📚The Book in 3 Bullets

• The current medical model is based on the treatment of symptoms once a disease arises. If we want to live healthier lives, we need to work on preventing the diseases that lead to a decrease in healthspan and lifespan—cardiovascular disease, metabolic dysfunction, cancer, and neurodegenerative disease.

• Exercise is the number one longevity “drug.” It helps manage metabolic disease, enhance cognitive health, and improve physical functioning.

• We should be training to be as functional as possible while we’re in our last decade. There is an inevitable decline in our strength, stability, and cardiovascular health, but we can impact the trajectory of the decline with specific, intentional training.

👤Who Should Read It?

• Anyone looking to optimize their physical and emotional health. Dr. Attia does a great job of breaking down complex medical topics into understandable and actionable pieces.

🌎 How the Book Changed Me

• The book made me reanalyze my training program and goals. Since reading this book, I’ve shifted my focus to improving all aspects of physical fitness—stability, strength, muscle mass, and cardiorespiratory fitness—instead of just training to stay in shape. I’m now thinking of how I can prevent chronic diseases for as long as possible in my life to maximize both healthspan and lifespan.

✍️ My Top Quotes

• There comes a point where we need to stop just pulling people out of the river. We need to go upstream and find out why they’re falling in.

• Just because your parents endured a painful old age, or died younger than they should have, does not mean that you must do the same. The past need not dictate the future. Your longevity is more malleable than you think.

• The time to repair the roof is when the sun is shining.

• It is impossible to produce superior performance unless you do something different from the majority.

• Religion is a culture of faith; science is a culture of doubt. — Richard Feynman

📖 Summary & Notes

• If you’re not engaging in high-risk activities like motorcycle racing or free solo climbing, the odds are overwhelming that you will die as a result of one of the chronic diseases of aging, the so-called Horsemen of deaths: heart disease, cancer, neurodegenerative disease, or type 2 diabetes.

• Longevity has two components. The first is how long you Iive, your chronological lifespan, the second and equally important part is how well you live—the quality of your years.

• When someone dies “suddenly” of a heart attack, the disease had likely been progressing in their coronary arteries for two decades. Slow death moves even more slowly than we realize.

• 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 percent 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 percent).

  • HbA1c measures the amount of glycosylated hemoglobin in the blood which allows an estimate of the patient’s average level of blood glucose over the past ninety days.

  • If their HbA1c comes back at 6.4 percent, they technically don’t have type 2 diabetes at all. Instead, they have a condition called prediabetes, where the standard-of-care guidelines recommend mild amounts of exercise, vaguely defined dietary changes, possible use of a glucose control medication, and annual monitoring—basically, to wait and see if the patient actually develops diabetes before treating it as an urgent problem.

  • The time to intervene is before a patient gets anywhere near the type 2 diabetes threshold. Even waiting till a patient is diagnosed with prediabetes is too late in the game. It should not be treated like a broken bone, where you either have it or you don’t; it’s not binary.

  • The goal should be to act as early as possible, to try to prevent people from developing type 2 diabetes and all the other Horsemen.

  • We want to delay or prevent these conditions so that we can live longer without disease, rather than lingering with disease.

• The metabolic derangement that leads to type 2 diabetes also helps foster and promote heart disease, cancer, and Alzheimer’s disease. Addressing our metabolic health can lower the risk of each of the Horsemen.

• Exercise is by far the most potent longevity “drug.” No other intervention does nearly as much to prolong our lifespan and preserve our cognitive and physical function.

Medicine 3.0

• Risk is not something to be avoided at all costs; rather, it’s something we need to understand, analyze, and work with. Every single thing we do, in medicine and in life, is based on some calculation of risk versus reward.

• Sometimes doing no harm is the worst option. Doing what you think will bring the greatest benefit with an adequately matching risk is typically the better option.

• A physician who has never done any harm, or at least confronted the risk of harm, has probably never done much of anything to help a patient either.

• Medicine 1.0 was the earliest form of medicine and was based on direct observation and abetted more or less by pure guesswork, some of which were on target and some not so much.

• Medicine 2.0 arrived in the mid-nineteenth century with the advent of the germ theory of disease, which supplanted the idea that most illnesses were spread by “miasmas,” or bad air.

• Medicine 3.0 is a new school of thought on preventing diseases altogether rather than waiting for them to arise and then treating them like medicine 2.0.

  • Atherosclerosis, for example, begins many decades before the person has a coronary “event” that could result in their death. But that event, even a heart attack, too often marks the point where treatment begins.

• There are few insurance reimbursement codes for most of the largely preventive interventions that are necessary to extend lifespan and healthspan. Health insurance companies won’t pay a doctor very much to tell a patient to change their diet or monitor blood glucose levels in order to prevent the development of type 2 diabetes.

• Nearly all the money flows to treatment rather than prevention.

Objective, Strategy, Tactics

• The Horsemen have one powerful risk factor in common, and that is age. As you grow older, the risk grows exponentially that one or more of these diseases has begun to take hold in your body.

• Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death.

• Someone who drops dead of a heart attack did not just get sick an hour earlier. The disease was working inside them, silently and invisibly, for decades.

• The actions we take to improve our healthspan will almost always result in a longer lifespan. This is why our tactics are largely aimed at improving healthspan first; the lifespan benefits will follow.

• Medicine 2.0 relies on two types of tactics broadly speaking: procedures (e.g., surgery) and medications. Medicine 3.0 tactics fall into five broad domains: exercise, nutrition, sleep, emotional health, and exogenous molecules, meaning drugs, hormones, or supplements.

• We want to maintain physical strength, stamina, and stability across a broad range of movements while remaining free from pain and disability.

• Exercise not only delays actual death but also prevents both cognitive and physical decline, better than any other intervention.

• Good sleep is critical to our innate physiological repair processes, especially in the brain, while poor sleep triggers a cascade of negative downstream consequences, from insulin resistance to cognitive decline, as well as mental health issues.

• Mendelian randomization helps tease out causal relationships between modifiable risk factors (e.g., LDL cholesterol) and an outcome of interest (e.g., cancer) in situations where actual 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.

Centenarians

• Genes may be responsible for only about 20-30% of the overall variation in human lifespan. The catch is that the older you get, the more your genes start to matter.

• We want to live longer with good function and without chronic disease, and with a briefer period of morbidity at the end of our lives.

• When we are young, our hair is full and glorious, helping us attract mates. But natural selection does not really care whether a man in his fifties has a full head of hair.

• Natural selection doesn’t care if we develop Alzheimer’s disease in old age. It doesn’t affect our reproductive fitness.

• It appears that no two centenarians follow the exact same genetic path to reaching extreme old age. There are many ways to achieve longevity; not just one or two.

• The APOE gene is 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. Of these, e3 is the most common by far, but having one or two copies of the e4 variant seems to multiply one’s risk of developing Alzheimer’s disease by a factor of between two and twelve.

