over the past ninety days.

CHAPTER 2: Medicine 3.0: Rethinking Medicine for the Age of Chronic Disease

Medicine 1.0: conclusions were based on direct observation and guesswork.

Medicine 2.0: arrived in the mid-nineteenth century with the advent of the germ theory of disease. This led to improved sanitary practices by physicians and the development of antibiotics.

• Sir Francis Bacon (1628) first articulated the scientific method. From observing and guessing to observing, and then forming a hypothesis, which as Richard Feynman pointed out is basically a fancy word for a guess.

Medicine 3.0: prevention.

• Greater emphasis is on prevention than treatment.
• Considers the patient as a unique individual.
• Our starting point is the honest assessment, and acceptance, of risk—including the risk of doing nothing.
• Pays more attention to maintaining health-span.
• You must be well-informed, medically literate to a reasonable degree, clear-eyed about your goals, and cognizant of the true nature of risk. You must be willing to change ingrained habits, accept new challenges, and venture outside of your comfort zone if necessary. You are always participating, never passive. You confront problems, even uncomfortable or scary ones, rather than ignoring them until it’s too late. 

CHAPTER 3: Objective, Strategy, Tactics: A Road Map for Reading This Book

We need to have a strategy: an overall approach, a conceptual scaffolding or mental model that is informed by science, is tailored to our goals, and gives us options. Our specific tactics flow from our strategy, and the strategy derives from our objective. 

“Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death,” wrote Otin, et al, 2013 (Hallmarks of Aging). “This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases.”

Health-span and its deterioration falls into these categories:

• Cognitive decline: Our processing speed slows down. We can’t solve complex problems as quickly. Our memory begins to fade. Our executive function is less reliable. Our personality changes, and if it goes on for long enough, even our sentience is lost.
• Decline and loss of physical function: We lose muscle mass and strength, along with bone density, stamina, stability, and balance, until it becomes almost impossible to carry a bag of groceries into the house. Chronic pains prevent us from doing things we once did with ease. At the same time, the inexorable progression of atherosclerotic disease might leave us gasping for breath. Or we could be living a relatively active and healthy life until we fall or suffer some unexpected injury that tips us into a downward spiral from which we never recover.
• Deterioration of emotional health: Largely independent of age; it can affect “healthy” young people, or later in life. Surveys show that happiness tends to reach its nadir in our forties (age forty-seven, to be exact) however, middle-aged distress often has its roots much earlier, in adolescence or childhood. And we may not recognize that we are in danger until we reach a crisis point.

Medicine 2.0 relies on two tactics: procedures (e.g., surgery) and medications. Medicine 3.0 relies on exercise, nutrition, sleep, emotional health, and exogenous molecules (drugs, hormones, or supplements).

We need to look at the different types of data that we have and then develop a strategy that triangulates between them. 

• What do centenarians have in common? What genes do they share that might give them an advantage? What explains their survival and their apparent slower rate of aging? And what can the rest of us do to emulate them? Unfortunately, centenarian data are almost entirely observational rather than experimental, so we can’t truly infer cause and effect.
• We have a huge amount of data about how different sorts of interventions, both dietary and in the form of exogenous molecules, affect mouse lifespan. If a given intervention can be shown to extend lifespan or health-span in multiple species spanning a billion years of evolution, for example, from worms to monkeys, then we should be inclined to take it seriously.
• Human studies of the Horsemen: cardiovascular and cerebrovascular disease, cancer, Alzheimer’s disease and related neurodegenerative conditions, and type 2 diabetes and related metabolic dysfunction. How do these diseases begin? How do they progress? What risk factors help to cause them, or fuel them? What underlying factors do they share? What are the cutting-edge treatment modalities for those with “advanced” disease and what do they tell us about developing a strategy for prevention?
• Molecular and mechanistic insights derived from the study of aging in both human and animal models: We have learned an enormous amount about the cellular changes that occur during the aging process and in specific diseases. From this, we also have developed some ideas for how to manipulate these changes, via exogenous molecules or behavioral changes.
• Mendelian randomization (MR): MR helps bridge the gap between randomized controlled trials, which can establish causality, and pure epidemiology, which often cannot.
  • MR helps tease out causal relationships between modifiable risk factors (e.g., LDL cholesterol) and an outcome of interest (e.g., cancer) in situations where randomized experiments cannot easily be done. It accomplishes this by letting nature do the randomization. By considering the random variation in relevant genes and comparing them against the observed results, it eliminates many of the biases and confounders that limit the usefulness of pure epidemiology.
  • For MR to work, the genetic variant(s) being considered must associate with the risk factor of interest, the genetic variant does not share a common cause with the outcome (independence assumption); and the genetic variant does not affect the outcome except through the risk factor (exclusion restriction assumption).

Part II

CHAPTER 4: Centenarians: The Older You Get, the Healthier You Have Been

Despite the fact that female centenarians outnumber males four to one, the men generally scored higher on both cognitive and functional tests. Perls believes selection process is at work, because men are more susceptible to heart attacks and strokes beginning in middle age, while women delay their vulnerability by a decade or two and die less often from these conditions. Women live longer but tend to be in poorer health.

Centenarians are often healthier at ninety than the average person in their sixties. And when they do decline, their decline is typically brief.

One of the most potent individual genes discovered is related to cholesterol metabolism, glucose metabolism, and Alzheimer’s disease risk: APOE. It’s typically known for its effect on Alzheimer’s disease risk. It codes for a protein called APOE (apolipoprotein E) that is involved in cholesterol transport and processing, and it has three variants: e2, e3, and e4.

• e3 is the most common by far.
• Having one or two copies of the e4 variant seems to multiply one’s risk of developing Alzheimer’s disease by a factor between two and twelve.
• The e2 variant of APOE seems to protect its carriers against dementia and is very highly associated with longevity.
• People with at least one copy of e2 (and no e4) were about 30% more likely to reach extreme old age (ninety-seven for men, one hundred for women) than people with the standard e3/e3 combination.
• Those with two copies of e4, one from each parent, were 81% less likely to live that long.

Researchers have identified two other cholesterol-related genes, known as CETP and APOC3, that are also correlated with extreme longevity (and may explain why centenarians rarely die from heart disease).

FOXO3 belongs to a family of “transcription factors,” which regulate how other genes are expressed (whether they are activated or “silenced”). It is responsible for cellular repair tasks, regulating metabolism, caring for stem cells, and various other kinds of housekeeping, including helping with disposal of cellular waste or junk.

• When FOXO3 is activated, it activates genes that help keep our cells healthier. It seems to play an important role in preventing cells from becoming cancerous as well. FOXO3 can be activated or suppressed by our behaviors. For example, when we are slightly deprived of nutrients, or when we are exercising, FOXO3 tends to be more activated.

More than anything, centenarians appear to have resilience, despite poor lifestyle behaviors.

CHAPTER 5: Eat Less, Live Longer: The Science of Hunger and Health

Rapamycin tends to slow down the process of cellular growth and division.

• Rapamycin acts directly on the intracellular protein complex called mTOR (mechanistic target of rapamycin).
• The job of mTOR is basically to balance an organism’s need to grow and reproduce against the availability of nutrients. When food is plentiful, mTOR is activated and the cell (or the organism) goes into growth mode, producing new proteins and undergoing cell division, as with the ultimate goal of reproduction. When nutrients are scarce, mTOR is suppressed and cells break down cellular components.

Limiting caloric intake can lengthen the lifespan of a mouse or a rat by anywhere from 15-45%, depending on the age of onset and degree of restriction. The underfed animals also seem to be healthier for their age, developing fewer spontaneous tumors than normally fed mice. CR seems to improve their health-span too.

• However, there is no evidence that extreme CR would truly maximize the longevity function in humans, who live in a more variable environment than mice or rats.

AMPK senses low levels of nutrients (fuel), it then activates, triggering a cascade of actions. While this typically happens as a response to lack of nutrients, AMPK is also activated when we exercise, responding to the transient drop in nutrient levels.

• AMPK prompts the cell to conserve and seek alternative sources of energy.
• It does this by stimulating the production of new mitochondria (mitochondrial biogenesis). Over time our mitochondria become vulnerable to oxidative stress and genomic damage, leading to dysfunction and failure. Restricting the amount of nutrients that are available, via dietary restriction or exercise, triggers the production of newer, more efficient mitochondria to replace old and damaged ones. These fresh mitochondria help the cell produce more ATP.
• AMPK also prompts the body to provide more fuel for new mitochondria, by producing glucose in the liver and releasing energy stored in fat cells.
• AMPK works to inhibit the activity of mTOR, the cellular growth regulator. A drop in amino acids induces mTOR to shut down, and with it all the anabolic processes that mTOR controls. Instead of making new proteins and undergoing cell division, the cell goes into a more fuel-efficient and stress-resistant mode, activating autophagy.
• This cellular cleanup is carried out by lysosomes, which package up the old proteins and other detritus, including pathogens, and grind them down (via enzymes) for reuse. The lysosomes also break up and destroy aggregates, which are clumps of damaged proteins that accumulate over time. Impaired autophagy has been linked to Alzheimer’s disease–related pathology and also to amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and other neurodegenerative disorders.

Rapamycin (and its derivatives) might actually be more of an immune modulator than an “immunosuppressor,”. Under some dosing regimens it can enhance immunity, while under completely different dosing regimens it may inhibit immunity.

• mTOR is composed of two separate complexes, called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The two complexes have different jobs, but the longevity-related benefits seem to result from inhibiting complex 1.
• Giving the drug daily, as with transplant patients, appears to inhibit both complexes, while dosing the drug briefly or cyclically inhibits mainly mTORC1, unlocking its longevity-related benefits, with fewer unwanted side effects.

Kaeberlein found that rapamycin actually seemed to improve cardiac function in older animals.

• Rapamycin seems to reduce systemic inflammation, perhaps by tamping down the activity of senescent cells, which have stopped dividing but not died; these cells secrete inflammatory cytokines.
• It also improves cancer surveillance.
• In another recent study, Kaeberlein’s group found that rapamycin appeared to improve periodontal (gum) health in older dogs.

Patients on metformin appeared to have a lower incidence of cancer than the general population. One large 2014 analysis seemed to show that diabetics on metformin actually lived longer than nondiabetics.

CHAPTER 6: The Crisis of Abundance: Can Our Ancient Genes Cope with Our Modern Diet?

Non-alcoholic fatty liver disease (NAFLD) generally only shows up on a blood test for the liver enzyme alanine aminotransferase (ALT). Rising levels of ALT are often the first clue that something is wrong with the liver, although they could also be a symptom of a recent viral infection or a reaction to a medication.

• According to Labcorp, the acceptable range for ALT is below 33 IU/L for women and below 45 IU/L for men (although the ranges can vary from lab to lab). But “normal” is not the same as “healthy.” The reference ranges are based on percentiles based on the population, which is not necessarily healthy.

NAFLD is the first stage, caused by more fat entering the liver or being produced there than exiting it. The next step is NASH, which is basically NAFLD plus inflammation, similar to hepatitis but without a viral infection. This inflammation causes scarring in the liver but there are no obvious symptoms.

• If you remove the fat from the liver (most commonly via weight loss), the inflammation will resolve, and liver function returns to normal.
• But if NASH is not kept in check or reversed, the damage and the scarring may progress into cirrhosis. This happens in about 11% of patients with NASH and is far more serious.
• Even in the early stages of NAFLD, you are likely to progress to one or more of the other three Horsemen diseases (cardiovascular disease, cancer, and Alzheimer’s disease).

“Metabolic Syndrome” (MetSyn):

1. High blood pressure (>130/85)
2. High triglycerides (>150 mg/dL)
3. Low HDL cholesterol (<40 mg/dL in men or <50 mg/dL in women)
4. Central adiposity (waist circumference >40 inches in men or >35 in women)
5. Elevated fasting glucose (>110 mg/dL)

If you meet three or more of these criteria, then you have the metabolic syndrome.

Carbs have two possible fates. First, it can be converted into glycogen, suitable for use in the near term. About 75% of this glycogen ends up in skeletal muscle and the other 25% goes to the liver, although this can vary. An adult male can typically store a total of about 1,600 calories worth of glycogen between these two sites, or about enough energy for two hours of vigorous endurance exercise.

