Outlive

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.—Bishop Desmond Tutu

None of our treatments for late-stage lung cancer has reduced mortality by nearly as much as the worldwide reduction in smoking that has occurred over the last two decades, thanks in part to widespread smoking bans. This simple preventive measure (not smoking) has saved more lives than any late-stage intervention that medicine has devised. Yet mainstream medicine still insists on waiting until the point of diagnosis before we intervene.

I used to prioritize nutrition over everything else, but I now consider exercise to be the most potent longevity “drug” in our arsenal, in terms of lifespan and healthspan. The data are unambiguous: exercise not only delays actual death but also prevents both cognitive and physical decline, better than any other intervention.

The best science out there says that what you eat matters, but the first-order term is how much you eat: how many calories you take into your body.

Not to be outdone, British World War I veteran Henry Allingham attributed his own 113-year lifespan to “cigarettes, whiskey, and wild, wild women.” It’s a shame he never met the adventurous Frenchwoman Jeanne Calment, who once joked, “I’ve only ever had one wrinkle, and I’m sitting on it.” She rode her bicycle until she was 100 and kept smoking until the age of 117. Perhaps she shouldn’t have quit, because she died five years later at 122, making her the oldest person ever to have lived.

According to research by Thomas Perls of Boston University and his colleagues, who run the New England Centenarian Study, one in five people in the general population will have received some type of cancer diagnosis by age seventy-two. Among centenarians, that one-in-five threshold is not reached until age one hundred, nearly three decades later. Similarly, one-quarter of the general population will have been diagnosed with clinically apparent cardiovascular disease by age seventy-five; among centenarians, that prevalence is reached only at age ninety-two.

The same pattern holds for bone loss, or osteoporosis, which strikes centenarians sixteen years later than average, as well as for stroke, dementia, and hypertension: centenarians succumb to these conditions much later, if at all.

When centenarians die, in contrast, they have generally (though not always) been sick and/ or disabled for a much shorter period of time than people who die two or three decades earlier. This is called compression of morbidity, and it basically means shrinking or shortening the period of decline at the end of life and lengthening the period of healthy life, or healthspan.

One of the most potent individual genes yet discovered is related to cholesterol metabolism, glucose metabolism—and Alzheimer’s disease risk. You may have heard of this gene, which is called APOE, because of its known 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.

people who carried at least one copy of APOE e2 (and no e4) were about 30 percent more likely to reach extreme old age (defined as ninety-seven for men, one hundred for women) than people with the standard e3/ e3

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. Its potent correlation with longevity suggests that we should focus our efforts on cognitive health and pay special attention to issues around cholesterol and lipoproteins (the particles that carry cholesterol, which we’ll discuss in chapter 7), as well as glucose metabolism (chapter 6).

Researchers have identified two other cholesterol-related genes, known as CETP and APOC3, that are also correlated with extreme longevity

In 2008, Bradley Willcox of the University of Hawaii and colleagues reported that a genetic analysis of participants in a long-running study of health and longevity in Hawaiian men of Japanese ancestry had identified three SNPs (or variants) in FOXO3 that were strongly associated with healthy aging and longevity. Since then, several other studies have found that various other long-lived populations also appear to have FOXO3 mutations, including Californians, New Englanders, Danes, Germans, Italians, French, Chinese, and American Ashkenazi Jews—making FOXO3 one of the very few longevity-related genes to be found across multiple different ethnic groups and geographical locations.

When FOXO3 is activated, it in turn activates genes that generally keep our cells healthier. It seems to play an important role in preventing cells from becoming cancerous as well.

Here’s where we start to see some hope, because 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.

While your genome is immutable, at least for the near future, gene expression can be influenced by your environment and your behaviors. For example, a 2007 study found that older people who were put on a regular exercise program shifted to a more youthful pattern of gene expression after six months.

This points to another flaw of Medicine 2.0, which is that it generally looks at these diseases as entirely separate 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.