• The e2 variant of APOE, on the other hand, seems to protect its carriers against dementia—and it also turns out to be very highly associated with longevity.

• APOE plays an important role in shuttling cholesterol around the body, particularly in the brain; one’s APOE variant also has a large influence on glucose metabolism.

• While your genome is immutable, at least in the near future, gene expression can be influenced by your environment and your behaviors.

• Genetics and environment both play a role in longevity and it may be possible to implement interventions that replicate at least some of the centenarians’ good genetic luck.

• We must focus on delaying the onset rather than extending the duration of disease—and not just one disease but all chronic diseases. Our goal is to live longer without disease.

• Medicine 2.0 also separates the Horsemen diseases from one another. We treat diabetes as if it were unrelated to cancer and Alzheimer’s, for example, even though it is a major risk factor for both.

The Science of Hunger and Health

• Rapamycin has many diverse applications because it tends to slow down the process of cellular growth and division.

• Rapamycin acts directly on a very important intracellular protein complex called mTOR, for “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 go into a kind of “recycling” mode, breaking down cellular components and generally cleaning house.

• With rigorous testing of resveratrol, it did not extend the lifespan in a diverse population of normal mice as rapamycin did.

  • The same is true for other well-hyped supplements such as nicotinamide riboside. It also failed to extend the lifespan in mice consistently.

• Rapamycin may have the potential as a longevity-enhancing drug.

• The results have been remarkably consistent. Studies dating back to the 1930s have found that limiting caloric intake and length in the lifespan of a mouse or rat by anywhere from 15 to 45%, depending on the age of onset in degree of restriction. Not only that, but the underfed animals also seem to be markedly healthier for their age, developing fewer spontaneous, tumors than normal fat mice. CR seems to improve their health span, in addition to their lifespan.

• It seems that hungry animals become more resilient and better able to survive, at least inside a well-controlled, germ, free laboratory.

• CR can be useful but it also has its cons. Very lean animals may be more susceptible to death from infection or cold temperatures.

• Reducing the amount of nutrients available to a cell seems to trigger a group of innate pathways that enhance the cell’s stress resistance and metabolic efficiency—all of them related, in some way, to mTOR.

• AMP-activated protein kinase, or AMPK for short, is like the low-fuel light on the dashboard of your car: when it senses low levels of nutrients (fuel), it activates, triggering a cascade of actions. While this typically happens as a response to a 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 first by stimulating the production of new mitochondria via mitochondrial biogenesis. Over time, or with disuse, our mitochondria become vulnerable to oxidative stress and genomic damage, leading to dysfunctional 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.

• More importantly, AMPK works to inhibit the activity of mTOR, the cellular growth regulator. Specifically, it seems to be a drop in amino acids that induces mTOR to shut down, and with it 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.”

• Lysosomes break up and destroy things called aggregates, which are clumps of damaged 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, Parkinson’s disease, and other neurodegenerative disorders.

• By cleansing our cells of damaged proteins and other cellular junk, autophagy allows cells to run more cleanly and efficiently and helps make them more resistant to stress. But as we get older, autophagy declines. Impaired autophagy is thought to be an important driver of numerous aging-related phenotypes and ailments, such as neurodegeneration and osteoarthritis.

• Historically, rapamycin was approved to treat patients indefinitely following organ transplantation, as part of a cocktail of three or four drugs meant to suppress the part of their immune system that would otherwise attack and destroy their new organ. This immune-suppressing effect explains why there has been some reluctance to consider using (or even studying) rapamycin in the context of delaying aging in healthy people, despite ample animal data suggesting that it might lengthen lifespan and healthspan.

• Rapamycin seems to reduce systemic inflammation, perhaps by tamping down the activity of so-called senescent cells, which are “older” cells that have stopped dividing but have not died; these cells secrete a toxic cocktail of inflammatory cytokines, chemicals that can harm surrounding cells. Rapamycin seems to reduce these inflammatory cytokines. It also improves cancer surveillance, the ways in which our body, most likely the immune system, detects and eliminates cancer cells.

• A small but growing number of people are already taking rapamycin off-label for its potential geroprotective benefits.

  • This drug represents Medicine 3.0, where we would be using a drug to help healthy people stay healthy, rather than to cure or relieve a specific ailment.

The Crisis of Abundance

• More than one in four people on the planet have some degree of nonalcoholic steatohepatitis, NASH, or its precursor, known as nonalcoholic fatty liver disease, or NAFLD. NAFLD is highly correlated with both obesity and hyperlipidemia (excessive cholesterol), yet it often flies under the radar, especially in its early stages.

• NAFLD is caused by more fat entering the liver or being produced there than exiting it.

• NASH is basically NAFLD plus inflammation, similar to hepatitis but without viral infection. The inflammation causes scarring in the liver but without obvious symptoms.

• When a healthy person donates a portion of their liver, both donor and recipient end up with an almost full-sized, fully functional liver within about eight weeks of the surgery.

• Metabolic dysfunction vastly increases your risk for CVD, cancer, and Alzheimer’s disease.

• Metabolic syndrome is defined in terms of the following five criteria:

  • High blood pressure (>130/85)

  • High triglycerides (>150 mg/dL)

  • Low HDL cholesterol (<40 mg/dL in men or <50 mg/dL in women)

  • Central adiposity (waist circumference >40 inches in men or >35 in women)

  • Elevated fasting glucose (>110 mg/dL)

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

• 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 their proper destinations. But when someone is metabolically unhealthy, many of the calories they consume end up where they are non needed or even harmful.

• If you eat a doughnut, your body can convert the carbohydrate into glycogen, the storage form of glucose, suitable for use in the near term. About 75 percent of this glycogen ends up in skeletal muscle and the other 25 percent goes to the liver.

• One of the liver’s many important jobs is to convert glycogen back to glucose and then to release it as needed to maintain blood glucose levels at a steady state, known as glucose homeostasis.

• 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.

• Subcutaneous fat is the layer of fat just beneath our skin—it is the safest place to store excess energy.

• Think of fat as acting like a metabolic buffer zone, absorbing excess energy and storing it safely until it is needed. If we eat extra doughnuts, those calories are stored in our subcutaneous fat; when we go on a long hike or swim, some of that fat is then released for use by the muscles. This fat flux goes on continually, and as long as you haven’t exceeded your own fat storage capacity, things are pretty much fine.

• 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, and even around your heart and pancreas.

• Visceral fat can be dangerous by secreting inflammatory cytokines such as TNF-alpha and IL-6, key markers and drivers of inflammation, in close proximity to your most important bodily organs.

• Individual fat-storage capacity seems to be influenced by genetic factors. This can explain why some people can be obese but metabolically healthy, while others can appear skinny while still walking around with three or more markers of metabolic syndrome.