• One of the liver’s many important jobs is to convert stored glycogen back to glucose and then to release it as needed to maintain blood glucose levels at a steady state. This is an incredibly delicate task: an average adult male will have about five grams of glucose circulating in his bloodstream at any given time. This won’t last more than a few minutes, as glucose is taken up by the muscles and especially the brain, so the liver has to continually feed in more, titrating it precisely to maintain a more or less constant level. Seven grams means you have diabetes.
• We have a far greater capacity for storing energy as fat—the second possible destination for calories. Even a relatively lean adult may carry ten kilograms of fat in their body (ninety thousand calories of stored energy).
• Insulin helps shuttle the glucose to where it’s needed, while maintaining glucose homeostasis. If you happen to be engaged in intense exercise, those calories will be consumed almost instantly in the muscles. In the typical sedentary person, the excess energy from food will largely end up in fat cells (or more specifically, as triglycerides contained within fat cells).
• Subcutaneous fat is actually the safest place to store excess energy. Fat in and of itself is not bad. It’s where we should put surplus calories. That’s how we evolved. 
• As more calories flood into your subcutaneous fat tissue, it eventually reaches capacity and the surplus begins spilling over into other areas of your body: into your blood, as excess triglycerides; into your liver, contributing to NAFLD; into your muscle tissue, contributing directly to insulin resistance in the muscle.
• Fat also begins to infiltrate your abdomen, accumulating in between your organs (visceral fat). These fat cells secrete inflammatory cytokines such as TNF-alpha and IL-6, key markers and drivers of inflammation, in close proximity to your most important bodily organs. This may be why visceral fat is linked to increased risk of both cancer and cardiovascular disease.
• If a person is not physically active, and they are not consuming energy via their muscles, then this fat-spillover-driven insulin resistance develops much more quickly.
• There are many other hormones involved in the production and distribution of fat, including testosterone, estrogen, hormone-sensitive lipase and cortisol. Cortisol is especially potent, with a double-edged effect of depleting subcutaneous fat (which is generally beneficial) and replacing it with more harmful visceral fat. This is one reason why stress levels and sleep, both of which affect cortisol release, are pertinent to metabolism. But insulin seems to be the most potent as far as promoting fat accumulation because it acts as kind of a one-way gate, allowing fat to enter the cell while impairing the release of energy from fat cells (via a process called lipolysis). Insulin is all about fat storage, not fat utilization.

Evolution wants us to get fat when nutrients are abundant: the more energy we could store, in our ancestral past, the greater our chances of survival and successful reproduction. Natural selection obliged, endowing us with genes that helped us conserve and store energy in the form of fat. That enabled our distant ancestors to survive periods of famine, cold climates, and physiologic stressors such as illness and pregnancy. But these genes have proved less advantageous in our present environment, where many people in the developed world have access to almost unlimited calories.

• Fructose is a powerful driver of metabolic dysfunction if consumed to excess. Humans have a unique capacity for turning calories from fructose into fat.
• When we metabolize fructose, along with certain other types of foods, it produces large amounts of uric acid, which is best known as a cause of gout but which has also been associated with elevated blood pressure.
• Other mammals, and even some other primates, possess an enzyme called uricase, which helps them clear uric acid. But we humans lack this, so uric acid builds up.
• At some point, our primate ancestors underwent a random genetic mutation that effectively switched on their ability to turn fructose into fat: the gene for the uricase enzyme was “silenced,” or lost. Now, when these apes consumed fructose, they generated lots of uric acid, which caused them to store many more of those fructose calories as fat. This newfound ability to store fat enabled them to survive in the colder climate. They could spend the summer gorging themselves on fruit, fattening up for the winter.
• These same ape species, or their evolutionary successors, migrated back down into Africa, where over time they evolved into hominids and then Homo sapiens—while also passing their uricase-silencing mutation down to us humans. This, in turn, helped enable humans to spread far and wide across the globe, because we could store energy to help us survive cold weather and seasons without abundant food.
• Fructose isn’t the only thing that creates uric acid; foods high in chemicals called purines, such as certain meats, cheeses, anchovies, and beer, also generate uric acid.
• High levels may promote fat storage and also because it is linked to high blood pressure. High uric acid is an early warning sign that we need to address a patient’s metabolic health, their diet, or both.

Glucose and fructose are metabolized differently at the cellular level.

• When a brain cell, muscle cell, gut cell, or any other type of cell breaks down glucose, it will almost instantly have more ATP at its disposal. But this energy is not free: the cell must expend a small amount of ATP in order to make more ATP. In glucose metabolism, this energy expenditure is regulated by a specific enzyme that prevents the cell from using too much of its ATP on metabolism.
• When we metabolize fructose in large quantities, a different enzyme takes over, and this enzyme does not put the brakes on ATP “spending.” Instead, energy (ATP) levels inside the cell drop rapidly and dramatically. This rapid drop in energy levels makes the cell think that we are still hungry.
• Even though it is rich in energy, fructose basically tricks our metabolism into thinking that we are depleting energy and we need to take in more food and store more energy as fat.
• This drop in cellular ATP triggers an enzyme called AMP deaminase (AMPD), which is sort of like the reverse–fuel gauge enzyme. When AMPK is activated, it triggers all sorts of cellular survival programs, including the burning of stored fat, that help enable the organism to survive without food. When fructose triggers AMPD, on the other hand, it sends us down the path of fat storage. (Also blocks leptin.)
• On a more macro level, consuming large quantities of liquid fructose overwhelms the ability of the gut to handle it; the excess is shunted to the liver, where many of those calories are likely to end up as fat.
• While it may be in vogue to vilify high-fructose corn syrup, which is 55% fructose and 45% glucose, it’s worth pointing out that table sugar (sucrose) is about the same, consisting of 50% fructose and 0% glucose. 

Peter monitors several biomarkers related to metabolism, things like elevated uric acid, elevated homocysteine, chronic inflammation, and mildly elevated ALT liver enzymes. Lipoproteins are also important, especially the ratio of triglycerides to HDL cholesterol (it should be less than 2:1 or better yet, less than 1:1), as well as levels of VLDL, a lipoprotein that carries triglycerides. These biomarkers help give us a clearer picture of a patient’s overall metabolic health than HbA1c, which is not very specific by itself. But the first thing he looks for is elevated insulin.

• He likes to give patients the oral glucose tolerance test (OGTT), where the patient swallows ten ounces of a sickly-sweet beverage (Glucola) that contains seventy-five grams of pure glucose. They then measure the patient’s glucose and insulin every thirty minutes over the next two hours. Typically, their blood glucose levels will rise, followed by a peak in insulin, but then the glucose will steadily decrease as insulin does its job and removes it from circulation.
• The insulin in someone at the early stages of insulin resistance will rise very dramatically in the first thirty minutes and then remain elevated, or even rise further, over the next hour.
• Studies have found that insulin resistance itself is associated with huge increases in one’s risk of cancer (up to twelvefold), Alzheimer’s disease (fivefold), and death from cardiovascular disease (almost sixfold).

CHAPTER 7: The Ticker: Confronting—and Preventing—Heart Disease, the Deadliest Killer on the Planet

Cholesterol is required to produce cell membranes; hormones such as testosterone, progesterone, estrogen, and cortisol; and bile acids, which are necessary for digesting food. All cells can synthesize their own cholesterol, but about 20% of our body’s supply is found in the liver, which acts as a sort of cholesterol repository, shipping it out to cells that need it and receiving it back via the circulation.

• Because cholesterol belongs to the lipid family, it is not water soluble and cannot dissolve in our plasma like glucose or sodium, and travel freely through our circulation. So, it must be carted around in lipoproteins.
• The protein is essentially the vessel that allows them to travel in our plasma while carrying their water-insoluble cargo of lipids, including cholesterol, triglycerides, and phospholipids, plus vitamins and other proteins that need to be distributed to our distant tissues.
• The reason they’re called high- and low-density lipoproteins (HDL and LDL) has to do with the amount of fat relative to protein that each one carries. LDLs carry more lipids, while HDLs carry more protein in relation to fat, and are denser. Also, these particles (and other lipoproteins) frequently exchange cargo with one another. It’s not the cholesterol that causes problems but the nature of the particle in which it’s transported.
• Each lipoprotein particle is wrapped by one or more apolipoproteins, that provide structure, stability, and solubility to the particle. HDL particles are wrapped in apolipoprotein A (apoA), while LDL is encased in apolipoprotein B (apoB). Every single lipoprotein that contributes to atherosclerosis carries this apoB protein signature.
• Another major misconception about heart disease is that it is somehow caused by the cholesterol that we eat in our diet. 
• Eating lots of saturated fat can increase levels of atherosclerosis-causing lipoproteins in blood, but most of the actual cholesterol that we consume in our food ends up being excreted. The vast majority of the cholesterol in our circulation is actually produced by our own cells.
• Even Ancel Keys knew that dietary cholesterol was not the cause of atherosclerosis. He realised that the research was done on rabbits, who can absorb cholesterol into their blood from food and form plaques.
• “There’s no connection whatsoever between cholesterol in food and cholesterol in blood,” Keys said in a 1997 interview. “None. And we’ve known that all along. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.”
• Half of all major adverse cardiovascular events in men (and a third of those in women), such as heart attack, stroke, or any procedure involving a stent or a graft, occur before the age of sixty-five. In men, one-quarter of all events occur before age fifty-four.

Atlas of Atherosclerosis Progression and Regression, by Herbert C. Stary

The endothelium acts as a semipermeable barrier between the vessel lumen and the arterial wall proper, controlling the passage of materials and nutrients and WBC into and out of the bloodstream. It also helps maintain our electrolyte and fluid balance; endothelial problems can lead to edema and swelling. It also dilates and contracts to allow increased or decreased blood flow, a process modulated by nitric oxide. Lastly, the endothelium regulates blood-clotting mechanisms.

• Lipoprotein particles will penetrate the barrier, into the subendothelial space. Normally, they enter, and then leave. This is what HDL particles generally do: particles tagged with apoA (HDL) can cross the endothelial barrier easily in both directions, in and out. LDL particles and other particles with the apoB protein are far more prone to getting stuck inside.
• The trouble starts when LDL particles stick in the arterial wall and subsequently become oxidized, meaning the cholesterol (and phospholipid) molecules they contain come into contact with reactive oxygen species (ROS). It’s the oxidation of the lipids on the LDL that kicks off the entire atherosclerotic cascade.
• Now that it is lodged in the subendothelial space and oxidized, rendering it somewhat toxic, the LDL/apoB particle refuses to leave and invites other LDLs. Many of these are also retained and oxidized. It is not an accident that the two biggest risk factors for heart disease, smoking and high blood pressure, cause damage to the endothelium. Smoking damages it chemically, while high blood pressure does so mechanically, but the end result is endothelial harm that leads to greater retention of LDL. As oxidized LDL accumulates, it causes more damage to the endothelium.
• The more apoB particles that you have in your circulation, not only LDL but VLDL and some others, the greater the risk that some of them will penetrate the endothelium and get stuck. So, to gauge the true extent of your risk, we have to know how many of these apoB particles are circulating in your bloodstream. That number is much more relevant than the total quantity of cholesterol that these particles are carrying.

If you take a healthy coronary artery and expose it to high enough concentrations of apoB particles, over a long enough time, a certain amount of LDL (and VLDL) will get stuck in that subendothelial space and become oxidized, which then leads to it sticking together in clumps or aggregates. In response, the endothelium summons monocytes.

• Monocytes are large white blood cells that enter the subendothelial space and transform into macrophages. The macrophage swallows up the aggregated or oxidized LDL, trying to remove it from the artery wall. But if it consumes too much cholesterol, then it blows up into a foam cell.
• When enough foam cells gather together, they form a “fatty streak”, a streak of fat that you can see during an autopsy of a splayed-open coronary artery. The fatty streak is a precursor of an atherosclerotic plaque.
• If an HDL particle arrives it can suck the cholesterol back out of the macrophages (delipidation). It then slips back across the endothelial layer and into the bloodstream, to deliver the excess cholesterol back to the liver and other tissues (including fat cells and hormone-producing glands) for reuse.
• Newer research suggests that HDL has multiple other atheroprotective functions that include helping maintain the integrity of the endothelium, lowering inflammation, and neutralizing or stopping the oxidation of LDL, like a kind of arterial antioxidant.
• In an attempt to control the damage, the “smooth muscle” cells in the artery wall then migrate to this toxic waste site and secrete a kind of matrix in an attempt to build a kind of barrier around it, like a scar. This matrix ends up as the fibrous cap on your brand-new arterial plaque.
• We might expect to see evidence of inflammation, such as elevated levels of C-reactive protein, a popular (but poor) proxy of arterial inflammation. But it’s still mostly flying below the medical radar. If you look at the coronary arteries with a CT scan at this very early stage, you will likely miss this if you’re only looking for calcium buildup. (You have a better chance with a CT angiogram, which he prefers to a calcium scan because it can also identify the noncalcified or “soft” plaque that precedes calcification.)
• As this maladaptive repair or remodeling process continues, the plaque will continue to grow. At first, this expansion is directed toward the outer arterial wall, but as it continues it may encroach on the lumen. This luminal narrowing, known as stenosis, can also be seen in an angiogram.
• At a certain point in this process, the plaque may start to become calcified. This is what shows up on a regular calcium scan. Calcification is merely another way in which the body is trying to repair the damage, by stabilizing the plaque to protect the arteries.
• If the plaque does become unstable, eroding or even rupturing, the damaged plaque may ultimately cause the formation of a clot, which can narrow and ultimately block the lumen of the blood vessel—or worse, break free and cause a heart attack or stroke. This is why we worry more about the noncalcified plaques than the calcified ones.
• Then, sudden demands on your circulatory system can trigger ischemia (decreased blood delivery of oxygen) or infarction (tissue death from no blood flow)/heart attack or stroke. 

