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Notes from "Outlive: The Science & Art of Longevity" by Dr. Peter Attia

"Outlive" is one of the best books I've ever read. It provides a no-nonsense roadmap to living longer and staying healthier by avoiding the major diseases of aging that lead to death and a poor quality of life. The time to start implementing these strategies is now – no matter how old you are. Everyone who likes living should read this book!


The only way to create a better future for yourself – to set yourself on a better trajectory – is to start thinking about it and taking action now.

Peter defines 3 eras of medicine:

Medicine 1.0 - Exemplified by Hippocrates and lasting 2,000 years after his death, consisting of observation and guesswork.

Medicine 2.0 - Arrived in the mid-nineteenth century with the advent of the germ theory of disease. Medicine 2.0 is our current system, consisting of treating injury and disease when they occur.

Medicine 3.0 - The goal of this new medicine is not to patch people up and get them out the door, removing their tumors and hoping for the best, but rather to prevent the tumors from appearing and spreading in the first place. Or to avoid that first heart attack. Or to divert someone from the path to Alzheimer's disease. Our treatments, and our prevention and detection strategies, need to change to fit the nature of these diseases, with their long, slow prologues.

Medicine 3.0 has 4 main points:

  1. Medicine 3.0 places a far greater emphasis on prevention than treatment.

  2. Medicine 3.0 considers the patient has a unique individual.

  3. In Medicine 3.0 our starting point is the honest assessment and acceptance of risk – including the risk of doing nothing.

  4. Where Medicine 2.0 focuses largely on lifespan, and is almost entirely geared towards staving off death, Medicine 3.0 pays far more attention to maintaining healthspan, the quality of life.

The key difference between Medicine 2.0 in Medicine 3.0 have to do with how and when we apply our tactics. Typically, Medicine 2.0 steps in only when something is acutely wrong, like an infection or a broken bone, with short-term fixes for the immediate problem. In Medicine 3.0, our tactics must become interwoven into our daily lives. We eat, breathe, and sleep them – literally.

Because medicine 2.0 often drags out lifespan in the context of low healthspan, it lengthens the window of morbidity, the period of disease and disability at the end of life. People are sicker for longer before they die. Shortening the period of decline at the end of life and lengthening the period of healthy life, or healthspan, is called compression of morbidity. This is what Medicine 3.0 seeks to do.

Researchers have found potential genes that correlate with longevity including APOE (E2 variant), CETP, APOC3, and FOXO3. FOXO3 belongs to a family of "transcription factors," which regulate how other genes are expressed – meaning whether they are activated or "silenced."

FOXO3 can be activated or suppressed by our own behaviors. For example, when we are slightly deprived of nutrients, or when we are exercising, FOXO3 tends to be more activated, which is what we want.

Chapter 5: Eat Less, Live Longer - The science of hunger and health

Rapamycin (being studied for longevity effects) acted directly on an intracellular protein complex called mTOR, for "mechanistic target of rapamycin." Why do we care about mTOR? Because this mechanism turns out to be one of the most important mediators of longevity at the cellular level. The job of mTOR it's basically to balance an organisms need to grow and reproduce against the availability of nutrients. When food is plentiful, mTOR is activated in 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 go into to a kind of "recycling" mode, breaking down cellular components and generally cleaning house. Cell division and growth slow down or stop, and reproduction is put on hold to allowed the organism to conserve energy.

The life-extending effects of caloric restriction seems to be almost universal.

Reducing the amount of nutrients available to a cell seems to trigger a group of pathways that enhance the cell's stress resistance and metabolic efficiency – all of them related, in someway, to mTOR. The first of these is an enzyme called AMP-activated protein kinase, or AMPK.

AMPK works to inhibit the activity mTOR, the cellular growth regulator. Specifically, it seems to be a drop in amino acids that induces mTOR to shut down, and with all the anabolic (growth) 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 an important cellular recycling process called autophagy, which means "self eating."

Autophagy is essential to life. If it shuts down completely, the organism dies. Imagine if you stopped taking out the garbage; your house would soon become uninhabitable. Except instead of trash bags, this cellular cleanup is carried out by specialized organelles called lysosomes, which package of the old proteins and other detritus, including pathogens, and grind them down (via enzymes) for reuse. In addition, the lysosomes also break up and destroy things called aggregates, which are clumps of damage proteins that accumulate over time. Protein aggregates have been implicated in diseases such as Parkinson's and Alzheimer's disease, so getting rid of them is good; 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. Mice who lack one specific autophagy succumb to neurodegeneration within 2 to 3 months.

As we get older autophagy declines. This very important cellular mechanism can be triggered by certain kinds of interventions, such as temporary reduction in nutrients (as when we are exercising and fasting) – and the drug rapamycin. Rapamycin has several side effects though, including immunosuppression.

What we eat and how we metabolize it appear to play an outside role in longevity.

Chapter 6: The Crisis of Abundance - Can our ancient genes cope with our modern diet?

NAFLD (non-alcoholic fatty liver disease) is highly correlated with both obesity and hyperlipidemia (excessive cholesterol).

Rising levels of the liver enzyme alanine amino transferase (ALT) are often the first clue that something is wrong with the liver.

It's important to understand that one looking at biomarkers "normal" is not the same as "healthy."

Metabolic syndrome (MetSyn) is defined in terms of the following five criteria:

  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 inches in women)

  5. elevated fasting glucose (>110 mg/dL)

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

Obesity and metabolic dysfunction are not the same thing.

Metabolism is the process by which we take in nutrients and break them down for use in the body. In someone who is metabolically healthy, those nutrients are processed and sent to the proper destinations. But when someone is metabolically unhealthy, many of the calories to consume end up where they are not needed, at best – or outright harmful, at worst.