• A thin person may simply have a much lower capacity to safely store fat. All other things being equal, someone who carries a bit of both fat may also have greater fat-storage capacity, and thus more metabolic leeway than someone who appears to be more lean.

• It’s important to get occasional DEXA scans to see how much visceral fat a person carries.

• Insulin resistance likely begins in the muscle, where fat worms its way in between muscle fibers.

• 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 is when cells, initially muscle cells, have stopped listening to insulin’s signals. The pancreas begins to secrete even more insulin, to try to remove excess glucose from the bloodstream and cram it into cells. Eventually, the pancreas becomes fatigued and less able to mount an insulin response.

• This is a vicious spiral: fat spillover helps initiate insulin resistance, which results in the accumulation of still more fat, eventually impairing our ability to store calories as anything other than fat.

• Cortisol is especially potent, it depletes subcutaneous fat (which is generally more beneficial) and replaces 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.

• 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 the condition, known as hyperinsulinemia.

• 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 that all these conditions have in common. This is why metabolic health is so important, and why the epidemic of metabolic disease is concerning.

• The prevalence of metabolic disease is rising likely due to our metabolisms not being equipped to cope with our ultramodern diet. Evolution is no longer our friend because our environment has changed much faster than our genome ever could. 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.

• It is very difficult to get fat from eating too many apples because the fructose in the apple enters our system relatively slowly, mixed with fiber and water, and our gut and our metabolism can handle it normally. But if we are drinking quarts of apple juice, it’s a different story.

• 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. This is why gout, was so common amount gluttonous aristocrats in the older days. Testing uric acid is important because high levels may promote fat storage, and is linked to high blood pressure. High uric acid is an early warning sign that we need to address a patient’s metabolic health, diet, or both.

• 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.

• We want to intervene before a patient develops metabolic syndrome.

• The ratio of triglycerides to HDL cholesterol should be less than 2:1 or better yet, less than 1:1.

• The body’s first response to incipient insulin resistance is to produce more insulin.

• Addressing and preventing metabolic dysfunction is a cornerstone of approaching longevity.

The Ticker

• Heart disease and stroke, which lump together under the single heading of atherosclerotic cardiovascular disease, or ASCVD, represent the leading cause of death, killing an estimated 2,300 people every day in the United States—more than any other cause, including cancer.

  • American women are up to ten times more likely to die from atherosclerotic disease than from breast cancer.

• It should be possible to eliminate much of the morbidity and mortality that is still associated with atherosclerotic cardiovascular and cerebrovascular disease. It should be the tenth leading cause of death, not the first.

• Cholesterol is essential to life. It is required to produce some of the most important structures in the body, including cell membranes; hormones such as testosterone, progesterone, estrogen, and cortisol; and bile acids, which are necessary for digesting food.

• Because cholesterol belongs to the lipid family, it is not water-soluble and thus cannot dissolve in our plasma like glucose or sodium and travel freely through our circulation. So it must be carted around in tiny spherical particles called lipoproteins—the final “L” in LEL and HDL—which act like little cargo submarines.

• The reason they’re called high- and low-density lipoproteins (HDL and LDL, respectively) has to do more 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 denser. Also, these particles frequently exchange cargo with one another, which is part of why they shouldn’t be labeled as “good” or “bad.” When an HDL transfers its “good cholesterol” to an LDL particle, does that cholesterol suddenly become “bad”?

• Each lipoprotein particle is enwrapped by one or more large molecules, called apolipoprotein, that provide structure, stability, and, most importantly, solubility to the particle. HDL particles are wrapped in a type of molecule called apolipoprotein A (or apoA), while LDL is encased in apolipoprotein B (or apoB).

• Every single lipoprotein that contributes to atherosclerosis—not only LDL but several others—carries this apoB protein signature.

• Eating lots of saturated fat can increase levels of atherosclerosis causing lipoproteins in the blood, but most of the actual cholesterol that we consume in our food ends up being excreted out our backsides. The vast majority of the cholesterol in our circulation is actually produced by our own cells.

• Most of the basic research into cholesterol and atherosclerosis had been conducted in rabbits, which have a unique ability to absorb cholesterol into their blood from their food and form atherosclerotic plaques from it; the mistake was to assume that humans also absorb dietary cholesterol as readily. But there is no connection whatsoever between cholesterol in food and cholesterol in the blood. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.

• 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 a highly reactive molecule known as a reactive oxygen species, or ROS, the cause of oxidative stress. 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 stops behaving like a polite guest, refusing to leave and inviting its friends, other LDLs, to join the party. 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.

  • The more of these 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.

• As many as a third of sixteen- to twenty-year-olds already have actual atherosclerotic lesions or plaques in their coronary arteries. This means we need to take steps to reduce CVD early.

• Newer research suggests that HDL has multiple 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.

• Lots of studies have shown a strong correlation between LDL-C and event risk. But the all-important “good cholesterol” number on your blood test, your HDL-C, doesn’t actually tell you much if anything about your overall risk profile. Risk does seem to decline as HDL-C rises to around the 80th percentile. But simply raising HDL cholesterol concentrations by brute force, with specialized drugs, has not been shown to reduce CVD at all.

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

• Measuring C-reactive protein is a popular (but poor) proxy of arterial inflammation. In order to see calcium buildup in the arteries, it is best viewed with a CT angiogram. This is because it can also identify the noncalcified or “soft” plaque that precedes calcification.

• Calcification is merely another way in which the body is trying to repair the damage, by stabilizing the plaque to protect the all-important arteries. But it’s like pouring concrete on the Chornobyl reactor: you’re glad it’s there, but you know there’s been an awful lot of damage in the area to warrant such an intervention.

• If the plaque does become unstable, eroding, or even rupturing, you’ve really got problems. 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.

• Evidence has piled up pointing to apoB as far more predictive of CVD than simple LDL-C, the standard “bad cholesterol” measure. Each standard deviation increase in apoB raises the risk of myocardial infarction by 38 percent in patients without a history of cardiac events or a diagnosis of CVD. Yet, even now, the American Heart Association guidelines still favor LDL-C testing instead of apoB. You should have your apoB tested regularly.

• The goal should be to get your apoB as low as possible, as early as possible.

• apo(a) wraps loosely around the LDL particle, with multiple looping amino acid 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 up bits of oxidized lipid molecules and carry them along.

• 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 gone bad. Even worse, once in there, it acts partly as a thrombotic or proclotting factor, which helps to speed the formation of arterial plaques.

• Elevated Lp(a) is mostly genetic and carries a high risk of heart disease. Everyone should test Lp(a) once to evaluate CVD risk.

• Beyond the harm it causes to coronary arteries, 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.

• The only real treatment available for elevated Lp(a) right now is aggressive management of apoB overall. Though we can’t reduce Lp(a) directly, beyond what a PSK9 inhibitor can do, we can lower the remaining apoB concentration sufficiently so that we can reduce a patient’s overall risk.