Evidence has piled up pointing to apoB as far more predictive of cardiovascular disease than LDL-C, the standard “bad cholesterol” measure. According to an analysis published in JAMA Cardiology in 2021, each standard-deviation increase in apoB raises the risk of myocardial infarction by 38% in patients without a history of cardiac events or a diagnosis of cardiovascular disease (i.e., primary prevention).

Lp(a) (pronounced “el-pee-little-A”). This lipoprotein is formed when an LDL particle is fused with another, rarer type of protein called apolipoprotein(a), or apo(a) for short (not to be confused with apolipoprotein A or apoA, the protein that marks HDL particles). The apo(a) wraps loosely around the LDL particle, with multiple looping amino acid segments called “kringles”. The kringles are what make Lp(a) so dangerous: as the LDL particle passes through the bloodstream, they scoop up bits of oxidized lipid molecules and carry them along.

• Lp(a) may act as a sort of cleansing agent that gathers up unpleasant and potentially harmful lipid junk and delivers it to the liver. But because Lp(a) is a member of the apoB particle family, it also has the potential to penetrate the endothelium and get lodged in an artery wall; because of its structure, Lp(a) may be even more likely than a normal LDL particle to get stuck, with its extra cargo of lipids. Even worse, once in there, it acts partly as a thrombotic or pro-clotting factor, which helps to speed the formation of arterial plaques.
• Most people have relatively small concentrations of this particle, but some individuals can have as much as one hundred times more than others. The variation is largely genetic, and an estimated 20-30% of the US population has levels high enough that they are at increased risk; also, people of African descent tend to have higher levels of Lp(a), on average, than Caucasians.
• Lp(a) is particularly destructive to the aortic valve, one of the more important structures in the heart, by promoting the formation of tiny, bony particles in the valve leaflets, which leads to stenosis or narrowing of the aortic outlet.
• It does not seem to respond to behavioral interventions such as exercise and dietary changes the way that LDL-C does. PCSK9 inhibitors which are aimed at lowering apoB concentrations, do seem to be able to reduce Lp(a) levels by approximately 30%, but as yet there are no data suggesting that they reduce the excess events (heart attacks) attributable to that particle. Thus, the only real treatment for elevated Lp(a) right now is aggressive management of apoB. Though we can’t reduce Lp(a) directly, beyond what a PCSK9 inhibitor can do, we can lower the remaining apoB concentration sufficiently that we can reduce a patient’s overall risk.

When he looks at his patient’s blood panel for the first time, he looks at apoB and Lp(a). These two tell him the most when it comes to predicting the risk of ASCVD. ApoB not only tells the concentration of LDL particles (which is more predictive of disease than the concentration of cholesterol found within LDL particles, LDL-C), but it also captures the concentration of VLDL particles, which as members of the apoB family can also contribute to atherosclerosis. Furthermore, even someone whose apoB is low can still have a dangerously elevated Lp(a).

Many doctors might be shocked to see such a low LDL-C target: 10 to 20 mg/dL. Most guidelines consider lowering LDL-C to 70 mg/dL to be “aggressive,” even for secondary prevention in high-risk patients, such as those who have already had a heart attack.

• It’s also natural to ask whether such extremely low levels of LDL-C and apoB are safe, given the ubiquity and importance of cholesterol in the human body. However, infants (who presumably require the most cholesterol in order to meet the enormous demands of their rapidly growing central nervous system) have similarly low levels of circulating cholesterol, without any developmental impairment. The total amount of cholesterol contained in all our lipoproteins—not just LDL, but also HDL and VLDL—represents only about 10-15% of our body’s total pool of cholesterol. 

We must also pay attention to other markers of risk, such as insulin, visceral fat, and homocysteine, an amino acid that in high concentrations is strongly associated with increased risk of heart attack, stroke, and dementia.

• While having very low HDL-C is associated with higher risk, it does not appear to be causal. This is why drugs aimed at raising HDL-C have generally failed to reduce risk and events in clinical trials.
• Whatever benefit HDLs provide in the battle for arterial supremacy, it seems to be driven by their function—which doesn’t seem to be related to their cholesterol content. But we cannot test for HDL functionality, and until we have a better grasp on how HDL actually works, it will likely remain elusive as a target of therapy.

About a third to half of people who consume high amounts of saturated fats (which sometimes goes hand in hand with a ketogenic diet) will experience a dramatic increase in apoB particles, which we don’t want. Monounsaturated fats, found in high quantities in extra virgin olive oil, macadamia nuts, and avocados (among other foods), do not have this effect, so it’s better to consume more of these, up to about 60% of total fat intake.

Statins inhibit cholesterol synthesis, prompting the liver to increase the expression of LDLR, taking more LDL out of circulation. They may have other benefits too, including an apparent anti-inflammatory effect.

• About 5% of patients experience side effects, most notably statin-related muscle pain. Also, a smaller subset of patients taking statins experience a disruption in glucose homeostasis, which may explain why statins are associated with a small increase in the risk for type 2 diabetes. Another fraction of patients experiences an asymptomatic rise in liver enzymes, which is even more common in patients also taking the drug ezetimibe. All these side effects are reversible when the drug is discontinued.

CHAPTER 8: The Runaway Cell: New Ways to Address the Killer That Is Cancer

Mortality rates from cardiovascular disease and cerebrovascular disease have dropped by two-thirds since the middle of the twentieth century. But cancer still kills Americans at almost exactly the same rate as it did fifty years ago.

We have made some progress against a few specific cancers, notably leukemia. For adults with leukemia, ten-year survival rates nearly doubled between 1975 and 2000, leaping from 23% to 44%. Survival rates for Hodgkin’s and non-Hodgkin’s lymphomas have increased as well, especially the former. Yet these represent relatively small victories in a “war” that has not gone particularly well.

Combining surgery and radiation therapy is pretty effective against most local, solid-tumor cancers. But while we’ve gotten fairly good at this approach, we have essentially maxed out our ability to treat cancers this way.

Metastatic cancers can be slowed by chemotherapy, but they usually come back, often more resistant to treatment. Our benchmark for success in a patient, or remission, is typically five-year survival.

What Is Cancer?

A gene called PTEN, which normally stops cells from growing or dividing, is often mutated or “lost” in people with cancer, including about 31% of men with prostate cancer and 70% of men with advanced prostate cancer.

The second property that defines cancer cells is metastasis, which enables a cancerous cell in the breast to spread to the lung.

A handful of genes emerged as drivers, including TP53 (also known as p53, found in half of all cancers), KRAS (common in pancreatic cancer), PIC3A (common in breast cancer), and BRAF (common in melanoma), but very few if any of these well-known mutations were shared across all tumors. In fact, there didn’t seem to be any individual genes that “caused” cancer at all; instead, it seemed to be random somatic mutations that combined to cause cancers.

Traditional chemotherapy drugs attack the replicative cycle of cells, and because cancer cells are rapidly dividing, the chemo agents harm them more severely than normal cells. But many important noncancerous cells are also dividing frequently, such as those in the lining of the mouth and gut, the hair follicles, and the nails, which is why typical chemotherapy agents cause side effects like hair loss and gastrointestinal misery. Robert Gatenby points out, those cancer cells that do manage to survive chemotherapy often end up acquiring mutations that make them stronger.

Many cancer cells have an altered metabolism, consuming huge amounts of glucose. Also, cancer cells seem to have an uncanny ability to evade the immune system, which normally hunts down damaged and dangerous cells—such as cancerous cells—and targets them for destruction.

Cancer Metabolism

Otto Warburg discovered that cancer cells had a high appetite for glucose, devouring it at up to 40x the rate of healthy tissues. But these cancer cells weren’t “respiring” the way normal cells do, consuming oxygen and producing lots of ATP via the mitochondria. They appeared to be using a different pathway that cells normally use to produce energy under anaerobic conditions despite having plenty of oxygen available to them.

In normal aerobic respiration, a cell can turn one molecule of glucose into as many as 36 units of ATP. But under anaerobic conditions, that same amount of glucose yields only 2 units of ATP. This phenomenon was dubbed the Warburg effect, and even today, one way to locate potential tumors is by injecting the patient with radioactively labeled glucose and then doing a PET scan to see where most of the glucose is migrating. Areas with abnormally high glucose concentrations indicate the possible presence of a tumor.

When Watson, Crick, and Franklin discovered the structure of DNA in 1953, biochemists jumped ship to become molecular biologists interested in finding out how DNA sequences were used to make nucleic acids and protein components. Eventually, even Watson admitted that cancer research should go back to metabolism rather than just genetics.

The Warburg effect generates lots of by-products, such as lactate, a substance that is also produced during intense exercise. In fact, turning glucose into lactate creates so many extra molecules that the authors argued that the relatively small amount of energy it produces may actually be the “by-product.”

Normal aerobic cellular respiration produces only energy, in the form of ATP, plus water and carbon dioxide, which aren’t much used as building materials. The Warburg effect, also known as anaerobic glycolysis, turns the same amount of glucose into a little bit of energy and a whole lot of chemical building blocks, which are then used to build new cells rapidly. Thus, the Warburg effect is how cancer cells fuel their own proliferation. 

This is not the only explanation for how the Warburg effect benefits a cancer cell. Another theory is that it helps protect the tumor from immune cells by making the tumor microenvironment less hospitable because of lower pH caused by the generation of lactic acid and reactive oxygen species. See Liberti and Locasale (2016).

The American Cancer Society reports that excess weight is a leading risk factor for both cancer cases and deaths, second only to smoking.

• Obesity is strongly associated with thirteen different types of cancers, including pancreatic, esophageal, renal, ovarian, and breast cancers, as well as multiple myeloma. Type 2 diabetes also increases the risk of certain cancers, by as much as double in some cases (such as pancreatic and endometrial cancers). And extreme obesity (BMI ≥ 40) is associated with a 52% greater risk of death from all cancers in men, and 62% in women.
• Obesity, especially when accompanied by accumulation of visceral fat, helps promote inflammation, as dying fat cells secrete an array of inflammatory cytokines into the circulation. This chronic inflammation helps create an environment that could induce cells to become cancerous. It also contributes to the development of insulin resistance, causing insulin levels to creep upwards.

PI3K helps to open a gate in the cell wall, allowing glucose to flood in to fuel its growth. Cancer cells possess mutations that turn up PI3K activity while shutting down the tumor-suppressing protein PTEN. When PI3K is activated by insulin and IGF-1, the insulin-like growth factor, the cell is able to use glucose to fuel its growth. Thus, insulin acts as a kind of cancer enabler, accelerating its growth.

New Treatments

Lew Cantley’s discovery of the PI3K pathway led to the development of a class of drugs that target cancer metabolism. Three of these drugs, known as PI3K inhibitors, have been FDA approved for certain relapsed leukemias and lymphomas, and a fourth was approved in late 2019 for breast cancer. But they haven’t seemed to work as well as predicted, based on PI3K’s role in the growth pathways of cancer cells. Also, they had the side effect of raising blood glucose, which in turn provokes a jump in insulin levels and IGF-1 as the cell tries to work around PI3K inhibition—the very thing we want to avoid.

A study found that a combination of a ketogenic diet and PI3K inhibitors improved the responses to treatment of mice that had been implanted with human cancer tumors.

A study by Valter Longo found that fasting, or a fasting-like diet, increases the ability of normal cells to resist chemotherapy, while rendering cancer cells more vulnerable to the treatment. It may seem counterintuitive to recommend fasting to cancer patients, but researchers have found that it caused no major adverse events in chemotherapy patients, and in some cases, it may have improved the patients’ quality of life.

More studies need to be done, but the working hypothesis is that because cancer cells are so metabolically greedy, they are more vulnerable to a reduction in nutrients—or more likely, a reduction in insulin, which activates the PI3K pathway essential to the Warburg effect.

The Promise of Immunotherapy

CAR-T treatments have proven successful only against one specific type of cancer called B-cell lymphoma. All B-cells, normal and cancerous alike, express a protein called CD19, which is the target used by the CAR-T cell to kill them. Since we can live without B-cells, CAR-T works by obliterating all CD19-bearing cells.

In addition to CAR-T, there is a class of drugs called “checkpoint inhibitors,” which take an opposite approach to the T cell–based therapies. Instead of activating T cells to go kill the cancer, the checkpoint inhibitors help make the cancer visible to the immune system.