The carbohydrates in foods we eat have two possible fates. First, it can be converted into glycogen, the storage form of glucose, 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 ratio 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. This is why if you are running a marathon or doing a long bike ride, and do not replenish your fuel stores in someway, you are likely to "bonk," or run out of energy.

One of the liver's many important jobs is to convert the stored glycogen back to glucose and then to release it as needed to maintain blood glucose levels at a steady state, known as glucose homeostasis. This is an incredibly delicate task: an average adult male will have about 5 grams of glucose circulating in his bloodstream given time, or about a teaspoon.

We have a far greater capacity, almost unlimited, for storing energy as fat – the second possible destination for the calories in the carbohydrates we eat. Even a relatively lean adult male may carry 10 kg of fat in their body, representing a whopping 90,000 calories of stored energy.

That decision – where to put the energy from carbohydrates we eat – is made via hormones, chief among them insulin, which is secreted by the pancreas when the body senses the presence of glucose, the final breakdown product of most carbohydrates. Insulin helps shuttle the glucose to where it's needed, while maintaining glucose homeostasis. If you happen to be exercising vigorously while you eat those carbohydrates, those calories will be consumed almost instantly in the muscles. But in a typical sedentary person who is not depleting muscle glycogen rapidly, the excess energy from the carbohydrates will largely end up in fat cells (or more specifically, as triglycerides contained within fat cells.)

Think of fat as acting like a kind of metabolic buffer zone, absorbing excess energy and storing at safely until it is needed.

As more calories flood into your subcutaneous fat tissue, it eventually reaches capacity in 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; and even around your heart and your pancreas. None of these, obviously, are ideal places for fat to collect.

Fat also begins to infiltrate your abdomen, accumulating in between your organs. Where subcutaneous fat is thought to be relatively harmless, this "visceral fat" is anything but. 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.

One of the first places where this overflowing fat will cause problems is in your muscle, as it worms its way in between your muscle fibers like marbling on a steak. As this continues, microscopic fat droplets even appear inside your muscle cells. This is where insulin resistance likely begins. These fat droplets may be among the first destinations of excess energy/fat spill over, and as they accumulate they begin to disrupt the complex network of insulin dependent transport mechanisms that normally bring glucose in to fuel the muscle cell. Wendys mechanisms lose their function, the cell becomes "deaf" to insulin's signals. Eventually, this insulin resistance will progress to other tissues such as the liver, but it is believed that it originates in the muscle. It's worth noting that one key ingredient in this process seems to be inactivity. 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.

Insulin resistance technically means that cells, initially muscle cells, have stopped listening to insulin's signals.

There are many other hormones involved in the production and distribution of fat, including testosterone, estrogen, hormone-sensitive lipase, and cortisol.

Insulin seems to be the most potent as far as promoting fat cumulation because it acts as a kind of one-way gate, allowing fat to enter the cell wall impairing the release of energy from fat cells (via a process called lipolysis). Insulin is all about fat storage, not fat utilization.

When insulin is chronically elevated, more problems arise. Fat gain and ultimately obesity are merely one symptom of this condition, known as hyperinsulinemia. I would argue that they are hardly even the most serious symptoms: as we'll see in the coming chapters, insulin is also a potent growth signaling hormone that helps foster both atherosclerosis and cancer.

Today over 11% of the US adult population, one in nine, has clinical type two diabetes. Another 38% of US adults – more than one and three – me at least one of the criteria for pre-diabetes.

Patients with diabetes have a much greater risk of cardiovascular disease, as well as cancer and Alzheimer's disease and other dementias; one could argue that diabetes with related metabolic dysfunction is one thing all these conditions have in common.

Fructose also turns out to be a very powerful driver of metabolic dysfunction if consumed to excess. The key factor here is that fructose is metabolized in a manner different from other sugars. 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 also has been associated with elevated blood pressure.

Foods high in chemicals called purines, such as certain meats, cheeses, anchovies, and beer, also generate uric acid. High levels of uric acid may promote fat storage but also is linked to high blood pressure. High uric acid is an early warning signs that we need to address a patient's metabolic health, their diet, or both.

Glucose and fructose are metabolized very differently at the cellular level. Cells must use 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 spending too much of its ATP on metabolism. But 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.

Technical explanation: This drop in cellular ATP triggers an enzyme called AMP deaminase, or AMPD, which is sort of like the evil twin to AMPK, the reverse-fuel gauge enzyme that we discussed in the previous chapter. When AMPK is activated, it triggers all sorts of cellular survival programs, including the burning of stored fat, that helps enable the organism to survive without food. When fructose triggers AMPD, on the other hand, it sends us down the path of fat storage. (This cascade also triggers hunger by blocking the satiety hormone leptin.)

On a more macro level, consuming large quantities of liquid fructose simply 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. I've seen patients work themselves into NAFLD by drinking too many "healthy" fruit smoothies.

In my patients, I monitor several biomarkers related to metabolism, keeping a watchful eye for things like elevated uric acid, elevated homocysteine, chronic inflammation, and even mildly elevated ALT liver enzymes. Lipoproteins, which we will discuss in detail in the next chapter, are also important, especially triglycerides; I watch the ratio of triglycerides to HDL cholesterol (it should be less than 2:1 or better yet 1:1), as well as VLDL, a lipoprotein that carries triglycerides – all of which would show up many years before a patient would meet the textbook definition of metabolic syndrome. 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 I look for, the canary in the coal mine of metabolic disorder, is elevated insulin.

This postprandial insulin spike, as measured with an Oral Glucose Tolerance Test, is one of the biggest early warning signs that all is not well.

Chapter 7: The Ticker - Confronting – and preventing – heart disease, the deadliest killer on the planet

The most common presentation of heart disease is not chest pain, arm pain, or shortness of breath; it's sudden death.

With the right strategy, and attention to the correct risk factors at the correct time, it should be possible to eliminate much of the morbidity and mortality that is still associated with atherosclerotic cardiovascular and cerebrovascular disease.