• Lp(a) and apoB are the best predictors of ASCVD risk.

• ApoB not only tells you the concentration of LDL particles, 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).

• Atherosclerosis probably wouldn’t occur in the absence of LDL-C concentrations in excess of physiological needs (on the order of 10 to 20 mg/dL). If the entire population maintained LDL concentrations akin to those of a neonate, atherosclerosis might well be an orphan disease.

• Most guidelines consider lowering LDL-C to 70mg/dL to be aggressive, even for secondary prevention in high-risk patients, such as those who have already had a heart attack.

• We want LDLs and VLDLs to be as low as possible, sooner rather than later.

• Having very low HDL-C is associated with higher risk, however, it does not appear to be causal.

• Smoking cessation and blood pressure control are non-negotiable first steps in reducing CVD risk.

• Monounsaturated fats, found in high quantities in extra virgin olive oil, macadamia nuts, and avocados don’t appear to increase apoB particles like saturated fats do.

• Statins are far and away the most prescribed class of drugs for lipid management. They help decrease apoB and LDL concentrations.

  • Mostly this is done by amplifying the activity of LDL receptors in the liver, which absorb cholesterol from the bloodstream.

  • Statins inhibit cholesterol synthesis, prompting the liver to increase the expression of LDLR, taking more LDL out of circulation.

• If we want to reduce deaths from cardiovascular disease, we need to begin thinking about prevention in people in their forties and even thirties.

• Looking at a thirty-year time frame rather than the standard ten years and taking aggressive precautionary measures early, like beginning statin treatment earlier in certain patients, could prevent hundreds of thousands more cardiac events.

• Risk is proportional to apoB exposure over time. The sooner we lower apoB exposure, thus lowering risk, the more benefits compound over time, and the greater our overall risk reduction.

• LDL receptors can be upregulated by a class of drugs called PCSK9 inhibitors, which attack a protein called PCSK9 that degrades LDL receptors. This increases the receptors’ half-life, thus improving the liver’s ability to clear apoB.

• Triglycerides also contribute to the apoB particle burden, because they are largely transported in VLDLs. Our dietary interventions are aimed at reducing triglycerides, but in cases where nutritional changes are insufficient, and in cases where genetics render dietary interventions useless, fibrates are the drug of choice.

• Ethyl eicosapentaenoic acid, a drug derived from fish oil and consisting of four grams of pharmaceutical-grade eicosapentaenoic acid (EPA), also has FDA approval to reduce LDL in patients with elevated triglycerides.

The Runaway Cell

• Cancer is the second leading cause of death in the United States, right behind heart disease.

• Our ability to detect cancer at an early stage is still very weak. We usually discover tumors only when they cause other symptoms, by which point they are often too locally advanced to be removed—or worse, the cancer has already spread to other parts of the body.

• We should be doing early, aggressive, and broad screening—such as a colonoscopy at age forty, as opposed to the standard recommendation of forty-five—because the evidence is overwhelming that it’s much easier to deal with most cancers in their early stages.

• Cancer cells are different from normal cells. They don’t stop growing when they are supposed to. They stop listening to the body’s signals that tell them when to grow and when to stop growing.

• Cancer cells are also able to travel from one part of the body to a distant site where they should not be. This is called metastasis, and it is what enables a cancerous cell in the breast to spread to the lung. This spreading is what turns cancer from a local, manageable problem to a fatal, systemic disease.

• Breast cancer kills only when it becomes metastatic. Prostate cancer kills only when it becomes metastatic. You could live without either of those organs. So when you hear of someone dying from breast or prostate cancer, or even pancreatic or colon cancer, they died because the cancer spread to other, more critical organs such as the brain, the lungs, the liver, and the bones. When cancer reaches those places, survival rates drop precipitously.

• In normal aerobic respiration, a cell can turn a molecule of glucose into as many as thirty-six units of ATP. But under anaerobic conditions, that same amount of glucose yields only two net units of ATP. 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.

• About 12 to 13 percent of all cancer cases are thought to be attributable to obesity. Obesity itself 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. Extreme obesity is associated with a 52 percent greater risk of death from all cancers in men, and 62 percent in women.

• The association between obesity, diabetes, and cancer is primarily driven by inflammation and growth factors such as insulin.

• Getting our metabolic health in order is essential to our anticancer strategy.

• To make immunotherapy more widely effective, we need to devise ways to help our immune cells detect and kill a broader array of cancers, not just a few specific types. Genetic analysis reveals that some 80 percent of epithelial cancers (that is, solid organ tumors) possess mutations that the immune system can recognize—thus making them potentially vulnerable to immune-based treatments.

• The purpose of the colonoscopy is to look not only for full-fledged tumors but also for polyps, which are growths that form in the lining of the colon. Most polyps remain small and harmless and never become cancerous, but some have the potential to become malignant and invade the wall of the colon. Not all polyps become cancer, but all colon cancers came from polyps.

• The bottom line is that it is far better to screen early than risk doing it too late. Think asymmetric risk: It’s possible that not screening early and frequently enough is the most dangerous option.

• The first rule of cancer is “Don’t get cancer.” The second rule is “Catch it as soon as possible.” Treating smaller tumors with fewer mutations is far easier than if we wait for cancer to advance and potentially acquire mutations that help it evade our treatments. The only way to catch it early is with aggressive screening.

Chasing Memory

• The APOE e4 allele, which is associated with a greater risk of Alzheimer’s disease—and not just one copy, but two (e4/e4) can increase the risk of developing Alzheimer’s disease by twelve times greater than that of someone with two copies of the common e3 allele. The e2 version of the APOE appears to protect carriers against Alzheimer’s disease: 10 percent reduced risk for someone with e2/e3, and about 20 percent for e2/e2.

• 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 which is the fastest-growing neurodegenerative disease.

• While it is true that over one-half of people with Alzheimer’s disease have at least one copy of e4, merely possessing this risk gene is not the same as being diagnosed with dementia due to Alzheimer’s disease.

• Having the e4 gene variant merely signals increased risk. It’s not a done deal.

• Amyloid-beta is a by-product 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 in thirds, one of the resulting fragments then becomes “misfolded,” meaning it loses its normal structure and becomes chemically stickier, prone to aggregating in clumps. This is amyloid-beta.

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

• The “amyloid hypothesis” as it’s called, has been the dominant theory of Alzheimer’s disease since the 1980s, and it has driven the research priorities of the NIH and the pharmaceutical industry alike. If you could eliminate the amyloid, the thinking has been, then you could halt or even reverse the progression of the disease. But it hasn’t worked out that way. Every single drug has failed.

• Autopsy studies have found that more than 25 percent of cognitively normal people had large deposits of amyloid in their brains when they died—some of them with the same degree of plaque buildup as patients who died with severe dementia. But for some reason, these people displayed no cognitive symptoms.