• Steve Rosenberg, figured out how cancer cells hide from the immune system by exploiting so-called checkpoints that are normally supposed to regulate our T cells and keep them from going overboard and attacking our normal cells, which would lead to autoimmune disease. Essentially, the checkpoints ask the T cells, one last time, “Are you sure you want to kill this cell?”
• Allison found that if you blocked specific checkpoints, particularly CTLA-4, you effectively unmasked the cancer cells, and the T cells would then destroy them.
• In 2018, Allison shared the Nobel Prize with Tasuku Honjo, who had been working on a slightly different checkpoint called PD-1. This led to two approved checkpoint-inhibiting drugs, ipilimumab (Yervoy) and pembrolizumab (Keytruda), targeting CTLA-4 and PD-1, respectively.
• About a third of cancers can be treated with immunotherapy, and of those patients, just one-quarter will survive. That means that only 8% of potential cancer deaths could be prevented by immunotherapy, according to an analysis by oncologists Nathan Gay and Vinay Prasad.
• Genetic analysis reveals that some 80% of epithelial cancers (solid organ tumors) possess mutations that the immune system can recognize, thus making them potentially vulnerable to immune-based treatments.

One promising technique is adoptive cell therapy (or adoptive cell transfer, ACT). ACT is a class of immunotherapy whereby supplemental T cells are transferred into a patient, like adding reinforcements to an army, to bolster their ability to fight their own tumor. These T cells have been genetically programmed with antigens specifically targeted at the patient’s individual tumor type. It is similar to CAR-T cell therapy, but much broader in scope.

• The idea behind ACT is basically to overwhelm the cancer with a huge number of targeted T cells, like supplementing an army with a brigade of trained assassins.
• There are two ways to do ACT. First, take a sample of a patient’s tumor and isolate those T cells that do recognize the tumor as a threat. These are called tumor-infiltrating lymphocytes (TILs), but there may only be a few million of them, not enough to mount a complete response against the tumor. By removing the TILs from the body and multiplying them by a factor of 1,000 or so, and then reinfusing them into the patient, you can expect to see a better response. Alternatively, T cells can be harvested from the patient’s blood and genetically modified to recognize the specific tumor.
• 80-90% of so-called complete responders to immunotherapy remain disease-free fifteen years out. Far better than the short-term, five-year time horizon of conventional cancer treatment.
• To learn more about the story of immunotherapy, read Charles Graeber’s 2018 book, Breakthrough, which goes into greater detail about Jim Allison’s work with checkpoint inhibitors.

Early Detection

A patient with metastatic colon cancer, which means the cancer has spread past their colon and adjacent lymph nodes to another part of the body, such as the liver, will typically be treated with a combination of three drugs known as the FOLFOX regimen. This treatment yields a median survival time of about 31.5 months, meaning about half of patients live longer than this, and half do not. Regardless, virtually none of these patients will be alive in ten years. If a patient undergoes successful surgery for stage III colon cancer, which means all the cancer was removed and there was no visible spread to distant organs, then the follow-up care is treatment with the exact same FOLFOX treatment regimen. But in this scenario, fully 78.5% of these patients will survive for another six years, more than twice as long as median survival for the metastatic patients, and 67% of them will still be alive ten years after surgery.

Patients with HER2-positive metastatic breast cancer can expect a median survival time of just under five years, with standard treatment consisting of three chemotherapy drugs. But if a patient has a smaller (< 3 cm), localized, HER2+ tumor that is removed surgically, plus adjuvant treatment with just two of these chemo drugs, she will have a 93% chance of living for at least another seven years without disease.

Reliable screening methods for only five: lung (for smokers), breast, prostate, colorectal, and cervical.

About 70% of people who are diagnosed with CRC before the age of fifty have no family history or hereditary conditions linked to the disease.

In his practice they typically encourage average-risk individuals to get a colonoscopy by age forty, and even sooner if anything in their history suggests they may be at higher risk. They then repeat the procedure as often as every 2-3 years, depending on the findings from the previous colonoscopy. If a sessile (flat) polyp is found, they’re inclined to do it sooner than if the endoscopist finds nothing at all. Two or three years might seem like a very short window of time to repeat such an involved procedure, but colon cancer has been documented to appear within the span of as little as six months to two years after a normal colonoscopy.

Colorectal cancer is one of the easiest to detect, with the greatest payoff in terms of risk reduction. It remains one of the top five deadliest cancers in the United States, behind lung (#1) and breast/prostate (#2 for women/men), and just ahead of pancreas (#4) and liver (#5) cancers. Of these five, though, CRC is the one we have the best shot at catching early.

Other cancers that are relatively easy to spot on visual examination include skin cancer and melanomas. The pap smear for cervical cancer is another well-established, minimally invasive test that he recommends his patients do yearly. Internal organ cancers can’t be seen directly, so we must rely on imaging technologies such as low-dose CT scans for lung cancer. These scans are currently recommended for smokers and former smokers, but he thinks they should be used more widely, because about 15% of lung cancers are diagnosed in people who have never smoked. Lung cancer is the #1 cause of cancer deaths overall, but lung cancer in never-smokers ranks seventh.

MRI has an advantage over CT as it does not produce any ionizing radiation but still provides good resolution. One newer technique that can enhance the ability of a screening MRI to differentiate between cancer and noncancer is diffusion-weighted imaging with background subtraction (DWI). The idea behind DWI is to look at water movement in and around tissue, at different points in time very close to each other (between 10-15 microseconds, typically). If the water is held or trapped, then it could indicate the presence of a tightly packed cluster of cells, a possible tumor. So, the higher the density of cells, the brighter the signal on the DWI phase of MRI, making DWI functionally a radiographic “lump detector.” Right now, DWI works best in the brain because it suffers least from movement artifacts.

• While the sensitivity of this test is very high (good at finding cancer and few false negatives), the specificity is relatively low (not as good at telling you when you don’t have cancer and a lot of false positives).

The Grail test, known as Galleri, looks at methylation patterns of cell-free DNA, which are basically chemical changes to the DNA molecules that suggest the presence of cancer. Using very-high-throughput screening and a massive AI engine, the Galleri test can glean two crucial pieces of information from this sample of blood: Is cancer present? And if so, where is it? From what part of the body did it most likely originate?

• The Galleri test proved to have a very high specificity, about 99.5%, meaning only 0.5% of tests yielded a false positive. If the test says you have cancer, somewhere in your body, then it is likely that you do. The trade-off is that the resulting sensitivity can be low, depending on the stage.
• This test still has much higher resolution than radiographic tests such as MRI or mammogram. Those imaging-based tests require “seeing” the tumor, which can happen only when the tumor reaches a certain size. With Galleri, the test is looking at cell-free DNA, which can come from any size tumor—even ones that remain invisible to imaging tests.
• The cancers that shed more cell-free DNA also tend to be more aggressive and deadly, and are thus the cancers that we want to detect, and treat, as soon as possible. This technology is still in its infancy, but he is hopeful that pairing different diagnostic tests ranging from radiographic (e.g., MRI) to direct visualization (e.g., colonoscopy) to biological/genetic (e.g., liquid biopsy) will allow them to correctly identify the cancers that need treatment the soonest, with the fewest possible false positives.

CHAPTER 9: Chasing Memory: Understanding Alzheimer’s Disease and Other Neurodegenerative Diseases

Lewy body dementia affects cognition, while Parkinson’s disease is considered primarily a movement disorder, although it does also result in cognitive decline. In the United States, about 6 million people are diagnosed with Alzheimer’s disease, while about 1.4 million have Lewy body dementia, and 1 million have been diagnosed with Parkinson’s. Beyond that, there are a variety of less common but also serious neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) and Huntington’s disease.

There are e4/e4-carrying centenarians without any signs of dementia, likely because they have other genes that protect them from e4; for example, a certain variant of the gene Klotho (KL), called kl-vs, seems to protect carriers of e4 from developing dementia. And plenty of “normal” e3/e3 carriers will still go on to develop Alzheimer’s.

Understanding Alzheimer’s

Amyloid-beta is a by-product that is created when amyloid precursor protein (APP), a membrane protein that is found in neuronal synapses, is cleaved into three pieces. Normally, APP is split into two pieces, and everything is fine. But when APP is cut in thirds, one of the resulting fragments then becomes “misfolded,” meaning it loses its normal structure (and thus its function) and becomes chemically stickier, prone to aggregating in clumps.

Amyloid also triggers the aggregation of another protein called tau, which in turn leads to neuronal inflammation and, ultimately, brain shrinkage. 

Scientists have identified a handful of genetic mutations that promote very rapid amyloid-beta accumulation, all but ensuring that someone will develop the disease, often at a fairly young age. These mutations, the most common of which are called APP, PSEN1, and PSEN2, typically affect the APP cleavage. In families carrying these genes, very-early-onset Alzheimer’s disease is rampant, with family members often developing symptoms in their thirties and forties.

• People with Down syndrome also tend to accumulate large amounts of amyloid plaques over time, because of genes related to APP cleavage that reside on chromosome 21.
• A 2013 analysis of preserved tissue from Auguste Deter’s brain found that she did in fact carry the PSEN1 mutation, one of the early-onset dementia genes.

Several dozen drugs have been developed that target amyloid-beta, but these drugs have yet to show benefit in improving patients’ cognitive function or slowing the progression of the disease.

Just as Alzheimer’s disease is defined (rightly or wrongly) by accumulations of amyloid and tau, Lewy body dementia and Parkinson’s disease are associated with the accumulation of a neurotoxic protein called alpha-synuclein, which builds up in aggregates known as Lewy bodies. The APOE e4 variant not only increases someone’s risk for Alzheimer’s but also significantly raises their risk of Lewy body dementia as well as Parkinson’s disease with dementia, further supporting the notion that these conditions are related on some level.

Can Neurodegenerative Disease Be Prevented?

While those of African descent are at an overall increased risk of developing Alzheimer’s disease, for unclear reasons, APOE e4 seems to present less risk to them than to people of Caucasian, Asian, and Hispanic descent. Regardless of APOE genotype, however, Alzheimer’s disease is almost twice as common in women than in men.

Some scientists believe there may be something about menopause, and the abrupt decline in hormonal signaling, that sharply increases the risk of neurodegeneration in older women. In particular, it appears that a rapid drop in estradiol in women with an e4 allele is a driver of risk; that, in turn, suggests a possible role for perimenopausal hormone replacement therapy in these women.

Other reproductive history factors, such as the number of children the woman has had, age of first menstruation, and exposure to oral contraceptives, may also have a significant impact on Alzheimer’s risk and later life cognition. New research suggests that women are more prone to accumulate tau. The end result is that women have a greater age-adjusted risk of Alzheimer’s, as well as faster rates of disease progression overall, regardless of age and educational level.

While female Alzheimer’s patients outnumber men by two to one, the reverse holds true for Lewy body dementia and Parkinson’s, both of which are twice as prevalent in men. Yet Parkinson’s also appears to progress more rapidly in women than in men, for reasons that are not clear.

Parkinson’s may show up as subtle changes in movement patterns, a frozen facial expression, stooped posture or shuffling gait, a mild tremor, or even changes in a person’s handwriting (which may become small and cramped). Someone in the early stages of Lewy body dementia may exhibit similar physical symptoms, but with slight cognitive changes as well; both may exhibit alterations in mood, such as depression or anxiety. 

Tests that cover every domain of cognition and memory assess executive function, attention, processing speed, verbal fluency and memory (recalling a list of words), logical memory (recalling a phrase in the middle of a paragraph), associative memory (linking a name to a face), spatial memory (location of items in a room), and semantic memory (how many animals you can name in a minute, for example).

• Frontal and vascular dementia primarily affects the frontal lobe, a region of the brain responsible for executive functioning such as attention, organization, processing speed, and problem solving. So, these forms of dementia rob an individual of such higher-order cognitive features.
• Alzheimer’s disease predominantly affects the temporal lobes, so the most distinct symptoms relate to memory, language, and auditory processing (forming and comprehending speech).
• Parkinson’s manifests primarily as a movement disorder, resulting from (in part) a deficiency in producing dopamine.

The more of these networks and subnetworks that we have built up over our lifetime, via education or experience, or by developing complex skills such as speaking a foreign language or playing a musical instrument, the more resistant to cognitive decline we will tend to be. The brain can continue functioning more or less normally, even as some of these networks begin to fail. This is called “cognitive reserve,” and it has been shown to help some patients to resist the symptoms of Alzheimer’s disease.

There is a parallel concept known as “movement reserve” that becomes relevant with Parkinson’s disease. People with better movement patterns, and a longer history of moving their bodies, such as trained or frequent athletes, tend to resist or slow the progression of the disease as compared to sedentary people.