Lipoproteins are part lipid (inside) and part protein (outside); 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 therefore more dense.

Each lipoprotein particle is enwrapped by one or more large molecules, called apolipoproteins, that provides structure, stability, and, most importantly solubility to the particle. HDL particles are wrapped in a type of molecule called apolipoprotein A (apoA), while LDL is encased in apolipoprotein B (apoB). This distinction may seem trivial, but it goes to the very root cause of atherosclerotic disease: every single lipoprotein that contributes to atherosclerosis – not only LDL but several others – carries this apoB protein signature.

A 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 out our backsides.

This is what actually makes HDL particle potentially "good" and LDL particles potentially "bad" – not the cholesterol, but the particles that. The trouble starts when LDL particles stick in the arterial wall and subsequently become oxidized, meaning the cholesterol (and phospholipid) molecules that contain come into contact with a highly reactive molecules known as a reactive oxygen species, or ROS, because of oxidative stress. It is 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 stops behaving like a polite guest, refusing to leave – and inviting its friends, other LDLs, to join the party. Many of these are also returned 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, in turn, leads to greater retention of LDL. As oxidized LDL accumulates, it causes still more damage to the endothelium.

So to gauge the true extent of your risk, we have to know how many of these apoB particles are circulating in your bloodstream.

Its role in the process of "cholesterol efflux" is one reason why HDL is considered "good."

Three of the most prominent "longevity genes" discovered to date are involved with cholesterol transport and processing (APOE and two others, CETP and APOC3).

A CT angiogram of your arteries can identify both calcified plaque and non-calcified "soft" plaque that precedes calcification.

I take a very hard line on lowering apoB, the particle that causes all this trouble. In short: get it as low as possible, as early as possible.

There is a deadly type of particle called Lp(a). This hot mess of a lipoprotein is formed when a garden-variety LDL particle is fused with another, rarer type of protein called apolipoprotein(a), or apo(a), (not to be confused with apolipoprotein A or apoA). The apo(a) wraps loosely around the LDL particle, with multiple looping amino acids segments called "kringles," so named because their structure resembles the ring-shaped Danish pastry by that name. The kringles are what make Lp(a) so dangerous: as the LDL particle passes through the bloodstream, they scoop of bits of oxidized lipid molecules and carry them along.

Lp(a) is the most prevalent hereditary risk factor for heart disease, and its danger is amplified by the fact that it is still largely flying under the radar of Medicine 2.0, although that is beginning to change.

The only real treatment for elevated Lp(a) right now is aggressive management of apoB overall.

apoB and Lp(a) tell me the most when it comes to predicting a patient's risk of atherosclerotic cardiovascular disease.

The various treatment guidelines specify target ranges for LDL-C, typically 100 mg/dL for patients at normal risk, or 70 mg/dL for high-risk individuals. In my view, this is still far too high. Simply put, I think you can't lower apoB and LDL-C too much. You want it as low as possible.

We must also pay attention to other markers of risk, notably those associated with metabolic health, 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.

Homocysteine is broken down by B vitamins, which is why deficiency in B vitamins or genetic mutations in enzymes involved in their metabolism (e.g. MTHFR) can raise homocysteine.

About one third to one 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 obviously don't want. Mono unsaturated fats, found in high quantities in extra-virgin olive oil, macadamia nuts, and avocados, do not have this effect.

Risk is proportional to apoB exposure over time. It's best to lower apoB as soon as possible.

Chapter 8: The Runaway Cell - New ways to address the killer that is cancer

Like heart disease, cancer is a disease of aging.

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.

Our first and most obvious wish is to avoid getting cancer at all, like the centenarians – in other words, prevention. But cancer prevention is tricky, because we do not yet fully understand what drives the initiation on progression of the disease with the same resolution that we have for atherosclerosis. Further, plain bad luck seems to play a major role in this largely stochastic process.

I feel that immunotherapy has enormous promise.

We need to try to detect cancer as early as possible so that our treatments can be deployed more effectively. I advocate early, aggressive, and broad screening for my patients.

Our best hope likely lies and figuring out better ways to attack cancer on all three of these fronts: prevention, more targeted and effective treatments, and comprehensive and accurate early detection.

Cancer cells are different from normal cells into important ways. Contrary to popular belief cancer cells don't grow faster than their non-cancerous counterparts; they just don't stop growing when they are supposed to. For some reason, they stop listening to the body's signals that tell them when to grow and when to stop growing. This process is thought to begin when normal cells acquire certain genetic mutations. For example, a gene called PTEN, which normally stops cells from growing or dividing (and eventually becoming tumors), 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: such "tumor suppressor" genes are critically important to our understanding of the disease.

The second property that defines cancer cells is their ability to travel from one part of the body to a distance of site where they should not be. This is called metastasis, and is what turns a cancer from a local, manageable problem to a fatal, systemic disease.

One of the biggest obstacles to a "cure" is the fact that cancer is not one single, simple, straightforward disease, but a condition with a mind-boggling complexity.

The gene TP53 (aka p53) is found in half of all cancers.

There doesn't seem to be any individual gene that "causes" cancer at all; instead, it seems to be random somatic mutations that combine to cause cancers.

Once cancer has spread, the entire game changes: we need to treated systemically rather than locally.

The game is won by killing cancers while sparing the normal cells. Selective killing is the key.

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.

Successful treatments will need to be both systemic and specific to a particular cancer type. They will be able to exploit some weakness that is unique to cancer cells, while largely sparing normal cells.

The first such hallmark is the fact that many cancer cells have an altered metabolism, consuming huge amounts of glucose. Second, 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 cells have a strangely gluttonous appetite for glucose, devouring it up to 40 times the rate of healthy tissues. But these cancer cells don't respire the way normal cells do, consuming oxygen and producing lots of ATP, the energy currency of the cell, via the mitochondria. Rather, they appear to be using a different pathway that cells normally use to produce energy under anaerobic conditions.