• It appears that the presence of amyloid-beta plaques may be neither necessary for the development of Alzheimer’s disease nor sufficient to cause it.

• The APOE e4 variant not only increases someone’s risk for Alzheimer’s but also 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.

• Regardless of the APOE genotype, Alzheimer’s disease is almost twice as common in women than in men.

• Olfactory neurons are amount the first to be affected by Alzheimer’s disease. So testing smell is an important section of cognitive testing.

• Exercise is the only intervention shown to delay the progression of Parkinson’s.

• People that have Alzheimer’s disease and are very cognitively engaged, and have a good backup pathway, are not going to decline as quickly.

• There is also a movement reserve that becomes relevant with Parkinson’s disease. People with better movement patterns, and a longer history of moving their bodies, tend to resist or slow the progression of the disease as compared to sedentary people.

• Activities that present more varied challenges, requiring more nimble thinking and processing, are more productive at building and maintaining cognitive reserve.

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

• Robust blood flow seems to be critical to maintaining brain health.

• The human brain depends on a steady supply of glucose and oxygen, delivered via a huge and delicate network of blood vessels. Even slight disruptions to this vascular network can result in a crippling or even fatal stroke.

• 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.

• 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 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.

• 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.

• Having type 2 diabetes doubles or triples your risk of developing Alzheimer’s disease. Chronically elevated blood glucose can directly damage the vasculature of the brain.

• Insulin seems to play a key role in memory function. Insulin receptors are highly concentrated in the hippocampus, the memory center of the brain.

• Clearly, it is helpful to get glucose into neurons; insulin resistance blocks this.

• Brain imaging studies reveal lower brain glucose metabolism, decades before the onset of other symptoms of vascular dementia.

• 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 protein for which APOE e4 codes, APOE (apolipoprotein E), 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.

• People with the e4 allele appear to have defects in both cholesterol transport and glucose metabolism to a degree not seen in those with e3 or e3. It appears to be less efficient at moving cholesterol into and especially out of the brain.

• The goal of Alzheimer’s prevention is to improve glucose metabolism, inflammation, and oxidative stress. 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.

• 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.

• The single most powerful item in our preventive tool kit for Alzheimer’s 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.

• Make sure to brush and floss your teeth. 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.

• Regular sauna use can help also decrease the risk of developing neurodegenerative disease. At least four sessions per week, of at least twenty minutes per session, at 179 degrees Fahrenheit or hotter seems to be the sweet spot to reduce the risk of Alzheimer’s by about 65 percent (and the risk of ASCVD by 50 percent).

• The longer we can go without developing dementia, the better our odds of living longer, and living in better health.

• Tips for preventing Alzheimer’s and other forms of neurodegenerative disease:

  • Vascular health (meaning low apoB, low inflammation, and low oxidative stress) is crucial to brain health.

  • What’s good for the liver (and pancreas) is good for the brain. Get your metabolic health in check.

  • Time is key. Start thinking about prevention early.

  • Our most powerful tool for preventing cognitive decline is exercise.

Thinking Tactically

• Long ago, when we consumed fructose mainly in the form of fruit and honey, it enabled us to store energy as fat to survive cold winters and periods of scarcity. Fructose was our friend. Now fructose is vastly overabundant in our diet, too much of it in liquid form, which disrupts our metabolism and our overall energy balance.

• Automotive fatality statistics reveal that almost 30 percent of deaths involve excessive speed.

• A very high proportion of fatalities occur at intersections. The most common way to be killed, as a driver, is by another car that hits yours from the left, on the driver’s side, having run a red light or traveling at high speed.

Exercise

• Exercise can lengthen your life by several years. It delays the onset of chronic diseases, pretty much across the board, but it is also amazingly effective at extending and improving healthspan.

• Study after study has found that regular exercisers live as much as a decade longer than sedentary people.

• Cardiorespiratory or aerobic fitness is how efficient your body is at delivering oxygen to your muscles, and how efficiently your muscles can extract that oxygen, enabling you to run or cycle long distances.

• 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. The more oxygen your body is able to use, the higher your VO2 max.

• Someone in the bottom quartile of VO2 max for their age group is nearly four times likelier to die than someone in the top quartile—and five times likelier to die than a person with elite-level (top 2.3 percent) VO2 max.

• Cardiorespiratory fitness is inversely associated with long-term mortality with no observed upper limit of benefit. Extremely high aerobic fitness is associated with the greatest survival.

• Having more muscle mass and stronger muscles helps support and protect the body—and also maintains metabolic health because those muscles consume energy efficiently.

• Exercise really does act like a drug. It prompts the body to produce its own, endogenous drug-like chemicals. When we are exercising, our muscles generate molecules known as cytokines that send signals to other parts of our bodies, helping to strengthen our immune system and stimulate the growth of new muscle and stronger bones. Endurance exercise such as running or cycling helps generate another potent molecule called brain-derived neurotrophic factor, or BDNF, that improves the health and function of the hippocampus, a part of the brain that plays an essential role in memory. Exercise helps keep the brain vasculature healthy, and it may also help preserve brain volume.

• One of the hallmarks of aging is that our physical capacity erodes. Our cardiorespiratory fitness declines for various reasons that begin with lower cardiac output, primarily due to reduced maximum heart rate. We lose strength and muscle mass with each passing decade, our bones grow fragile and our joints stiffen, and our balance falters.

• Continued muscle loss and inactivity literally puts our lives at risk. Seniors with the least muscle mass are at the greatest risk of dying from all causes.

• Muscle helps us survive old age.

• Having more muscle mass delays death precisely because it also preserves healthspan.

• It’s only after we get injured or become so weak that we are in danger of losing our independence, that we are deemed eligible for physical therapy and rehabilitation.

The Centenarian Decathlon

• Think of the Centenarian Decathlon as the ten most important physical tasks you will want to be able to do for the rest of your life. Some of the items on the list resemble actual athletic events, while some are closer to activities of daily living, and others might reflect personal interests.

  1. Hike 1.5 miles on a hilly trail.

  2. Get up off the floor under your own power, using a maximum of one arm for support.

  3. Pick up a young 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 thirty seconds, eyes open.

  7. Have sex.

  8. Climb four flights of stairs in three minutes.

  9. Open a jar.

  10. Do thirty consecutive jump-rope skips.

• The full list can be much longer, with more than fifty different items, but you get the idea.

• Over the next thirty to forty years, your muscle strength will decline by about 8 to 17 percent per decade—accelerating as time goes on. So if you want to pick up that thirty-pound grandkid or great-grandkid when you’re eighty, you’re going to have to be able to lift about fifty to fifty-five pounds now. Without hurting yourself.

• In every case, you need to be doing much more now, to armor yourself against the natural and precipitous decline in strength and aerobic capacity that you will undergo as you age.