Alternatives to Amyloid

On autopsy, Alzheimer’s brains often display marked calcification of the blood vessels and capillaries that feed them as well as vascular damage.

Jack de la Torre: Didn’t agree with the amyloid hypothesis as in his experiments he found that when he had restricted the amount of blood flowing to the rats’ brains, over time they had developed symptoms remarkably similar to those of Alzheimer’s disease in humans: memory loss and severe atrophy of the cortex and hippocampus.

Brain cells metabolize glucose in a different way from the rest of the body; they do not depend on insulin, instead absorbing circulating glucose directly, via transporters that essentially open a gate in the cell membrane. This enables the brain to take top priority to fuel itself when blood glucose levels are low. If we lack new sources of glucose, the brain’s preferred fuel, the liver converts our fat into ketone bodies, as an alternative energy source that can sustain us for a very long time, depending on the extent of our fat stores. (Unlike muscle or liver, the brain itself does not store energy.)

• When our fat runs out, we will begin to consume our own muscle tissue, then our other organs, and even bone, all in order to keep the brain running at all costs. The brain is the last thing to shut off.

His “barf bag theory,” was that Alzheimer’s disease is primarily a vascular disorder of the brain. The dementia symptoms that we see result from a gradual reduction in blood flow, which eventually creates what he calls a “neuronal energy crisis,” which in turn triggers a cascade of unfortunate events that harms the neurons and ultimately causes neurodegeneration. The amyloid plaques and tangles come later, as a consequence rather than a cause. “We believed, and still do, that amyloid-beta is an important pathological product of neurodegeneration,” de la Torre wrote recently, “…[but] it is not the cause of Alzheimer’s disease.”

It has been established that people with a history of cardiovascular disease are at a higher risk of developing Alzheimer’s disease. Evidence also demonstrates a linear relationship between cognitive decline and increased intimal media thickness in the carotid artery, a major blood vessel that feeds the brain. Cerebral blood flow already declines naturally during the aging process, and this arterial thickening, a measure of arterial aging, could cause a further reduction in cerebral blood supply. In all, some two dozen known risk factors for Alzheimer’s disease also happen to reduce blood flow, including high blood pressure, smoking, head injury, and depression, among others.

• Improved neuroimaging techniques have confirmed not only that cerebral perfusion is decreased in brains affected by Alzheimer’s disease but also that a drop in blood flow seems to predict when a person will transition from preclinical Alzheimer’s disease to MCI, and on to full-fledged dementia.

Having type 2 diabetes doubles or triples your risk of developing Alzheimer’s disease, about the same as having one copy of the APOE e4 gene. On a purely mechanistic level, chronically elevated blood glucose, as seen in type 2 diabetes and prediabetes/insulin resistance, can directly damage the vasculature of the brain. But insulin resistance alone is enough to elevate one’s risk.

• Insulin receptors are highly concentrated in the hippocampus, the memory center of the brain. Several studies have found that spraying insulin right into subjects’ noses— administering it as directly as possible into their brains—quickly improves cognitive performance and memory, even in people who have already been diagnosed with Alzheimer’s disease. One study found that intranasal insulin helped preserve brain volume in Alzheimer’s patients. Clearly, it is helpful to get glucose into neurons; insulin resistance blocks this.
• Reduction of glucose metabolism appears to be especially dramatic in brain regions that are also affected in Alzheimer’s disease, including the parietal lobe, which is important for processing and integrating sensory information; and the hippocampus of the temporal lobe, which is critical to memory. Just like reduced blood flow, reduced glucose metabolism essentially starves these neurons of energy, provoking a cascade of responses that include inflammation, increased oxidative stress, mitochondrial dysfunction, and ultimately neurodegeneration itself.

The Role of APOE e4

e4 seems to accelerate other risk factors and driver mechanisms for Alzheimer’s, particularly metabolic factors such as reduced brain glucose metabolism.

The protein for which it codes, APOE, plays an important role in both cholesterol transport and glucose metabolism. It serves as the main cholesterol carrier in the brain, moving cholesterol across the blood-brain barrier to supply the neurons with the large amounts of it they require. There is also some evidence that the APOE e4 protein may also cause early breakdown of the blood-brain barrier itself, making the brain more susceptible to injury and eventual degeneration.

For millions of years, our post-primate ancestors were e4/e4. The e3 mutation showed up about 225,000 years ago, while e2 is a relative latecomer, arriving only in the last 10,000 years. Data from present-day populations with a high prevalence of e4 suggest that it may have been helpful for survival in environments with high levels of infectious disease: children carrying APOE e4 in Brazilian favelas are more resistant to diarrhea and have stronger cognitive development.

• This survival benefit may have been due to the role of APOE e4 in promoting inflammation, which can be beneficial in some situations (e.g., fighting infection) but harmful in others (e.g., modern life).
• People with Alzheimer’s disease often have high levels of inflammatory cytokines such as TNF-alpha and IL-6 in their brains, and studies have also found higher levels of neuroinflammation in e4 carriers.
• Not only are e4 carriers more likely to develop metabolic syndrome in the first place, but the APOE e4 protein may be partially responsible for this, by disrupting the brain’s ability to regulate insulin levels and maintain glucose homeostasis in the body. This phenomenon becomes apparent when these patients are on continuous glucose monitoring.

The Preventative Plan

Our goal is to improve glucose metabolism, inflammation, and oxidative stress. One possible recommendation would be to switch to a Mediterranean-style diet, relying on more monounsaturated fats and fewer refined carbohydrates, in addition to regular consumption of fatty fish.

• Higher doses of DHA may be required because of e4-induced metabolic changes and dysfunction of the blood-brain barrier.
• This is also one area where a ketogenic diet may offer a real functional advantage: when someone is in ketosis, their brain relies on a mix of ketones and glucose for fuel. Studies in Alzheimer’s patients find that while their brains become less able to utilize glucose, their ability to metabolize ketones does not decline.

The single most powerful item in our preventive tool kit is exercise, which has a two-pronged impact on Alzheimer’s disease risk: it helps maintain glucose homeostasis, and it improves the health of our vasculature.

• Focus on steady endurance exercise to improve mitochondrial efficiency. It also helps manage high cortisol levels due to stress; stress and anxiety-related risk seem more significant in females.
• A study looking at nearly half a million patients in the United Kingdom found that grip strength was strongly and inversely associated with the incidence of dementia.

While we are in deep sleep our brains are sweeping away intracellular waste that can build up between our neurons. Sleep disruptions and poor sleep are potential drivers of increased risk of dementia. If poor sleep is accompanied by high stress and elevated cortisol levels, that acts almost as a multiplier of risk, as it contributes to insulin resistance and damaging the hippocampus at the same time. Furthermore, hypercortisolemia (excess cortisol due to stress) impairs the release of melatonin, the hormone that normally signals to our brains that it is time to go to sleep.

When the brain is deprived of inputs, it withers. Patients with hearing loss miss out on socializing, intellectual stimulation, and feeling connected; prescribing them hearing aids may help relieve some symptoms.

Researchers have found that one pathogen in particular, a microbe called P. gingivalis that commonly causes gum disease, is responsible for large increases in levels of inflammatory markers such as IL-6. P. gingivalis has also shown up inside the brains of patients with Alzheimer’s disease, although scientists are not certain that this bacterium is directly causing dementia.

At least four dry sauna sessions per week, of at least twenty minutes per session, at 179 degrees Fahrenheit (82 degrees Celsius) or hotter seems to be the sweet spot to reduce the risk of Alzheimer’s by about 65% (and the risk of ASCVD by 50%).

Other potential interventions that have shown some promise in studies include lowering homocysteine with B vitamins, while optimizing omega-3 fatty acids. Higher vitamin D levels have been correlated with better memory in e4/e4 patients but it’s difficult to know from the current literature if this means supplementing with vitamin D will reduce risk of AD. Hormone replacement therapy for women during the transition from perimenopause to menopause seems promising, especially for women with at least one copy of e4.

Principles

1. WHAT’S GOOD FOR THE HEART IS GOOD FOR THE BRAIN. That is, vascular health (meaning low apoB, low inflammation, and low oxidative stress) is crucial to brain health.

2. WHAT’S GOOD FOR THE LIVER (AND PANCREAS) IS GOOD FOR THE BRAIN. Metabolic health is crucial to brain health.

3. TIME IS KEY. We need to think about prevention early, and the more the deck is stacked against you genetically, the harder you need to work and the sooner you need to start. As with cardiovascular disease, we need to play the long game.

4. OUR MOST POWERFUL TOOL FOR PREVENTING COGNITIVE DECLINE IS EXERCISE. Exercise appears to act in multiple ways (vascular, metabolic) to preserve brain health.

Part III

CHAPTER 10: Thinking Tactically: Building a Framework of Principles That Work for You

New patients:

a. Are they overnourished or undernourished? That is, are they taking in too many or too few calories?

b. Are they undermuscled or adequately muscled?

c. Are they metabolically healthy or not?

They rely heavily on data in their decision-making and developing tactics, including static biomarkers such as triglycerides and liver function tests, as well as dynamic biomarkers such as oral glucose tolerance tests, along with anthropometric measures such as data on body composition, visceral adipose tissue, bone density, and lean mass.

CHAPTER 11: Exercise: The Most Powerful Longevity Drug

Going from no exercise to 90 minutes per week can reduce all-cause mortality by 14%. Regular exercisers have been found to live as much as a decade more than sedentary people. They also have better health and less morbidity related to metabolic dysfunction.

Cardiovascular/aerobic fitness: how efficiently your muscles can extract and deliver oxygen. Peak aerobic cardiorespiratory fitness, measured as VO2 max (volume of O2 a person can use, per kg of bodyweight, per minute), is one of the most powerful markers of longevity. It represents the maximum rate at which a person can utilise oxygen. The more oxygen your body is able to use, the higher the VO2 max, which leads to greater ATP production.

• An average 45-year-old man will have a VO2 max of around 40ml/kg/min, while an elite endurance athlete will likely score around 40ml/kg/min.
• A person who smokes has a 40% greater all-cause mortality risk than somebody who doesn’t, whereas someone with a below-average VO2 max is at double the risk compared to someone in the top quartile. Someone in the bottom quartile is nearly four times more likely to die than someone in the top quartile and five times compared to an elite-level VO2 max person.
• The magnitude of the effect size is large, the data is consistent and reproducible across disparate populations, there is a dose-dependent response, there is biologic plausibility, and all experimental data on exercise in humans suggest it supports improved health.

A 10-year observational study found that those with low muscle mass were at 40-50% greater risk of mortality than controls. More specifically, muscular made the greatest difference. Those with low- muscle strength were at double the risk of death, plus metabolic syndrome had a 3-3.33 times greater risk.

There are no drugs or interventions that come close to rivalling the benefits of exercise. It has been found that it is just as good or better than any drugs for reducing mortality of coronary heart disease, diabetes, or stroke. Exercise strengthens the heart and circulatory system, and improves mitochondrial health, which in turn improves glucose and fat metabolism.

• Exercise prompts cytokine release which helps to strengthen our immune system and stimulate the growth of new and stronger muscles and bone density.
• Endurance exercise helps to release BDNF, which improves hippocampal health and function, as well as improves brain vasculature to preserve brain volume.
• Exercise is more effective at improving health-span than lifespan. However, when cardiovascular fitness declines this leads to lower cardiac output, primarily due to a reduced maximum heart rate, we then lose strength and muscle mass, our bones grow fragile, our joints stiffen, and our balance falters. Meaning, preserving cardiovascular fitness and muscle mass and strength will increase longevity by improving health-span (fewer falls and withdrawal from society in old age).

The Centenarian Decathlon (example)

1. Hike 1.5 miles on a hilly trail. Requires a VO2 max of about 30ml/kg/min.
2. Get up off the floor under your own power, using a max of one arm for support
3. Pick up a child from the floor
4. Carry two five-pound bags of groceries for five blocks
5. Lift a twenty-pound suitcase into the overhead compartment of a plane
6. Balance on one leg for 30s, eyes open
7. Have sex
8. Climb four flights of stairs in three minutes
9. Open a jar
10. Do 30 consecutive jump-rope skips

Over the next 30-40 years (after 40) your muscle strength will decrease by about 8-17% per decade.

CHAPTER 12: Training 101: How to Prepare for the Centenarian Decathlon

Cardio: long, steady endurance work, such as jogging or cycling or swimming, where we train zone 2 and maximal aerobic efforts, where VO2 max comes into play.

Strength: Use your muscles to counter resistance, such as gravity, weights, or elastic bands to grow stronger. The goal is to gain muscle and strength whilst avoiding injury.

Stability: A solid foundation that allows you to move without getting injured.