The Warburg effect generates lots of by-products, such as lactate.

The Warburg effect, also know 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. But it also represents a potential vulnerability and cancer's armor.

Obesity and type 2 diabetes were snowballing into national and then global epidemics, and they seemed to be driving increased risk for many types of cancers, including esophageal, liver, and pancreatic cancer. The American Cancer Society reports that excess weight is a leading risk factor for both cancer cases and deaths, second only to smoking.

Type 2 diabetes also increases the risk of certain cancers, by as much as double in some cases.

I suspect that the association between obesity, diabetes, and cancer is primarily driven by inflammation and growth factors such as insulin. Obesity, especially when accompanied by accumulation of visceral fat (and other fat outside of subcutaneous storage deposits), helps promote inflammation, as dying fat cells secrete an array of inflammatory cytokines into the circulation. This chronic information 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 – and, as we'll see shortly, insulin itself is a bad actor in cancer metabolism.

Cancer cells possess specific 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 devour glucose at a great rate to fuel its growth. Thus, insulin acts as a kind of cancer enabler, accelerating it's growth. This in turn suggests that metabolic therapies, including dietary manipulations that lower insulin levels, could potentially help slow the growth of some cancers and reduce cancer risk. There is already some evidence that tinkering with metabolism can affect cancer rates. As we have seen, laboratory animals on calorically restricted (CR) diets tend to die from cancer at far lower rates than control animals on an "ad libitum" (all-they-can-eat) diet.

Some studies have 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.

By stacking different therapies, such as combining a PI3K inhibitor with a ketogenic diet, we can attack cancer on multiple fronts, while also minimizing the likelihood of the cancer developing resistance (via mutations) to any single treatment.

An immunotherapy is any therapy that tries to boost or harness the patient's immune system to fight an infection or other condition.

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.

One striking feature of immune-based cancer treatment is that when it works, it really works. It is not uncommon for a patient with metastatic cancer to enter remission after chemotherapy. The problem is that it virtually never lasts. The cancer almost always comes back in some form. But when patients do respond to immunotherapy, and go into complete remission, they often stay in remission. Between 80 and 90 percent of so-called complete responders to immunotherapy remain disease-free fifteen years out.

Early detection is our best hope for radically reducing cancer mortality.

I am cautiously optimistic about the emergence of so-called "liquid biopsies" that seek to detect the presence of cancers via blood test.

Liquid biopsies could be viewed as having two functions: first, to determine cancer's presence or absence, a binary question; and second, to gain insight into the specific cancer's biology.

Of all the Horsemen, cancer is probably the hardest to prevent. It is probably also the one where bad luck in various forms plays the greatest role, such as in the form of accumulated somatic mutations. The only modifiable risks that really stand out in the data are smoking, insulin resistance, and obesity – and maybe pollution (air, water, etc.), but the data here are less clear.

Chapter 9: Chasing Memory - Understanding Alzheimer's disease and other neurodegenerative diseases

The APOE gene is a risk factor for Alzheimer's disease. The E3/E3 allele is the most common. Having E2/E3 is associated with a 10% reduced risk, and E2/E2 is associated with a 20% reduced risk. E4/E4 however, is associated with a 12 times increased risk. E3/E4 is associated with a 2-3 times increased risk.

Lewy body dementia is primarily a dementing disorder, meaning it affects cognition, while Parkinson's disease is considered primarily (but not entirely) a movement disorder.

A certain variant of the gene Klotho (KL), called kl-vs, seems to protect carriers of APOE E4 from developing dementia.

Amyloid-beta is a byproduct that is created when a normally occurring substance called amyloid precursor protein, or 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 into 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 into clumps.

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

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 proteins 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 disease but also significantly raises the 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.

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.

One important section of the cognitive testing evaluates the patient's sense of smell. Olfactory neurons are among the first to be affected by Alzheimer's disease.

When we have a thought or a perception, it's not just one neural networks that is responsible for that insight, or that decision, but many individual networks working simultaneously on the same problem. 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 compared to sedentary people. Exercise is the only intervention shown to delay the progression of Parkinson's.

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 sources that can sustain us for a very long time.

Jack de la Torre came up with an alternative theory of Alzheimer's disease. He believes Alzheimer's disease is primarily a vascular disorder of the brain. The dementia symptoms that we see results 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.

People with a history of cardiovascular disease are at a higher risk of developing Alzheimer's disease.

Having type two diabetes doubles or triples your risk of developing Alzheimer's disease, about the same as having one copy of the APOE E4 gene.

The protein for which codes, APOE (apolipoprotein E), plays in 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.

Not only are the 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 (CGM). Thus, E4 itself could help drive the very same metabolic dysfunction that also increases risk of dementia. At the same time, it appears to intensify the damage done to the brain by metabolic dysfunction. Researchers have found that in high-glucose environments, the aberrant form of the APOE protein encoded by APOE E4 works to block insulin receptors in the brain, forming sticky clumps or aggregates that prevent neurons from taking in energy.

Because metabolism plays such an outsize roll with at-risk E4 patients, our first step is to address any metabolic issues they may have. Our goal is to improve glucose metabolism, inflammation, and oxidative stress. One possible recommendation would be to switch to a Mediterranean style diet, relying I'm more monounsaturated fats and fewer refined carbohydrates, in addition to regular consumption of fatty fish. There is some evidence that supplementation with the omega-3 fatty acid DHA, found in fish oil, may help maintain brain health, especially in E4/E4 carriers.

This is also one area where a ketogenic diet may offer a real functional advantage: when someone is in ketosis, the 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. So it may make sense to try to diversify the brain's fuel source from only glucose to both glucose and ketones. A systematic review of randomized controlled trials found that ketogenic therapies improved general cognition and memory and subjects with mild cognitive impairment and early stage Alzheimer's disease. Think of it as a flex-fuel strategy.