• Start training with a very specific purpose, which is to be a kick-ass one-hundred-year-old.

• It’s not about being great at any one pursuit, but about being pretty good at just about everything. As Centenarian Decathletes, we are no longer training for a specific event, but to become a different sort of athlete altogether: an athlete of life.

Training 101

• The three dimensions we want to optimize our fitness are aerobic endurance and efficiency (aka cardio), strength, and stability. All three of these are key to maintaining your health and strength as you age.

• When we say “cardio,” we are talking about not one thing, but a physiologic continuum, ranging from an easy walk to an all-out sprint.

• We are interested in two particular regions of this continuum: long, steady endurance work, such as jogging or cycling or swimming, where we are training in what physiologist call zone 2, and maximal aerobic efforts, where VO2 max comes into play.

• Our most important goal is not only to build strength and muscle mass. It’s equally important that we avoid injury in the process.

Aerobic Efficiency: Zone 2

• Aerobic exercise, don't in a very specific way, improves our ability to utilize glucose and especially fat as fuel. The key here is the mitochondria. These cellular “engines” can burn both glucose and fat and thus they are fundamental to our metabolic health. Healthy mitochondria are also important to maintaining the health of our brain, and to controlling potential bad actors like oxidative stress and inflammation.

• Typically, zone 1 is a walk in the park and zone 5 (or 6 or 7) is an all-out spring. Zone 2 is more or less the same in all training models: going at a speed slow enough that one can still maintain a conversation but fast enough that the conversation might be a little strained. It translates to aerobic activity at a pace somewhere between easy and moderate.

• 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.

• 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, fat and glucose, is called “metabolic flexibility.”

• Zone 2 training builds a base of endurance for anything else you do in life, whether that is riding your bike in a one-hundred-mile century ride or playing with your kids or grandkids. The other reason that it’s important is that it plays a crucial role in preventing chronic disease by improving the health and efficiency of your mitochondria, which is why training aerobic endurance and efficiency (i.e. zone 2 work).

• Lactate itself is not bad: trained athletes are able to recycle it as a type of fuel. The problem is that lactate becomes lactic acid when paired with hydrogen ions, which is what causes the acute burning you feel in your muscles during a hard effort. This is because the hydrogen ion does not allow the actin and myosin filaments in your muscles to relax, causing pain and stiffness in the muscle.

• Zone 2 is the maximum level of effort that we can maintain without accumulating lactate. We still produce it, but we’re able to match production with clearance.

• The goal is to keep lactate levels constant, ideally between 1.7 and 2.0 millimoles. This is the zone 2 threshold for most people.

• If you know your true maximum heart rate, your zone 2 will correspond to between approximately 70 and 85 percent of that peak number, depending on your fitness levels.

• If you’re at the top of zone 2, you should be able to talk but not particularly interested in holding a conversation. If you can’t speak in complete sentences at all, you’re likely into zone 3, which means you’re going too hard, but if you can comfortably converse, you’re likely in zone 1, which is too easy.

• One of the most significant hallmarks of aging is a decline in the number and quality of our mitochondria. 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 called mitophagy. A person who exercises frequently in zone 2 is improving their mitochondria with every run, swim, or bike. But if you don’t use them, you lose them.

• Studies have found that while we are exercising, our overall glucose uptake increases as much as one-hundred-fold compared to when we are at rest. There is the usual, insulin-signaled way that we’re 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 in turn explains why exercise, especially in zone 2, can be so effective in managing both type 1 and 2 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.

• A side benefit of zone 2 is that it also helps with cognition, by increasing cerebral blood flow and by stimulating the production of BDNF, brain-derived neurotrophic factor.

Maximum Aerobic Output: VO2 max

• This is a hard, minutes-long effort, but still well short of an all-out sprint.

• Zone 2 helps raise your VO2 max, but if you really want to raise your VO2 max, you need to train this zone more specifically.

• Even if you are not competing in high-level endurance sports, your VO2 max is an important number that you can and should know.

• Our VO2 max is a good proxy measure of our physical capability. It tells us what we can do—and what we cannot do.

• Your VO2 max will decline by roughly 10 percent per decade—and up to 15 percent per decade after the age of fifty. So simply having average or even above-average VO2 max now just won’t cut it.

• Increasing your VO2 max makes you functionally younger.

• VO2 max intervals are a bit longer, ranging from three to eight minutes. They can be done on a bike, rowing machine, or running on a treadmill or track. They should supplement your zone 2 training and be done 1 to 2 times per week.

• The typical exercise prescription for this type of training is 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 for four minutes easily, which should be enough time for your heart rate to come back down to below about one hundred beats per minute. Repeat this four to six times.

  • You want to make sure that you get as close to fully recovered as possible before beginning the next set. Also, make sure you have a proper warm-up and cool-down for this intense effort.

Strength

• Our muscle mass begins to decline as early as our thirties. An eighty-year-old man will have about 40 percent less muscle tissue than he did at twenty-five.

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

• Daily life and zone 2 endurance work may be enough to prevent the atrophy of type 1 fibers, but unless you are working against significant resistance, your type 2 muscle fibers will wither away.

• Risk factors for low bone density include menopause because estrogen is essential for bone strength, smoking, long use of corticosteroids, drugs that block estrogen, low muscle mass, and being undernourished.

• Up to one-third of people over sixty-five who fracture their hip are dead within a year.

• When low bone mineral density is detected in a middle-aged person, the treatment is as follows:

  • Optimize nutrition, focusing on protein and total energy needs.

  • Heavy loading-bearing activity. Strength training, especially with heavy weights, stimulates the growth of bone—more than impact sports such as running. Bones respond to mechanical tension and estrogen is the key hormone in mediating the mechanical signal (weight bearing) to a chemical one telling your body to lay down more bone.

  • HRT, if indicated.

  • Drugs to increase bone mineral density, if indicated.

• Carrying stuff over long distances is an essential skill our ancestors had to carry their kills back to camp to feed everyone.

• If you can grip strongly, you can open a jar with ease. If you can pull, you can carry groceries and lift heavy objects. If you can do a hip hinge correctly, you can get up out of a chair with no problem. You’re setting yourself up to age well. It’s not about how much weight you can deadlift now, but how well you will function in twenty or thirty or forty years.

• Training grip strength is not overly complicated. One of the best ways to do it is the classic farmer’s carry, where you walk for a minute or so with a loaded hex bar of a dumbbell or kettlebell in each hand. Men should be able to carry half their body weight in each hand, and females should get close to 75 percent of their body weight in each hand.

• You can also do a dead hang for grip strength. Men should hang for at least two minutes and women for at least ninety seconds at the age of forty.

• In older age, eccentric strength is where many people falter. Eccentric strength in the quads is what gives us the control we need when we are moving down an incline or walking down a set of stairs.

The Gospel of Stability

• The loftier the building, the deeper the foundation must be laid.