Aerobic Efficiency: Zone 2

Healthy mitochondria, which burn glucose and fat for fuel, are essential for maintaining the brain’s health and managing oxidative stress and inflammation. The healthier and more efficient your mitochondria, the greater your ability to utilize fat, which allows greater metabolic flexibility.

Zone 2 is a speed where you can still speak but the conversation will be a little strained. When we exercise in Zone 2, most of the work being done is by slow twitch (type 1) fibres. These are dense with mitochondria. Once you pick up the pace, more fast-twitch fibres are recruited, which are more forceful but less efficient. They also generate more lactate because of the way they generate ATP. Lactate is not necessarily bad in trained athletes as it can be recycled as fuel. It becomes a problem when it binds with hydrogen ions to become lactic acid. The more efficient the mitochondria, the better able we are to clear lactate and create more force in Zone 2. If you “feel the burn” you are creating more than you can clear.

• You want to keep your lactate levels around 1.7-2.0 millimoles to stay in Zone 2.

Professional cyclists whose oxygen consumption and CO2 exhaled were measured during a stationary bike session (80% of maximum HR) could produce large amounts of power whilst burning fat. Comparatively, those with metabolic syndrome relied on glucose, even at the beginning of the exercise.

People with obesity or other metabolic problems will tend to have higher resting lactate levels, a sign that their mitochondria are not functioning optimally.

One of the hallmarks of ageing is the decline in the number and quality of mitochondria. Aerobic exercise stimulates mitochondrial biogenesis and mitophagy. Also, the more mitochondria we have the greater our capacity to dispose of glycogen stores from the muscle rather than it turning to fat stores or remaining in plasma.

Glucose uptake increases 100-fold during exercise compared to rest. It occurs via two pathways: non-insulin-mediated glucose uptake (NIMGU), where it is transported across the cell membrane without insulin or the usual insulin-signalled way. Exercise activates NIMGU. A type 1 diabetic may benefit from a zone 2 walk to clean up glucose from the body.

Zone 2 can also increase cerebral blood flow and BDNF, improving Alzheimer’s prevention.

Maximum Aerobic Output: VO2 Max

At VO2 max we use a combination of aerobic and anaerobic pathways to produce energy, but we are at our maximum rate of oxygen consumption. Zone 2 increases VO2 somewhat, but you really want to train VO2 max work specifically.

The bulk of the literature suggests it is possible to improve an elderly person’s aerobic capacity by about 13% over 8-10 weeks of training and 17% after 24-52 weeks.

To improve VO2 max, we should supplement our Zone 2 work with 1-2 VO2 max workouts per week.

• On a stationary bike, treadmill, or rower spend 4 minutes at the maximum pace you can sustain. Not an all-out sprint, but very difficult. Then do another 4 minutes easily to allow the HR to decrease to about 100 beats. Repeat 4-6 times and cool down.

Strength

An 80-year-old man will have 40% less muscle tissue in their quad than he did at 25. We lose muscle strength about 2-3 times faster than we lose muscle mass and we lose power 2-3 times faster than we lose strength. This is because fast-twitch muscle fibres atrophy predominantly.

Bone mineral density is measured with DEXA in both hips and the lumbar spine. Bone density declines on a parallel trajectory to muscle mass, peaking in our 20s and declining thereafter. This is particularly fast in menopausal women because estrogen is essential for bone strength.

• Other risk factors are genetics, smoking history, long use of corticosteroids (asthma and autoimmunity conditions), drugs that block estrogen (breast cancer drugs), low muscle mass, and being undernourished.

When Attia detects BMD decline in a middle-aged person he uses these strategies:

• Optimize nutrition, focusing on protein and total energy needs.
• Heavy load-bearing activities. Bones respond to mechanical tension and estrogen is the key hormone in mediating the mechanical signal to a chemical one.
• HRT
• Drugs to increase BMD

He structures his own training around exercises that improve the following:

1. Grip strength, how hard you can grip with your hands, which involves everything from your hands to your lats. Almost all actions begin with the grip.
2. Attention to both concentric and eccentric loading for all movements. We need to be able to lift the weight up and put it back down, slowly and with control. Rucking down hills is a great way to work on eccentric strength because it forces you to put on the “brakes.”
3. Pulling motions, at all angles from overhead to in front of you, which also require grip strength (e.g., pull-ups and rows).
4. Hip-hinging movements, such as the deadlift and squat, but also step-ups, hip-thrusters, and countless single-leg variants of exercises that strengthen the legs, glutes, and lower back.

Grip strength literature suggests that better grip strength in midlife and beyond demonstrates a decreased risk of overall mortality.

• In 1985, men aged 20-24 had an average right-handed grip strength of 121 pounds, while in 2015 this dropped to 101.
• Males should be able to carry half their bodyweight in each hand (full bodyweight in total) and women should be able to carry 75% of theirs.
• You can also dead-hang for as long as you can. Men for 2 minutes and women for 90s at the age of 40.

Eccentric and concentric strength is also an important measure, such as a step up and a slow 3-second descent. Pulling and hip-hinging are good exercises to focus on for longevity too.

CHAPTER 13: The Gospel of Stability: Relearning How to Move to Prevent Injury

The theory behind dynamic neuromuscular stabilization (DNS) is that the sequence of movements that young children undergo on their way to learning how to walk is not random or accidental but part of a program of neuromuscular development that is essential to our ability to move correctly. As we go through this sequence of motions, our brain learns how to control our body and develop ideal patterns of movement.

• The point of DNS is to retrain our bodies and brains in those patterns of movement that we learned as little kids.
• Home (rehabps.com)
• PRI | Home (posturalrestoration.com)

Poor or disordered breathing can affect our motor control and make us susceptible to injury, studies have found. In one experiment, researchers found that combining a breathing challenge (reducing the amount of oxygen available to study subjects) with a weight challenge reduced the subjects’ ability to stabilize their spine.

• The way in which someone breathes gives tremendous insight to how they move their body and, more importantly, how they stabilize their movements.

One simple test that we ask of everyone, early on, looks like this: lie on your back, with one hand on your belly and the other on your chest, and just breathe normally, without putting any effort or thought into it.

Mr Stay Puft: HYPERINFLATED. This person is an upper-chest breather who tends to pull up into spinal extension for both respiration and stability. Their lumbar spine is in hyperextension, while their pelvis lives in anterior (forward) tilt, meaning their butt sticks out. They are always pulling up into themselves, trying to look like they are in charge. They have a limited sense of grounding in the feet, and limited ability to pronate to absorb shock (the feet turn outward, or supinate). All of the above makes them quite susceptible to lower back pain, as well as tightness in their calves and hips.

• When he inhaled, his ribs would flare out and up. This got air into his lungs, but it also pulled his center of mass forward. To balance, his spine would curve into kyphosis, and his butt would stick out. This hyperextended his hamstrings, effectively disconnecting them from the rest of his body, so he was unable to access these muscles.
• He needed to think about getting air out, the exhale—while someone who tends more toward the Sad Guy type should work on getting air in, inhaling via the nose rather than the mouth.
• The Stay Puft people tend to need more grounding through the feet and more work with weight in front of them so as to pull their shoulders and hips into a more neutral position. Beth typically has someone like him hold a weight in front of my body, a few inches in front of the sternum. This forces his center of mass back, more over his hips. Try it with a light dumbbell or a milk carton. It’s a subtle but noticeable change of position.

Sad Guy: COMPRESSED. Everything about them is sort of scrunched down and tight. Their head juts forward, and so do their shoulders, which kind of roll to the front because they are always pulling forward to try and take in more air. Their midback rolls in an overly flexed or hyperkyphotic posture, and they have limited neck and upper limb motion. Sometimes their lower legs rotate externally, and the feet overpronate. Gravity is weighing them down.

• With the Sad Guys, Beth tends to work more on cross-body rotation, having them swing the arms across the body to open up the chest and shoulders. She is cautious about loading the back and shoulders, preferring to begin with body weight exercises and split-leg work, such as a walking lunge with a reach, either across the body or to the ceiling, on each step.

Yogini: UNCONTROLLED. They have an extreme passive range of motion (flexibility) and extremely limited ability to control it. They can often do a toe touch and put their palms flat on the floor, but because of their lack of control, these people are quite prone to joint injuries. They are always trying to find themselves in space, fidgeting and twitching; they compensate for their excessive flexibility by trying to stabilize primarily with their neck and jaw. It is very hard for them to put on lean mass (muscle). Sometimes they have very high anxiety, and possibly also a breathing pattern disorder.

• Beth recommends doing “closed-chain” exercises such as push-ups, using the floor or wall for support, as well as using exercise machines with a well-defined and limited range of motion, given their lack of joint control. Machines are important for them, and also for people who have not lifted much or at all, because machines keep their movements within safe boundaries. For the Yoginis, and newbies, it’s important to become more aware of where they are in space, and where they are relative to their range of motion.

Proper breathing affects so many other physical parameters: rib position, neck extension, the shape of the spine, even the position of our feet on the ground. The way in which we breathe reflects how we interact with the world.

• Beth Lewis likes to start with an exercise that builds awareness of the breath and strengthens the diaphragm, which not only is important to breathing but is an important stabilizer in the body. She has the patient lie on their back with legs up on a bench or chair, and asks them to inhale as quietly as possible, with the least amount of movement possible. An ideal inhalation expands the entire rib cage—front, sides, and back—while the belly expands at the same time, allowing the respiratory and pelvic diaphragm to descend. The telltale is that it is quiet. A noisy inhale looks and feels more dramatic, as the neck, chest, or belly will move first, and the diaphragm cannot descend freely, making it more difficult to get air in.
• Now, exhale fully through pursed lips for maximum compression and air resistance, to strengthen the diaphragm. Blow all that air out, fully emptying yourself before your shoulders round or your face or jaw gets tense. Very soon, you will see how a full exhale prepares you for a good inhale, and vice versa. Repeat the process for five breaths and do two to three sets. Be sure to pause after each exhale for at least two counts to hold the isometric contraction.
• In DNS, you learn to think of the abdomen as a cylinder, surrounded by a wall of muscle, with the diaphragm on top and the pelvic floor below. When the cylinder is inflated, what you’re feeling is called intra-abdominal pressure (IAP). It’s critical to true core activation and foundational to DNS training. Learning to fully pressurize the cylinder, by creating IAP, is important to safe movement because the cylinder effectively stabilizes the spine.
• Breathe all the way in, so you feel as if you are inflating the cylinder on all sides and pulling air all the way down into your pelvic floor, the bottom of the cylinder. You’re not actually “breathing” there, in the sense that air is actually entering your pelvis; you’re seeking maximal lung expansion, which in turn sort of pushes your diaphragm down. With every inhale, focus on expanding the cylinder around its whole diameter and not just raising the belly. If you do this correctly, you will feel the entire circumference of your shorts expand evenly around your waist, even in the back, not just in the front. When you exhale, the diaphragm comes back up, and the ribs should rotate inward again as your waistband contracts.
• This inhalation develops tension, and as you exhale, pushing out air, you keep that muscular tension all around your cylinder wall. Intra-abdominal pressure is the basic foundation for everything that we do in stability training.

Our feet are literally the foundation for any movement we might make. Whether we’re lifting something heavy, walking or running (or rucking), climbing stairs, or standing waiting for a bus, we’re always channeling force through our feet. Unfortunately, too many of us have lost basic strength and awareness of our feet, thanks to too much time spent in shoes, especially big shoes with thick soles.

• They play a crucial role in dampening force before it reaches the knees, the hips, and the back.
• Toe yoga is a series of exercises intended to improve the dexterity and intrinsic strength of our toes, as well as our ability to control them with our mind. Our toes are crucial to walking, running, lifting, and, most importantly, decelerating or lowering. The big toe especially is necessary for the push-off in every stride. Lack of big-toe extension can cause gait dysfunction and can even be a limiting factor in getting up off the floor unassisted as we age. If toe strength is compromised, everything up the chain is more vulnerable – ankle, knee, hip, spine.
• Beth tells her students to think of their feet as having four corners, each of which needs to be rooted firmly on the ground at all times. As you stand there, try to feel each “corner” of each foot pressing into the ground: the base of your big toe, the base of your pinky toe, the inside and outside of your heel.
• Try to lift all ten toes off the ground and spread them as wide as you can. Now try to put just your big toe back on the floor, while keeping your other toes lifted. Now do the opposite: keep four toes on the floor and lift only your big toe. Then lift all five toes, and try to drop them one by one, starting with your big toe.
• Beth compares pronation to driving a car with too little air in the tires, meaning you kind of slosh through your movements, unable to transfer force efficiently to the ground. Supination, on the other hand, is like having overinflated tires, so you skid and bounce around. Your feet are unable to absorb shock, and all that bouncing and jarring gets transferred straight to the ankles, hips, knees, and lower back. Both syndromes, pronation and supination, also expose us to risk of plantar fasciitis and knee injury, among other issues.
• One key test is to have people stand with one foot in front of the other and try to balance. Now close your eyes and see how long you can hold the position. Ten seconds is a respectable time; in fact, the ability to balance on one leg at ages fifty and older has been correlated with longevity, just like grip strength.