The single most powerful item in our preventative 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.

Endurance exercise produces factors that directly target regions of the brain responsible for cognition and memory. It also helps lower inflammation and oxidative stress.

Exercise is, full stop and hands-down, the best tool we have in neurodegeneration prevention.

Saunas seem to show the ability to reduce disease. The best interpretation I can draw from the literature suggests that at least four sessions per week, of at least 20 minutes per session, at 179°F 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 percent).

Other potential interventions that have shown promise in studies include lowering homocysteine with B vitamins, while optimizing omega-3 fatty acids.

Broadly, our strategy should be based on the following 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 a very long game.

  4. Our most powerful tool for preventing cognitive decline is exercise. We've talked a lot about diet and metabolism, but exercise appears to act in multiple ways (vascular, metabolic) to preserve brain health. Exercise, lots of it, is the foundation of our Alzheimer's prevention program.

Chapter 10: Thinking Tactically - Building a framework of principles that work for you

In Medicine 3.0, we have five tactical domains that we can address in order to alter someone's health:

  1. exercise

  2. nutritional biochemistry

  3. sleep

  4. emotional health

  5. exogenous molecules

Chapter 11: Exercise - The most powerful longevity drug

Going from zero weekly exercise to just 90 minutes per week can reduce your risk of dying from all causes by 14%.

Let's start with cardiorespiratory or aerobic fitness. This means how efficiently your body can deliver oxygen to your muscles, and how efficiently your muscles can extract that oxygen, enabling you to run, or walk, or cycle, or swim long distances. It also comes in to play in daily life, manifesting as physical stamina. The more aerobically fit you are, the more energy you will have for whatever you enjoy doing – even if your favorite activity is shopping.

It turns out that peak aerobic cardiorespiratory fitness, measured in terms of VO2 max, is perhaps the single most powerful marker for longevity. VO2 max represents the maximum rate at which a person can utilize oxygen.

An average 45-year-old man will have a VO2 max around 40 ml/kg/min, while an elite endurance athlete will likely score in the high 60s and above. An unfit person in their 30s or 40s, on the other hand, might score only in the high 20s.

A study found that someone of below average VO2 max for their age and sex (that is, between the 25th and 50th percentiles) is a double the risk of all cause mortality compared to someone in the top quartile (75th to 97.6th percentiles). Thus, poor cardio respiratory fitness carries a greater relative risk of death than smoking.

As the authors of the JAMA study concluded, "Cardiorespiratory fitness is inversely associated with long-term mortality with no observed upper limit of benefit. Extremely high aerobic fitness was associated with the greatest survival."

A ten-year observational study of roughly 4,500 subjects ages 50 and older found that those with low muscle mass were at 40 to 50% greater risk of mortality than controls, over the study period. Further analysis revealed that it's not the mere muscle mass that matters but the strength of those muscles, their ability to generate force.

At a deeper biochemical level, exercise really does act like a drug. To be more precise, it prompts the body to produce its own, endogenous drug like chemicals.

Exercise in all its forms is our most powerful tool for fighting this misery and reducing our risk of death across the board.

Think of the Centenarian Decathlon as the 10 most important physical tasks that you will want to be able to do for the rest of your life.

Chapter 12: Training 101 - How to prepare for the Centenarian Decathlon

The three dimensions in which we want to optimize our fitness are aerobic endurance and efficiency, strength, and stability.

Aerobic exercise, done in a very specific way (zone 2), improves our ability to utilize glucose and especially fat as fuel.

Healthy mitochondria are key to both athletic performance and metabolic health. Our mitochondria can convert both glucose and fatty acids to energy – but while glucose can be metabolized in multiple different ways, fatty acids can be converted to energy only in the mitochondria. Typically, someone working at a lower relative intensity will be burning more fat, while it higher intensity they would rely more on glucose. The healthier and more efficient your mitochondria, the greater your ability to utilize fat, which is by far the body's most efficient and abundant fuel source. This ability to use both fuels, and glucose, it's called "metabolic flexibility," and is what we want.

Iñigo San Millan describes zone 2 as the maximum level of effort that we can maintain without accumulating lactate. We still produce it, but we are able to match production with clearance. The more efficient our mitochondrial "engine," the more rapidly we can clear lactate, and the greater effort we can sustain while remaining in zone 2. If we are "feeling the burn" in this type of workout, then we are likely going too hard, creating more lactate and then we can eliminate.

Your zone 2 will correspond to between approximately 70 and 85% of your maximum heart rate. Another way to give you a rough idea of your zone 2 is an intensity that you can hold a conversation at, but you wouldn't want to.

Even when we are at rest, our lactate levels tell us much about our metabolic health. People with obesity or other metabolic problems will tend to have much higher resting lactate levels, a clear sign that their mitochondria are not functioning optimally, because they are already working too hard just to maintain baseline energy levels. This means that they are relying almost totally on glucose for all their energy needs – and that they are totally unable to access their fat stores. It seems unjust, but the people who most need to burn their fat, the people with the most of it, are unable to unlock virtually any of that to use as energy, while the lean, well-trained professional athletes are able to do so because they possess greater metabolic flexibility (and healthier mitochondria).

Mitochondrial health becomes especially important as we grow older, because one of the most significant hallmarks of aging is a decline in the number and quality of our mitochondria. But the decline is not necessarily a one-way street. Mitochondria are incredibly plastic, and when we do aerobic exercise, it stimulates the creation of many new and more efficient mitochondria through a process called mitochondrial biogenesis, while eliminating ones that have become dysfunctional via a recycling process call to mitophagy. A person who exercises frequently in zone 2 is improving their mitochondria with every run, swim, or bike ride. But if you don't use them, you lose them.