• Older people tend to exercise less, or not at all, because they simply can’t. They have hurt themselves in some way, at some point in their lives, and they just never got back on the horse.

• More than 27 percent of Americans over the age of forty-five report suffering from chronic pain, and about 10 to 12 percent say that pain has limited their activities on “most days or every day” in the previous six months.

• Pushing oneself so hard all the time, without adequate stability, almost inevitably leads to injury.

• Most “acute” injuries such as a torn ACL or hamstring are rarely sudden. They are often the result of chronic weakness or instability.

• Stability is the subconscious ability to harness, decelerate, or stop force. A stable person can react to internal or external stimuli to adjust position and muscular tension appropriately without a tremendous amount of conscious thought.

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

• We need to train the diaphragm to increase intra-abdominal pressure and local stabilization.

  • Try placing two tennis balls in an athletic sock about four to six inches apart, and position then bout at the level of the kidney, or where your thoracic spine meets the lumbar spine. Then try to breathe and expand fully to feel the tennis balls on both sides.

• Our feet are literally the foundation for any movement we might make.

• 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.

• If toe strength is compromised, everything up the chain is more vulnerable—ankle, knee, hip, and spine.

• Our shoulders are incredibly mobile, but because of that, they are also inherently unstable. Working shoulder stability directly is a must to fend off injury.

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

• Drop the weights until your form is perfect. Our goal should be to lift for our entire lives, not to set a PR every week.

• Don’t trade health for wealth.

Nutrition 3.0

• Thanks to the poor quality of the science, we actually don’t know that much about how what we eat affects our health. That creates a tremendous opportunity for a multitude of would-be nutrition gurus to insist, loudly, that only they know the true and righteous diet. There are forty thousand diet books on Amazon; they can’t all be right.

• It’s not about telling you what to eat; it’s about figuring out what works for your body and your goals—and, just as important, what you can stick to.

• The correlation between poor metabolic health and being overnourished and under-muscled is very high.

• Nutritional interventions can be powerful tools with which to restore someone’s metabolic equilibrium and reduce the risk of chronic disease. But can they extend and improve lifespan and healthspan the way exercise does? Probably not.

• Nutrition is actually relatively simple. 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.

• Plants are very good to eat. Animal protein is “safe” to eat. We evolved as omnivores; ergo, most of us can probably find excellent health as omnivores.

• Our knowledge of nutrition primarily comes from 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. These epidemiological studies generate much of the diet “news” that pops up in our daily internet feed, about whether coffee is good for you and bacon is bad, or vice versa.

• The problem is that epidemiology is incapable of distinguishing between correlation and causation.

• Humans are terrible study subjects for nutrition because we are unruly, disobedient, messy, forgetful, confounding, hungry, and complicated creatures.

• Food is so complex, made up of thousands of chemical compounds in millions of possible combinations that interact with human physiology in so many ways—in other words, nutritional biochemistry—that epidemiology is simply not up to the task of disentangling the effect of any individual nutrient or food.

Putting Nutritional Biochemistry into Practice

• The Standard American Diet (SAD) disrupts the body’s metabolic equilibrium. It places enormous strain on our ability to control our blood glucose levels and causes us to store fat when we should be utilizing it.

CR (Calorie Restriction): 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.

• The quality of your diet may matter as much as the quantity.

  • Avoiding diabetes and related metabolic dysfunction—especially by eliminating or reducing junk food—is very important to longevity.

  • If you’re on the SAD, then you should be eating less of it.

  • Conversely, if your diet is high quality to begin with, and you are metabolically healthy, then only a slight degree of caloric restriction can still be beneficial.

• Limiting calories can be helpful for people who are metabolically unhealthy and/or overnourished. But deep caloric restriction may have some trade-offs—including potentially weakened immunity and greater susceptibility to cachexia and sarcopenia, not to mention constant hunger.

DR (Dietary Restriction): The Nutritional Biochemistry “Diet”

• Our ancestors were opportunistic omnivores, out of necessity. They ate anything and everything they could get their hands on: lots of plants, starch, animal protein whenever they could, honey and berries whenever possible.

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

• Type 2 diabetes is a condition of impaired carbohydrate metabolism.

Alcohol

• Alcohol should be considered as its own category of macronutrient because it is so widely consumed, it has such potent effects on our metabolism, and it is so calorically dense at 7kcal/g.

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

• If you drink, try to be mindful of it. You’ll enjoy it more and suffer fewer consequences. Try to limit alcohol to fewer than seven servings per week, and ideally no more than two on any given day.

Carbohydrates

• Carbohydrates are our primary energy source. In digestion, most carbohydrates are broken down into 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 socked away in adipose tissue as fat. This decision is made with the help of the hormone insulin, which surges in response to the increase in blood glucose.

• A continuous glucose monitor, or CGM, is a device consisting of a microscopic filament sensor that is implanted in the upper arm, attached to a fingertip-sized transmitter that sends data to your phone in real-time.

• The power of the CGM is that it enables us to view a person’s response to carbohydrate consumption in real-time and make changes rapidly to flatten the curve and lower the average.

• By wearing a CGM you can see what foods or external events affect your glucose reading.

• Overall, you should keep average glucose at or below 100 mg/dL, with a standard deviation of less than 15 mg/dL.

• 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.

• Sleep disruption or reduction dramatically impairs glucose homeostasis over time.

• Timing of carbohydrate intake matters: If you scarf a large baked potato before working out, it will leave much less of a footprint on your daily glucose profile than if you eat it right before bedtime.

• Not all carbs are created equal. The more refined the carb, the faster and higher the glucose spike. Less processed carbs are those with more fiber and blunt the glucose impact.

• Brown rice is only slightly less glycemic than long-grain white rice.

• 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 circulation to fuel the muscles.

• Foods high in protein and fat have virtually no effect on blood sugar, but large amounts of lean protein will elevate glucose slightly. Protein shakes, especially if low in fat, have a more pronounced effect.

Protein

• Protein and amino acids are the essential building blocks of life. Without them, we simply cannot build or maintain the lean muscle mass that we need.

• Unlike carbs and fat, protein is not a primary source of energy. We do not rely on it in order to make ATP (although it can), 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 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.

• 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.

• Right now the US recommended dietary allowance for protein is 0.8 g/kg of body weight. This may reflect how much protein we need to stay alive, but it is a far cry from what we need to thrive.

• Certainly, a number of mouse studies suggest that restricting protein can improve mouse lifespan. But that doesn’t mean these results are applicable to humans. Mice and human beings respond very differently to low protein, and numerous studies suggest that low protein in the elderly leads to low muscle mass, yielding greater morality and worse quality of life.

• We should aim to get 1.6 g/kg/day as the minimum protein intake, which is twice as much as the RDA.