The spine has three parts: lumbar (lower back), thoracic (midback), and cervical (neck) spine. Radiologists see so much degeneration in the cervical spine, brought on by years of hunching forward to look at phones, that they have a name for it: “tech neck.”

• This is why it’s important to put down the phone, and try to develop some proprioceptive awareness around your spine, so that you really understand what extension (bending back) and flexion (bending forward) feel like, at the level of each single vertebra. The easiest way to start this process is to get on your hands and knees and go through an extremely slowed-down, controlled Cat/Cow sequence.
• You have to slow down, moving so slowly and deliberately from one end of your spine to the other that you can feel each individual vertebra changing position, all the way from your tailbone up to your neck, until your spine is bent like a sway-backed cow. Then reverse the movement, tilting your pelvis forward and bending your spine one vertebra at a time until your back is arched again.

The shoulder joint is controlled by a complex set of muscles that attach in various positions to the scapula and the upper portion of the humerus, the long bone in the upper arm (glenohumeral joint).

• Scapular CARs, for controlled articular rotations: Stand with your feet shoulder-width apart and place a medium to light resistance band under your feet, one handle in each hand (or a very light dumbbell). Keeping your arms at your sides, raise your shoulder blades, and then squeeze them back and together; this is retraction, which is where we want them to be when under load. Then drop them down your back. Finally, bring them forward to the starting point. The goal is to learn enough control so that we can move our scapulae in smooth circles. 

CHAPTER 14: Nutrition 3.0: You Say Potato, I Say “Nutritional Biochemistry”

1. Are you undernourished, or overnourished?
2. Are you undermuscled, or adequately muscled?
3. Are you metabolically healthy or not?

A nutritional intervention aimed at correcting a serious problem (e.g., highly restricted diets, even fasting, to treat obesity, NAFLD, and type 2 diabetes) might be different from a nutritional plan calibrated to maintain good health (e.g., balanced diets in metabolically healthy people).

Nutrition boils down to a few rules:

• Don’t eat too many calories, or too few
• Consume sufficient protein and essential fats
• Obtain the vitamins and minerals you need
• Avoid pathogens like E. coli and toxins like mercury or lead.
• Beyond that, we know relatively little with complete certainty.

What We Sort of Know About Nutritional Biochemistry (and How We Sort of Know It)

Efficacy tests how well the intervention works under perfect conditions. Effectiveness tests how well intervention works under real-world conditions, in real people.

PREDIMED (Spanish study): rather than telling the nearly 7,500 subjects exactly what they were supposed to eat, the researchers gave one group a weekly “gift” of a liter of olive oil, which was meant to nudge them toward other desired dietary changes (i.e., to eat the sorts of things that one typically prepares with olive oil). A second group was given a quantity of nuts each week and told to eat an ounce per day, while the control group was simply instructed to eat a lower-fat diet, with no nuts, no excess fat on the meat they did eat, no sofrito (a garlicky Spanish tomato sauce with onions and peppers that sounds delicious), and no fish.

• The study was meant to last six years, but in 2013 the investigators announced that they had halted it prematurely, after just four and a half years, because the results were so dramatic. The group receiving the olive oil had about a one-third lower incidence (31%) of stroke, heart attack, and death than the low-fat group, and the mixed-nuts group showed a similar reduced risk (28%). It was deemed unethical to continue the low-fat arm of the trial. The nuts-or-olive-oil “Mediterranean” diet appeared to be as powerful as statins, in terms of number needed to treat (NNT), for primary prevention of heart disease, meaning in a population that had not yet experienced an “event” or a clinical diagnosis.
• It helped that the subjects already had at least three serious risk factors, such as type 2 diabetes, smoking, hypertension, elevated LDL-C, low HDL-C, overweight or obesity, or a family history of premature coronary heart disease. Yet despite their elevated risk, the olive oil (or nuts) diet had clearly helped them delay disease and death. A post hoc analysis of PREDIMED data also found cognitive improvement in those allocated the Mediterranean-style diet(s), versus cognitive decline in those allocated the low-fat diet.

The Bradford Hill criteria:

1. Strength of the association (i.e., effect size)
2. Consistency (i.e., reproducibility)
3. Specificity (i.e., is it an observation of disease in a very specific population at a specific site, with no other likely explanation?)
4. Temporality (i.e., does the cause precede the effect?)
5. Dose response (i.e., does the effect get stronger with a higher dose?)
6. Plausibility (i.e., does it make sense?)
7. Coherence (i.e., does it agree with data from controlled experiments in animals?)
8. Experiment (i.e. is there experimental evidence to back up the findings?)
9. Analogy (i.e., the effect of similar factors may be considered).

CHAPTER 15: Putting Nutritional Biochemistry into Practice: How to Find the Right Eating Pattern for You

Almost all diets rely on at least one of the following three strategies:

1. CALORIC RESTRICTION (CR): eating less in total, but without paying attention to what is being eaten or when it’s being eaten.

• From the standpoint of pure efficacy, CR or caloric restriction is the winner. This is how bodybuilders shed weight while holding on to muscle mass, and it also allows the most flexibility with food choices. The catch is that you have to do it perfectly, tracking every single thing you eat, and not succumbing to the urge to cheat or snack.

2. DIETARY RESTRICTION (DR): eating less of some particular element(s) within the diet (e.g., meat, sugar, fats).

• Pick a type of food, and then don’t eat that food. It only works if that food is both plentiful and significant enough that eliminating it will create a caloric deficit. Saying you’re going on the “no lettuce” diet is pretty much doomed to fail. And you can still overeat while adhering perfectly to a particular DR.

3. TIME RESTRICTION (TR): restricting eating to certain times, up to and including multiday fasting

• A downside of this approach is that most people who try it end up very protein deficient. One not uncommon scenario with TR is that a person loses weight on the scale, but their body composition alters for the worse: they lose lean mass (muscle) while their body fat stays the same or even increases.

CR: Calories Matter

If we take in more energy than we require, the surplus ends up in our adipose tissue, one way or another. If this imbalance continues, we exceed the capacity of our “safe” subcutaneous fat tissue, and excess fat spills over into our liver, our viscera, and our muscles.

Summarising two rhesus monkey studies where the Wisconsin study gave a standard American diet (SAD) styled food to CR and non-CR monkeys and the NIH study gave more “natural” food. Wisconsin CR monkeys lived longer due to not eating as much crap.

1. Avoiding diabetes and related metabolic dysfunction, especially by eliminating or reducing junk food is very important to longevity.
2. There appears to be a strong link between calories and cancer, the leading cause of death in the control monkeys in both studies. The CR monkeys had a 50% lower incidence of cancer.
3. The quality of the food you eat could be as important as the quantity. If you’re eating the SAD, then you should eat much less of it.
4. Conversely, if your diet is high quality to begin with, and you are metabolically healthy, then only a slight degree of caloric restriction can be beneficial.

DR: The Nutritional Biochemistry “Diet”

One reason carbohydrate restriction is so effective is that it tends to reduce appetite as well as food choices. But some people have a harder time maintaining it than others.

While fat restriction also limits food choices, it can be less effective at reducing appetite if you pick the wrong low-fat foods to eat (e.g., high-carb junk food). 

Any form of DR that restricts protein, for example, is probably a bad idea for most people, because it likely also impairs the maintenance or growth of muscle. Similarly, replacing carbohydrates with lots of saturated fats can backfire if it sends your apoB concentration (and thus your cardiovascular disease risk) sky-high.

How well do you tolerate carbohydrates? How much protein do you require? What sorts of fats suit you best? How many calories do you require each day? What is the optimal combination for you?

Alcohol:

It has such potent effects on our metabolism, and it is so calorically dense at 7 kcal/g (closer to the 9 kcal/g of fat than the 4 kcal/g of both protein and carbohydrate).

It’s an “empty” calorie source that offers zero nutrition value; the oxidation of ethanol delays fat oxidation, which is the exact opposite of what we want if we’re trying to lose fat mass; and drinking alcohol very often leads to mindless eating.

Ethanol is a potent carcinogen, and chronic drinking has strong associations with Alzheimer’s disease, mainly via its negative effect on sleep, but possibly via additional mechanisms. Like fructose, alcohol is preferentially metabolized in the liver, with well-known long-term consequences in those who drink to excess. Last, it loosens inhibitions around other kinds of food consumption.

Carbohydrates:

Most carbohydrates are broken down to glucose, which is consumed by all cells to create energy in the form of ATP. Excess glucose, beyond what we need immediately, can be stored in the liver or muscles as glycogen for near-term use or stored in adipose tissue (or other places) as fat. This decision is made with the help of the hormone insulin, which surges in response to the increase in blood glucose.

Continuous glucose monitoring (CGM) has proved especially useful in patients with APOE e4, where they often see big glucose spikes. In these patients, the behavior modification that CGM prompts is an important part of their Alzheimer’s disease prevention strategy.

1. Not all carbs are created equal. The more refined the carb, the faster and higher the glucose spike. Less processed carbohydrates and those with more fiber, on the other hand, blunt the glucose impact. He tries to eat more than 50g of fiber per day.
2. Rice and oatmeal are surprisingly high glycemic, despite not being particularly refined; more surprising is that brown rice is only slightly less glycemic than long-grain white rice.
3. Fructose does not get measured by CGM, but because fructose is almost always consumed in combination with glucose, fructose-heavy foods will still likely cause blood-glucose spikes.
4. Timing, duration, and intensity of exercise matter a lot. In general, aerobic exercise seems most efficacious at removing glucose from circulation, while high-intensity exercise and strength training tend to increase glucose transiently, because the liver is sending more glucose into the circulation to fuel the muscles. Don’t be alarmed by glucose spikes when you are exercising.
5. A good versus bad night of sleep makes a world of difference in terms of glucose control. All things equal, it appears that sleeping just five to six hours (versus eight hours) accounts for about a 10 to 20 mg/dL jump in peak glucose response, and about 5 to 10 mg/dL in overall levels.
6. Stress, presumably, via cortisol and other stress hormones, has a surprising impact on blood glucose, even while one is fasting or restricting carbohydrates. The effect is most visible during sleep or periods long after meals.
7. Non starchy veggies, such as spinach or broccoli, have virtually no impact on blood sugar. 
8. Foods high in protein and fat (e.g., eggs, beef short ribs) have virtually no effect on blood sugar (assuming the short ribs are not coated in sweet sauce), but large amounts of lean protein (e.g., chicken breast) will elevate glucose slightly. Protein shakes, especially if low in fat, have a more pronounced effect (particularly if they contain sugar).
9. Stacking the above insights is very powerful. So, if you’re stressed out, sleeping poorly, and unable to make time to exercise, be as careful as possible with what you eat.
10. Tracking his glucose has a positive impact on his eating behavior. It creates the Hawthorne effect, where study subjects change their behavior because they are being observed. 

An athlete can consume more carbs per day because they are using them and have a greater ability to dispose of glucose via the muscles and more efficient mitochondria. Sleep disruption or reduction also impairs glucose homeostasis over time.

Stress prompts an elevation in cortisol, which in turn stimulates the liver to drip more glucose into circulation (which they detect during sleep). This tells him that they need to address a person’s stress levels and probably also their sleep quality.

Protein:

Unlike carbs and fat, protein is not a primary source of energy. We do not rely on it in order to make ATP, nor do we store it the way we store fat (in fat cells) or glucose (as glycogen). If you consume more protein than you can synthesize into lean mass, you will simply excrete the excess in your urine as urea. The twenty amino acids that make up proteins are the building blocks for our muscles, our enzymes, and many of the most important hormones in our body. They go into everything from growing and maintaining our hair, skin, and nails to helping form the antibodies in our immune system. On top of this, we must obtain nine of the twenty amino acids that we require from our diet, because we can’t synthesize them.

For active people with normal kidney function, one gram per pound of body weight per day (or 2.2 g/kg/day) is a good place to start—nearly triple the minimal recommendation.

• So, if someone weighs 180 pounds, they need to consume a minimum of 130g of protein per day, and ideally closer to 180g, especially if they are trying to add muscle mass.
• It should not be taken in one sitting but rather spread out over the day to avoid losing amino acids to oxidation (i.e., using them to produce energy when we want them to be available for muscle protein synthesis).
• A six-ounce serving of chicken, fish, or meat will provide about 40 to 45g (at about 7g of actual protein per ounce of meat), so our hypothetical 180-pound person should eat four servings a day.

The protein found in plants is there for the benefit of the plant, which means it is largely tied up in indigestible fiber, and therefore less bioavailable to the person eating it. Because much of the plant’s protein is tied to its roots, leaves, and other structures, only about 60-70% of what you consume is contributing to your needs.