Glucose uptake occurs via multiple pathways. There is the usual, insulin signaled way that we are familiar with, but exercise also activates other pathways, including one called non-insulin-mediated glucose uptake, or NIMGU, where glucose is transported directly across the cell membrane without insulin being involved at all. This intern explains why exercise, especially in zone 2, can be so effective in managing both type one and type two diabetes: it enables the body to essentially bypass insulin resistance in the muscles to draw down blood glucose levels.

It seems that about three hours per week of zone 2, or four 45-minute sessions, is the minimum required for most people to derive a benefit and make improvements, once you get over the initial hump of trying it for the first time.

Zone 2 can be a bit boring on its own, so I typically use the time to listen to podcasts or audiobooks, or just think about issues that I'm working on – a side benefit of zone 2 is that it also helps with cognition, by increasing cerebral blood flow and by stimulating production of BDNF, brain-derived neurotropic factor. This is another reason why zone 2 is such an important part of our Alzheimer's disease prevention program.

V02 max efforts are hard, minutes-long efforts, but still well short of an all out sprint. At V02 max, we are using a combination of aerobic and anaerobic pathways to produce energy, but we are at our maximum rate of oxygen consumption. Oxygen consumption is the key.

The way we train VO two max is pretty similar to the way elite athletes do it: by supplementing our zone 2 work with one or 2 VO2 max workouts per week.

The tried and true formula for these VO2 max intervals is to go four minutes at the maximum pace you can sustain for this amount of time – not an all out sprint, but still a very hard effort. Then ride or jog four minutes easy, which should be enough time for your heart rate to come back down to below about 100 bpm. Repeat this 4 to 6 times and cool down.

Training and maintaining a high level of aerobic fitness, and doing it now, is essential to preserving this range of function in your later years.

We lose muscle strength about 2 to 3 times more quickly than we lose muscle mass. And we lose power (strength x speed) 2 to 3 times faster than we lose strength. This is because the biggest single change in the aging muscle is the atrophy of a fast twitch or type 2 muscle fibers.

Bone density diminishes on a parallel trajectory to muscle mass.

I think of strength training as a form of retirement savings. Just as we want to retire with enough money saved up to sustain us for the rest of our lives, we want to reach older age with enough of a "reserve" of muscle (and bone density) to protect us from injury and allow us to continue to pursue the activities that we enjoy.

Carrying is our superpower as a species.

A great activity to do is called "rucking," which basically means hiking or walking at a fast pace with a loaded backpack.

I structure my training around exercises that improve the following:

  1. Grip strength

  2. Concentric and eccentric loading

  3. Pulling motions

  4. Hip-hinging movements

Many studies suggest that grip strength – how hard you can squeeze something with one hand – predicts how long you are likely to live.

You can test your grip strength by dead-hanging from a pull up bar for as long as you can. We like to see men hang for at least two minutes and women for 90 seconds at the age of forty.

Eccentric loading means loading the muscle as it is lengthening.

Chapter 13: The Gospel of Stability - Relearning how to move to prevent injury

I think the missing X factor that explains why so many people just stop moving is injury. That is, older people tend to exercise less, or not at all, because they simply can't. They have hurt themselves in some way, at some way at some point in their lives , and they just never got back on the horse. So they continue to decline.

First, do thyself no harm. How do we do this? I think stability is the key ingredient.

Stability is essential to any kind of movement, particularly if our goal is to be able to keep doing that movement for years or decades. It is the foundation on which our twin pillars of cardiovascular fitness and strength must rest.

Stability is the subconscious ability to harness, decelerate, or stop force.

We want to think about how efficiently and safely force can be transmitted through something.

In our bodies, force dissipation leaks out via the path of least resistance – typically joints like knees, elbows, and shoulders, and/or the spine, any or all of which will give out at some point. Joint injuries are almost always the result of this kind of energy leak.

We try to cheat or work around our existing injuries and limitations and end up creating new problems.

The theory behind Dynamic Muscular 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. Visit and for more information.

Stability training begins at the most basic level, with the breath.

The way we breathe has tremendous influence on how we move our body, and even our mental state.

Intra-abdominal pressure is the basic foundation for everything that we do in stability training.

If the road to stability begins with the breath, it travels through the feet – the most fundamental point of contact between our bodies and the world. 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.

The structure we most want to protect – and a major focus of stability training in general – is the spine.

A large part of what we're working on in stability training is neuromuscular control, reestablishing the connection between our brain and key muscle groups and joints.

Chapter 14: Nutrition 3.0 - You say potato, I say "nutritional biochemistry"

Diet and nutrition or so poorly understood by science, so emotionally loaded, and so muddled by lousy information and lazy thinking that it is impossible to speak about them in nuanced terms at a party or, say, on social media.

There is not one diet that works best for every single person.

I believe that most people need to address their eating pattern in order to get control of their metabolic health, or at least not make things worse. But I also believe that we need to differentiate between behavior that maintains good health versus tactics that correct poor health and disease. Wearing a cast on a broken bone will allow it to heal. Wearing a cast on a perfectly normal arm will cause it to atrophy.

Nutrition is relatively simple, actually. It boils down to a few basic rules: don't eat too many calories, or too few; consume sufficient protein and essential fats; obtain the vitamins and minerals you need; and avoid pathogens like E. coli and toxins like mercury or lead. Beyond that, we know relatively little with complete certainty.

Our knowledge of nutrition comes primarily from two types of studies: epidemiology and clinical trials. In epidemiology, researchers gather data on the habits of large groups of people, looking for meaningful associations or correlations with outcomes such as a cancer diagnosis, cardiovascular disease, or mortality. The problem is that epidemiology is incapable of distinguishing between correlation and causation.

Humans are terrible study subjects for nutrition.

It is easy to be misled by epidemiology. One reason is because general health is a massive confounder in these kinds of studies. This is also known as healthy user bias.