Sehgal found that this soil sample was saturated with a strange and potent antifungal agent that was seemingly produced by a soil bacterium called Streptomyces hygroscopicus. Curious, Sehgal isolated the bacterium and grew it in culture, then began testing this mysterious compound in his lab. He named it rapamycin, after Rapa Nui, the native name for Easter Island (mycin is the suffix typically applied to antimicrobial agents).

The reason rapamycin has so many diverse applications is thanks to a property that Sehgal had observed, but never explored, which is that it tends to slow down the process of cellular growth and division.

Ultimately, he and others discovered that rapamycin acted directly on a very important intracellular protein complex called mTOR (pronounced “em-tor”), for “mechanistic target of rapamycin.”[* 2] 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.

this exotic molecule, found only on an isolated scrap of land in the middle of the ocean, acts almost like a switch that inhibits a very specific cellular mechanism that exists in nearly everything that lives.

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.

The life-extending effect of CR seems to be almost universal. Numerous labs have found that restricting caloric intake lengthens lifespan not only in rats and mice (usually) but also in yeast, worms, flies, fish, hamsters, dogs, and even, weirdly, spiders. It has been found to extend lifespan in just about every model organism on which it has been tried, with the odd exception of houseflies.

there is no evidence that extreme CR would truly maximize the longevity function in an organism as complex as we humans, who live in a more variable environment than the animals described above. While it seems likely that it would reduce the risk of succumbing to at least some of the Horsemen, it seems equally likely that the uptick in mortality due to infections, trauma, and frailty might offset those gains.

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.

The first of these is an enzyme called AMP-activated protein kinase, or AMPK for short. AMPK 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 lack of nutrients, AMPK is also activated when we exercise,

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,

Autophagy represents the catabolic side of metabolism, when the cell stops producing new proteins and instead begins to break down old proteins and other cellular structures into their amino acid components, using the scavenged materials to build new ones. It’s a form of cellular recycling, cleaning out the accumulated junk in the cell and repurposing it or disposing of it.

In 1980, a team at the Mayo Clinic dubbed this “hitherto unnamed disease” nonalcoholic steatohepatitis, or NASH. Since then, it has blossomed into a global plague. More than one in four people on this planet have some degree of 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. Most patients are unaware that they have it—and so are their doctors, because NAFLD and NASH have no obvious symptoms. The first signs would generally show up only on a blood test for the liver enzyme alanine aminotransferase (ALT for short). Rising levels of ALT are often the first clue that something is wrong with the liver, although they could also be a symptom of something else, such as a recent viral infection or a reaction to a medication.

What is normal? According to Labcorp, a leading testing company, the acceptable range for ALT is below 33 IU/ L for women and below 45 IU/ L for men (although the ranges can vary from lab to lab). But “normal” is not the same as “healthy.” The reference ranges for these tests are based on current percentiles,[* 1] but as the population in general becomes less healthy, the average may diverge from optimal levels.

With regard to ALT liver values, the American College of Gastroenterology recently revised its guidelines to recommend clinical evaluation for liver disease in men with ALT above 33 and women with ALT above 25—significantly below the current “normal” ranges. Even that may not be low enough: a 2002 study that excluded people who already had fatty liver suggested upper limits of 30 for men, and 19 for women. So even if your liver function tests land within the reference range, that does not imply that your liver is actually healthy.

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

Both NAFLD and NASH are still reversible. If you can somehow remove the fat from the liver (most commonly via weight loss), the inflammation will resolve, and liver function returns to normal. The liver is a highly resilient organ, almost miraculously

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,

In other words, your liver can recover from fairly extensive damage, up to and including partial removal. But if NASH is not kept in check or reversed, the damage and the scarring may progress into cirrhosis.

Today we call this cluster of problems “metabolic syndrome” (or MetSyn), and it 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)

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 not needed, at best—or outright harmful, at worst.

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 (as we’ll see); and even around your heart and your pancreas (figure 4). None of these, obviously, are ideal places for fat to collect; NAFLD is just one of many undesirable consequences of this fat spillover.