• Some of this can be overcome by cooking the plants, but that still leaves us with the second issue. The distribution of amino acids is not the same as in animal protein. In particular, plant protein has less of the essential amino acids methionine, lysine, and tryptophan, potentially leading to reduced protein synthesis.

Whey protein isolate is richer in available amino acids than soy protein isolate. So, if you forgo protein from animal sources, you need to do the math on your protein quality score.

Digestible Indispensable Amino Acid Score (DIAAS) and the Protein Digestibility Corrected Amino Acid Score (PDCAAS).

Layman suggests focusing on a handful of important amino acids, such as leucine, lycine, and methionine. Focus on the absolute amount of these amino acids found in each meal, and be sure to get about 3-4g per day of leucine and lycine and at least one gram per day of methionine for maintenance of lean mass. If you are trying to increase lean mass, you’ll need even more leucine, closer to 2-3g per serving, four times per day.

One study found that giving elderly people supplements containing essential amino acids (that is, mimicking some effects of increasing dietary protein) lowered their levels of liver fat and circulating triglycerides. Another study in men with type 2 diabetes found that doubling their protein intake from 15-30% of total calories, while cutting carbohydrates by half, improved their insulin sensitivity and glucose control. Eating protein also helps us feel satiated, inhibiting the release of the hunger-inducing hormone ghrelin, so we eat fewer calories overall.

Fat:

While carbohydrates are primarily a source of fuel and amino acids are primarily building blocks, fats are both. They are very efficient fuel for oxidation and also the building blocks for many of our hormones (in the form of cholesterol) and cell membranes.

Three types of fats: saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA).

• A “monounsaturated” fat refers to the fact that the chain is not fully saturated with hydrogens, and in this case, the reason is that there is one (i.e., mono) double bond in the chain of carbons rather than a single bond.
• A “saturated” fat simply has more hydrogen atoms attached to its carbon chain. Saturated fats are more stable and do not easily react with other molecules. Since saturated fats are linear and can be densely packed together, they can be more solid at room temperature. Because unsaturated fats have kinks in their structure, they are more likely to be liquid at room temperature.
• With polyunsaturated fats, there is more than one double bond. Double bonds cause bends in the carbon chain and make the fatty acid more prone to oxidation. Within PUFA, we separate the omega-6 from the omega-3 variants (also a chemical distinction having to do with the position of the first double bond).
• The omega-3 PUFA can be broken down into marine (EPA, DHA) and nonmarine sources (ALA). Salmon and other oil-rich seafood provide the former, nuts and flaxseed the latter.

All foods that contain fats typically contain all three categories of fat: PUFA, MUFA, and SFA.

They try to boost MUFA closer to 50–55%, while cutting SFA down to 15–20% and adjusting total PUFA to fill the gap. They also boost EPA and DHA, those fatty acids that are likely important to brain and cardiovascular health, with marine fat sources and/or supplementation. They titrate the level of EPA and DHA in their patients’ diets by measuring the amount of each found in the membranes of their red blood cells (RBC), using a specialized but readily available blood test. Their target depends on a person’s APOE genotype and other risk factors for neurodegenerative and cardiovascular disease, but for most patients the range they look for is between 8-12% of RBC membrane composed of EPA and DHA.

• Putting all these changes into practice typically means eating more olive oil and avocados and nuts, cutting back on (but not necessarily eliminating) things like butter and lard, and reducing the omega-6-rich corn, soybean, and sunflower oils, while also looking for ways to increase high-omega-3 marine PUFAs from sources such as salmon and anchovies.

TR: The Case for (and Against) Fasting

There is no denying that some good things happen when we are not eating. Insulin drops dramatically because there are no incoming calories to trigger an insulin response. The liver is emptied of fat in a fairly short order. Over time, within three days or so, the body enters “starvation ketosis,” where fat stores are mobilized to fulfill the need for energy, yet at the same time, hunger virtually disappears. This is likely due to the high levels of ketones that this state produces, which tamp down feelings of hunger.

Fasting over long periods also turns down mTOR, the pro-growth and pro-aging pathway. This would also be desirable, one might think, at least for some tissues. At the same time, lack of nutrients accelerates autophagy, the cellular “recycling” process that helps our cells become more resilient, and it activates FOXO, the cellular repair genes that may help centenarians live so long. In short, fasting triggers many of the physiological and cellular mechanisms that we want to see.

There are three distinct categories of time-restricted feeding.

• First, we have the short-term eating windows, where someone will limit their consumption of food to a specific time frame, such as six or eight hours out of the day. In practice, that could mean skipping breakfast, eating a first meal at 11 a.m. and finishing dinner by 7 p.m. every evening; or someone could eat breakfast at 8 a.m., another meal at 2 p.m., and nothing thereafter. Although, sixteen hours without food simply isn’t long enough to activate autophagy or inhibit chronic mTOR elevation, or engage any of the other longer-term benefits of fasting that we would want to obtain.
• Next, we have alternate-day fasting (ADF). This is where you eat normally or even a bit more than normal one day, and then very little (or nothing) the next. The cost, in terms of lost lean mass (muscle) and reduced activity levels, simply does not justify whatever benefits it may bring.
• “Hypocaloric” because you are not truly fasting in the sense of eating no food at all. You are eating just enough to quell the worst hunger pangs, but not so much that your body thinks you are fully fed.

CHAPTER 16: The Awakening: How to Learn to Love Sleep, the Best Medicine for Your Brain

Old Man Blood

Studies have found that sleep-deprived people tend to have older, flabbier skin.

Even short-term sleep can cause profound insulin resistance. A University of Chicago study with healthy, young participants showed that those sleeping 4.5 hours a night for 4 days had insulin levels of obese middle-aged diabetics and a 50% reduction in glucose disposal capacity.

Poor/short sleep = 17% increase in hypertension, 16% increase in cardiovascular diseases, 26% increase in coronary heart disease, and 38% increase in obesity.

High-stress interferes with sleep and lack of sleep increases stress. Cortisol raises blood pressure; causes glucose to be released from the liver, while inhibiting uptake and utilisation of glucose in the muscle and fat tissues, perhaps to prioritize glucose to the brain. This results in elevated blood glucose due to stress-induced insulin resistance. Elevated blood glucose leads to type 2 diabetes.

Poor sleep also affects our relationship with food. It suppresses levels of leptin and increases ghrelin. Making us irrationally hungry and more likely to reach for high-calorie and sugary foods. It has been found that sleep-deprived subjects eat up to an additional 300 calories the following day.

Sleep and Cardiovascular Disease

Poor sleep will result in a higher resting heart rate and lower HRV. Sleeping less than 6 hours was associated with a 20% increase in heart attack risk.

Sleep and the Brain

Poor sleep was long considered to be one of the first symptoms of incipient Alzheimer’s disease. Subsequent research, however, has pointed out that chronic bad sleep is a powerful cause of AD and dementia.

Deep sleep is where we clear the cache of short-term memories in the hippocampus and select the important ones for long-term storage in the cortex.

• During deep sleep, cerebrospinal fluid moves between the neurons to remove intercellular junk. Without this, amyloid and tau build-up occurs.
• Successfully treating sleep disturbances may delay the onset of MCI by about 11 years.

REM sleep is important for forming new connections, creativity, and problem-solving. It is also useful for procedural memory and separating emotions from the memory of the experience.

• Without the work of REM sleep disconnecting the valence from a memory, we live in a constant state of anxiety as memories are triggering emotions all over again. Just like PTSD. Noradrenaline prevents the brain from relaxing enough to get into REM.
• Without REM sleep we also struggle to read others’ facial expressions.

GH typically releases an hour after we go to sleep (deep sleep), whereas inhibiting GH reduces deep sleep. GH reaches its peak during adolescence and then declines thereafter.

Sleeping Better

Rules:

1. Don’t drink any alcohol, and if you must, limit yourself to one drink before about 6 p.m. Alcohol probably impairs sleep quality more than any other factor we can control. Don’t confuse the drowsiness it produces with quality sleep.
2. Don’t eat anything less than three hours before bedtime. It’s best to go to bed with just a little bit of hunger (although being ravenous can be distracting.)
3. Abstain from stimulating electronics, beginning two hours before bed. Try to avoid anything involving a screen if you’re having trouble falling asleep. If you must, use a setting that reduces the blue light from your screen.
4. For at least one hour before bed, if not more, avoid doing anything that is anxiety-producing or stimulating, such as reading work email or checking social media. These get the ruminative, worry-prone areas of our brain humming, which is not what you want.
5. For those who have access, spend time in a sauna or hot tub prior to bed. Once you get into the cool bed, your lowering body temperature will signal to your brain that it’s time to sleep. 
6. The room should be cool, ideally in the mid-sixties. The bed should be cool too. Use a “cool” mattress or one of the many bed-cooling devices out there. These are also great tools for couples who prefer different temperatures at night, since both sides of the mattress can be controlled individually.
7. Darken the room completely. Make it dark enough that you can’t see your hand in front of your face with your eyes open, if possible. If that is not achievable, use an eye shade. 
8. Give yourself enough time to sleep (sleep opportunity). This means going to bed at least eight hours before you need to wake up, preferably nine. If you don’t even give yourself a chance to get adequate sleep, then the rest of this chapter is moot.
9. Fix your wake-up time and don’t deviate from it, even on weekends. If you need flexibility, you can vary your bedtime, but make it a priority to budget for at least eight hours in bed each night.
10. Don’t obsess over your sleep, especially if you’re having problems. If you need an alarm clock, make sure it’s turned away from you so you can’t see the numbers. Clock-watching makes it harder to fall asleep. And if you find yourself worrying about poor sleep scores, give yourself a break from your sleep tracker.

CHAPTER 17: Work in Progress: The High Price of Ignoring Emotional Health

Trauma generally falls into five categories:

1. Abuse (physical or sexual, but also emotional or spiritual)
2. Neglect
3. Abandonment
4. Enmeshment (the blurring of boundaries between adults and children)
5. Witnessing tragic events

Trauma, big T or little t, means having experienced moments of perceived helplessness.

The most important thing about childhood trauma is not the event itself but the way the child adapts to it. Children are remarkably resilient, and wounded children become adaptive children. The problems begin when these adaptive children grow up to become maladaptive, dysfunctional adults.

This dysfunction is represented by the four branches of the trauma tree:

1. Addiction, not only to vices such as drugs, alcohol, and gambling, but also to socially acceptable things such as work, exercise, and perfectionism
2. Codependency, or excessive psychological reliance on another person
3. Habituated survival strategies, such as a propensity to anger and rage
4. Attachment disorders, difficulty forming and maintaining connections or meaningful relationships with others

The DSM is an attempt to organize and codify all of the forms of mental disorders, to scientize it and also to facilitate insurance reimbursement.

Mental health encompasses disease-like states such as clinical depression and schizophrenia, which are complex and difficult to treat but are present with recognizable symptoms. Emotional health has more to do with the way we regulate our emotions and manage our interpersonal relationships.

The practice of DBT is predicated on learning to execute concrete skills, repetitively, under stress, that aim to break the chain reaction of negative stimulus → negative emotion → negative thought → negative action.

• DBT consists of four pillars joined by one overarching theme. The overarching theme is mindfulness, which gives you the ability to work through the other four: emotional regulation (getting control over our emotions), distress tolerance (our ability to handle emotional stressors), interpersonal effectiveness (how well we make our needs and feelings known to others), and self-management (taking care of ourselves, beginning with basic tasks like getting up in time to go to work or school).
• Many behaviors expand this window: exercise, sound sleep, good nutrition, time with my family, medications such as antidepressants or mood stabilizers, deep social connections, spending time in nature, and recreational activities that do not emphasize self-judgment.
• One simple tactic he uses is inducing an abrupt sensory change—typically, by throwing ice water on his face, taking a cold shower, or stepping into an ice bath. This simple intervention stimulates the vagus nerve, which causes our heart rate and respiratory rate to slow and switches us into a calm, parasympathetic mode (and out of our fight-or-flight sympathetic mode). Interventions like these are often enough to help refocus and think about a situation more calmly and constructively.
• Another technique is slow, deep breathing: four seconds to inhale, six seconds to exhale. Repeat. As the breath goes, the nervous system follows.
• Michael Easter: there is actual research suggesting that exposing oneself to the fractal geometric patterns in nature can reduce physiological stress, and that these effects show up on an EEG.

“All that time, I had been obsessed about longevity for the wrong reason. I was not thinking about a long, healthy life ahead; instead, I was mourning the past. I was trapped by the pain that my past had caused and was continuing to cause. I wanted to live longer, I think, only because deep down I knew I needed more runway to try to make things right. But I was only looking backward, not forward.”