There is no dose of alcohol that is "healthy."

Chapter 15: Putting Nutritional Biochemistry into Practice - How to find the right eating pattern for you

The standard american diet, SAD, it's not so much a diet as a business model for how to feed the world efficiently.

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

  1. Caloric restriction (CR): eating less in total, but without attention to what is being eaten or when it's being eaten.

  2. Dietary restriction (DR): eating less of some particular elements within the diet (e.g., meat, sugar, fats).

  3. Time restriction (TR): restricting eating to certain times, up to and including multi day fasting.

If we take in more energy than we require, the surplus ends up in our adipose tissue, one way or another.

Eating fewer calories tends to lengthen lifespan, at least in lab animals.

Studies done with monkeys have shown that the quality of our diet may matter as much as the quantity. These monkey studies tell us the following about nutritional biochemistry:

  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 caloric restriction 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 – or simply not eating to excess – can still be beneficial.

It seems quite clear that, even for monkeys, limiting caloric intake and improving diet quality "works."

One reason carbohydrate restriction is so effective for many people is that it tends to reduce appetite as well as food choices.

A more significant issue with DR is that everyone's metabolism is different. Some people will lose tremendous amount of weight and improve their metabolic markers on a low carbohydrate or ketogenic diet, while others will actually gain weight and see their lipid markers go haywire – on the exact same diet. Conversely, some people might lose weight on a low fat diet, while others will gain weight. I have seen this happen time and again in my own practice, where similar diet yields very different outcomes depending on the individual.

It's easy to overlook, but alcohol should be considered as its own category of macro nutrient because it is so widely consumed, it has such potent effects on our metabolism, and it is so calorically dense at 7 kcal/g.

Alcohol serves no nutritional or health purpose but is a purely hedonic pleasure that needs to be managed.

Ethanol (alcohol) is a potent carcinogen, and chronic drinking has strong associations with Alzheimer's disease, mainly via its negative affect on sleep, but possibly via additional mechanisms.

Carbohydrates are our primary energy source. In digestion, 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 stocked away 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.

CGM (continuous glucose monitoring) represents a huge improvement over the medicine 2.0 standard of one fasting glucose test per year.

A 2011 study looking at 20,000 people, mostly without type two diabetes, found that the risk of mortality increased monotonically with their average blood glucose levels (measured via HbA1c). The higher their blood glucose, the greater the risk of death – even in the non-diabetic range of blood glucose.

Overall I like to keep average glucose at or below 100 mg/dL, with a standard deviation of less than 15 mg/dL. These are aggressive goals: 100 mg/dL corresponds to an HbA1c of 5.1 percent.

Everyone tends to be more insulin sensitive in the morning than in the evening, so it makes sense to front-load our carb consumption earlier in the day.

One thing CGM pretty quickly teaches you is that your carbohydrate tolerance is heavily influenced by other factors, especially your activity level and sleep. An ultra endurance athlete, someone who is training for long rides or swims or runs, can eat many more grams of carbs per day because they are blowing through those carbs every time they train – and they are also vastly increasing their ability to dispose of glucose via the muscles and their more efficient mitochondria. Also, sleep disruption or reduction dramatically impairs glucose homeostasis overtime. From years of experience with my own CGM and that of my patients, it still amazes me how much even one night of horrible sleep cripples our ability to dispose of glucose the next day.

Unlike carbs and fats, proteins 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.

In my patients I typically set 1.6 g/kg/day as the minimum, which is twice the recommended daily allowance. The ideal amount can vary from person to person, but the data suggest that for active people with normal kidney function, 1 g per pound of body weight per day (or 2.2 g/kg/day) is a good place to start.

The literature suggests that the ideal way to achieve this is by consuming four servings of protein per day, each at ~0.25 g/lb of body weight.

The safe upper limit for protein consumption is 3.7 g/kg/day.

If you choose to get all of your protein from plants, you need to understand two things. First, 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. Second, plant protein has less of the essential amino acids methionine, lysine, and tryptophan, potentially leading to reduced proteins synthesis. Taken together, these two factors tell us that the overall quality of protein derived from plants is significantly lower than that from animal products.

Fat is essential, but too much can be problematic both in terms of total energy intake and also metabolically.

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 (think: slow burning logs) and also the building blocks for many of our hormones (in the form of cholesterol) and cell membranes. Eating the right mix of fats can help maintain metabolic balance but it is also important for the health of our brain, much of which is composed of fatty acids. On a practical level, dietary fat also tends to leave one feeling more satiated than many types of carbohydrates, especially when combined with protein.

There are (broadly) three types of fats: saturated fatty (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA). The differences between these have to do with differences in their chemical structure; a "saturated" fat simply has more hydrogen atoms attached to its carbon chain. Within PUFA, we make one more important distinction, which is to separate the omega-6 from the omega-3 variants (also a chemical distinction having to do with the position of the first double bond). We can further subdivided omega-3 PUFA into marine (EPA, DHA) and nonmarine sources (ALA). Salmon and other oil rich seafood provide the former, nuts and flaxseed the latter.

From our empirical observations and what I considered the most relevant literature, which is less than perfect, we try to boost MUFA closer to 50 to 55%, while cutting SFA down to 15 to 20% and adjusting total PUFA to fill the gap. We also boost EPA & DHA, those fatty acids that are likely important to brain and cardiovascular health, with marine fat sources and/or supplementation. We titrate the level of EPA and DHA in our patients' diets by measuring the amount of each found in the membranes of the red blood cells (RBC), using a specialized but readily available blood test. Our target depends on a person's APOE genotype and other risk factors for neurodegenerative and cardiovascular disease, but for most patients the range we look for is between 8 and 12% of RBC membrane composed of EPA and DHA.