  • This is a lot of protein to eat, and the added challenge is that it should not be taken in one sitting but rather spread out over the day to avoid losing amino acids to oxidation. The literature suggests that the ideal way to achieve this is by consuming four servings of protein per day, each at about 0.25 g/lb of body weight.

• Most people don’t need to worry about consuming too much protein. It would require an overwhelming effort to eat more than 3.7 g/kg/day, defined as the safe upper limit of protein consumption (too much stress on the kidneys, for one).

• Older people should try to keep track of their lean mass, such as via a DEXA scan, and adjust their protein intake upwards if lean mass declines.

• 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 to 70 percent of what you consume is contributing to your needs.

• 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. Taken together, these two factors tell us that the overall quality of protein derived from plants is significantly lower than that from animal products.

• Whey protein isolate is richer in amino acids than soy protein isolate.

• Make sure that you get about three to four grams per day of leucine and lycine and at least one gram per day of methionine for the maintenance of lean mass. If you are trying to increase lean mass, you’ll need even more leucine, closer to two to three grams per serving, four times per day.

• Multiple studies suggest that the more protein we consume, in general, the better.

• 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 (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.

• There are three types of fats: saturated fatty acids (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. We can further subdivide 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.

• Olive oil and safflower oil might be as close as you can get to a pure monounsaturated fat, while palm and coconut oil might be as close as you can get to a pure saturated fat, but all foods that contain fats typically contain all three categories of fat: PUFA, MUFA, and SFA.

• We try to boost MUFA closer to 50-55 percent, while cutting SFA down to 15-20 percent and adjusting total PUFA to fill the gap. We also boost EPA and DHA, those fatty acids that are likely important to brain and cardiovascular health, with marine fat sources and/or supplementation.

  • Putting these changes into practice typically means eating more olive oil and avocados and nuts, cutting back on 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.

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

• Increasing PUFA probably makes little or no difference to our risk of death, and may make little or no difference to our risk of dying from cardiovascular disease. However, increasing PUFA probably slightly reduces our risk of heart disease events and of combined heart and stroke events.

• Subtle changes in fat intake, particularly of saturated fats, can make a significant difference in lipid levels in some people, but not in others. Some people can consume saturated fats with near impunity, while others can hardly even look at a slice of bacon without their apoB number jumping to the 90th percentile.

• Overall, 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 toss-up, and the actual ratio of SFA and PUFA probably comes down to individual factors such as lipid response and measured inflammation.

TR (Time Restriction): The Case for (and Against) Fasting

• Intermittent fasting can be useful sometimes, typically in people with severe metabolic dysfunction—but it is unlikely the panacea that some believe it to be.

• 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.

• Another drawback is that you are virtually guaranteed to miss your protein target with this approach. This means that a person who needs to gain lean body mass, should either abandon this approach completely or consume a pure protein source outside their feeding window.

• Time-restricted feeding is a way of putting the brakes on snacking and late-night meals—the type of mindless eating-just-to-eat. But beyond that, it’s likely not particularly useful.

• Fasting might cause some people, especially lean people, to lose too much muscle.

• The cost, in terms of lost lean mass 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.

Conclusion

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

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

• Zone 2 aerobic 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.

• Excessive carbohydrate intake can also have spillover effects on apoB, in the form of elevated triglycerides.

The Awakening

• 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.

• Good sleep, in terms of both quantity and quality, is critical to our cognitive function, our memory, and even our emotional equilibrium.

• 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.

• If sleep was so unimportant, then why hasn’t evolution gotten rid of it?

  • When we are asleep, we are accomplishing nothing useful: we are not reproducing, gathering food, or protecting our family. Even worse, in that slumbering state we are extremely vulnerable to predators and enemies.

  • If sleep wasn’t absolutely essential, natural selection would have eliminated the need to sleep hundreds of millions of years ago.

• A 2014 observational study found that young athletes who slept less than six hours per night were more than two and a half times more likely to experience an injury than their peers who slept eight hours or more.

• Sleep deprivation can cause profound insulin resistance.

• Long sleep is also a sign of problems. People who sleep eleven hours or more nightly have a nearly 50 percent higher risk of all-cause mortality, likely because long sleep = poor quality sleep, but it may also reflect an underlying illness. Similar risk associations have been found between poor and short sleep and hypertension, cardiovascular diseases, coronary heart diseases, and obesity.

• Higher stress levels can make us sleep poorly, as we all know, but poor sleep also makes us more stressed.

• 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.

• When we sleep poorly, we can be desperately, irrationally hungry the next day, and more likely to reach for high-calorie and sugary foods than their healthy alternatives.

• Good sleep may help mitigate some of the genetic risk of heart disease.

• Both REM and deep NREM 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 deep sleep we get in a given night and how well we will perform on a memory test the next day.

• Superior sleep quality in older adults is associated with a lower risk of developing MCI and Alzheimer’s disease, and with maintaining a higher level of cognitive function.

• Sleep medications such as Ambien and Lunesta do not promote healthy, long-lasting sleep so much as they tend to promote a sleep-like state of unconsciousness that does not really accomplish much if any of the brain-healing work of either REM or deep sleep.

• A couple of hours before bed, begin turning off unnecessary lights in your house, gradually reducing your light exposure from there. Also, try to swap out blue-intensive LED bulbs for those on the warmer end of the spectrum.

• Most people think of caffeine as a stimulant that somehow gives us energy, but actually, it functions more as a sleep blocker.

• Don’t eat anything less than three hours before bedtime—and ideally longer. It’s best to go to bed with just a little bit of hunger.

• Abstain from stimulating electronics, beginning two hours before bed. Try to avoid anything involving a screen if you’re having trouble falling asleep.

Work in Progress

• Emotional health is the most important component of healthspan. Nothing else about longevity is really worth much without some degree of happiness, fulfillment, and connection to others.

• Children are remarkably resilient, and wounded children become adaptive children. The problems begin when these adaptive children grow up to become maladaptive, dysfunctional adults.

• Emotional health has more to do with the way we regulate our emotions and manage our interpersonal relationships.

• With women, depression is generally overt, or obvious, but men are socialized to conceal their depression, channeling it inward or into other emotions, such as anger, without ever wanting to discuss it.

• It’s easy to miss the other person’s perspective. We know our story and how busy we’ve been, but we really don’t know what the other person’s day has been like.

• In reframing, you have to step back from a situation, temper your reflexive reaction, and try to see what is actually happening.

• We often forget our “eulogy virtue,” the things that our friends and family will about us when we’re gone, and spend too much time chasing job titles and accomplishments.

• We need to spot potential problems in our emotional health early and take preventive action as soon as possible.

• Dialectical behavior therapy (DBT) is based on the principles of cognitive behavioral therapy, which seeks to teach patients new ways of thinking about or acting on their problems.

• 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 for work or school).

• Changing the behavior can change the mood. You do not need to wait for your mood to improve to make a behavior change.