Over the course of the 20th century, advances in food processing technology enabled us to chemically and mechanically extract oil from vegetables and seeds that otherwise would have been impossible to get. These new technologies suddenly allowed vast quantities of oils high and poly unsaturated fats, such as corn and cottonseed oil, to flood into the food supply.

Trans fats also contributed to atherosclerosis (by raising apoB) and have been banned by the FDA.

In the final analysis, I tell my patients that on the basis of the least bad, least ambiguous data available, MUFAs are probably the fat that should make up most of our dietary fat mix, which means extra-virgin olive oil and high MUFA vegetable oils. After that, it's kind of a tossup, and the actual ratio of SFA & PUFA probably comes down to individual factors such as lipid response and measured inflammation. Finally, unless they are eating a lot of fatty fish, filling their coffers with marine omega-3 PUFA, they almost always need to take EPA and DHA supplements and capsule or oil form.

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 fairly short order. Overtime, within three days or so, the body enters a state called "starvation ketosis," where fat stores are mobilized to fulfill the need for energy – yet at the same time, as I often noticed when I was undergoing regular lengthy fast, hunger virtually disappears. This paradoxical phenomenon is likely due to the ultra high levels of ketones that the state produces, which tamp down feelings of hunger.

Fasting over long periods also turns down mTOR, the pro-growth and pro-aging pathway discussed in chapter 5. 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 activates FOXO, the cellular repair genes that may help centenarians live so long. In short, fasting triggers many of the physiological and cellular mechanisms we want to see.

A drawback to fasting is that you're virtually guaranteed to miss your protein target with this approach.

The cost of fasting, in terms of lost lean mass (muscle), and reduced activity levels, simply does not justify whatever benefits it may bring. My rule of thumb for any eating pattern, in fact, is that you must eat enough to maintain lean mass and long-term activity patterns.

Bad nutrition can hurt us more than good nutrition can help us. If you're already metabolically unhealthy, nutritional interventions can only do so much.

We have to focus on eliminating those types of foods that raise blood glucose too much, but in a way that also does not compromise protein intake and lean body mass.

Zone 2 training can have a huge impact on our ability to dispose of glucose safely, and also on our ability to access energy we have stored as fat. And the more muscle mass we have, the more capacity we have to use and store excess glucose, and utilize stored fat.

If your issues fall more in the domain of lipoproteins and cardiovascular risk, then it makes sense to focus on the fats side of the equation as well, meaning mostly saturated fats, which raise apoB in some people, although this is relatively easy to control pharmacologically. Excessive carbohydrate intake and also have spill over effects on apoB, in the form of elevated triglycerides. (If there is one type of food that I would eliminate from everyone's diet if I could, it would be fructose-sweetened drinks, including both sodas and fruit juices, which deliver too much fructose, too quickly, to a gut and liver that much prefer to process fructose slowly.)

Chapter 16: The Awakening - How to learn to love sleep, the best medicine for your brain

Poor sleep dramatically increases one's propensity for metabolic dysfunction, up to and including type 2 diabetes, and it can wreak havoc with the body's hormonal balance.

There is a growing body of evidence that sleeping well is essential to preserving our cognition as we age and staving off Alzheimer's disease.

We need to sleep about 7 1/2 to 8 1/2 hours a night.

Good sleep is like a performance-enhancing drug.

Sleep deprivation can cause profound insulin resistance.

It's a feedback loop. Both poor sleep and high stress activate the sympathetic nervous system, which despite its name, is the opposite of calming. It is part of our fight or flight response, prompting the release of hormones called glucocorticoids, including the stress hormone cortisol. Cortisol raises blood pressure; it also causes glucose to be released from the liver, while inhibiting the uptake and utilization of glucose in the muscle and fat tissues, perhaps in order to prioritize glucose delivery to the brain. In the body, this manifests as elevated glucose due to stress induced insulin resistance.

Sleep plays a major role in brain health, especially as we get older, not only in terms of daily cognitive function but also in terms of our long-term cognitive health.

Both REM and deep NREM sleep (which we'll call "deep sleep" for convenience) are crucial to learning and memory, but in different ways. Deep sleep is when the brain clears out its cache of short term memories in the hippocampus and selects the important ones for long-term storage in the cortex, helping us to store and reinforce our most important memories of the day. Researchers have observed a direct, linear relationship between how much sleep we get in a given night and how well we will perform on a memory test the next day.

While we are in deep sleep, the brain activates a kind of internal waste disposal system that allows cerebrospinal fluid to flood in between the neurons and sweep away intercellular junk.

There are the old benzodiazepine drugs, such as Valium and Xanax, which remain very popular and are used to treat insomnia. These typically induce unconsciousness without improving sleep quality. Somewhat worryingly, their use has also been associated with cognitive decline, and they are generally not recommended for older adults beyond very short-term time horizons.

We have had good results with the supplement ashwagandha for sleep quality.

The first requirement for good sleep is darkness.

Another very important environmental factor is temperature. One of the signal events as we are falling asleep is that our body temperature drops by about 1°C.

Most people think of caffeine as a stimulant that somehow gives us energy, but actually it functions more as a sleep blocker. It works by inhibiting the receptor for a chemical called adenosine, which normally helps us to go to sleep every night. Over the course of the day, adenosine builds up in our brain, creating what scientist called "sleep pressure," or the drive to sleep. We may be tired and needing sleep, but if we ingest caffeine, it effectively takes the phone off the hook so our brain never gets the message.

Another way to help cultivate sleep pressure is via exercise, particularly sustained endurance exercise (e.g., zone 2).

Another way to turn down the sympathetic nervous system and prepare the brain for sleep is through meditation.

Chapter 17: Work in Progress - The high price of ignoring emotional health

Emotional health and physical health are closely intertwined.

True recovery requires probing the depths of what shaped you, how you adapted to it, and how those adaptations are now serving you (or not).

Changing the behavior can change the mood.


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