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.

Fat storage capacity varies widely among individuals. Going back to our tub analogy, some people have subcutaneous fat-storage capacity equivalent to a regular bathtub, while others may be closer to a full-sized Jacuzzi or hot tub. Still others may have only the equivalent of a five-gallon bucket.

It doesn’t take much visceral fat to cause problems. Let’s say you are a forty-year-old man who weighs two hundred pounds. If you have 20 percent body fat, making you more or less average (50th percentile) for your age and sex, that means you are carrying 40 pounds of fat throughout your body. Even if just 4.5 pounds of that is visceral fat, you would be considered at exceptionally high risk for cardiovascular disease and type 2 diabetes, in the top 5 percent of risk for your age and sex. This is why I insist my patients undergo a DEXA scan annually—and I am far more interested in their visceral fat than their total body fat.

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.

As type 2 diabetes emerged, beginning in the early 1700s, it was at first largely a disease of the superelite, popes and artists and wealthy merchants and nobles who could afford this newly fashionable luxury food known as sugar.

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.

When we metabolize fructose, along with certain other types of foods, it produces large amounts of uric acid, which is best known as a cause of gout but which has also been associated with elevated blood pressure.

“We realized fructose was having effects that could not be explained by its calorie content,” Johnson says. The culprit seemed to be uric acid. Other mammals, and even some other primates, possess an enzyme called uricase, which helps them clear uric acid. But we humans lack this important and apparently beneficial enzyme, so uric acid builds up, with all its negative consequences.

At some point, our primate ancestors underwent a random genetic mutation that effectively switched on their ability to turn fructose into fat: the gene for the uricase enzyme was “silenced,” or lost. Now, when these apes consumed fructose, they generated lots of uric acid, which caused them to store many more of those fructose calories as fat. This newfound ability to store fat enabled them to survive in the colder climate. They could spend the summer gorging themselves on fruit, fattening up for the winter. These same ape species, or their evolutionary successors, migrated back down into Africa, where over time they evolved into hominids and then Homo sapiens—while also passing their uricase-silencing mutation down to us humans. This, in turn, helped enable humans to spread far and wide across the globe, because we could store energy to help us survive cold weather and seasons without abundant food.

Fructose isn’t the only thing that creates uric acid; foods high in chemicals called purines, such as certain meats, cheeses, anchovies, and beer, also generate uric acid. This is why gout, a condition of excess uric acid, was so common among gluttonous aristocrats in the olden days (and still today).

High uric acid is an early warning sign that we need to address a patient’s metabolic health, their diet, or both.

The mechanisms are a bit complicated, but the bottom line is that even though it is rich in energy, fructose basically tricks our metabolism into thinking that we are depleting energy—and need to take in still more food and store more energy as fat.[* 5]

I’ve seen patients work themselves into NAFLD by drinking too many “healthy” fruit smoothies, for the same reason: they are taking in too much fructose, too quickly.

But the first thing I look for, the canary in the coal mine of metabolic disorder, is elevated insulin. As we’ve seen, the body’s first response to incipient insulin resistance is to produce more insulin. Think back to our analogy with the balloon: as it gets harder to get air (glucose) into the balloon (the cell), we have to blow harder and harder (i.e., produce more insulin).

One test that I like to give patients is the oral glucose tolerance test, or OGTT, where the patient swallows ten ounces of a sickly-sweet, almost undrinkable beverage called Glucola that contains seventy-five grams of pure glucose,

Typically, their blood glucose levels will rise, followed by a peak in insulin, but then the glucose will steadily decrease as insulin does its job and removes it from circulation.

But the insulin in someone at the early stages of insulin resistance will rise very dramatically in the first thirty minutes and then remain elevated, or even rise further, over the next hour. This postprandial insulin spike is one of the biggest early warning signs that all is not well.

Studies have found that insulin resistance itself is associated with huge increases in one’s risk of cancer (up to twelvefold), Alzheimer’s disease (fivefold), and death from cardiovascular disease (almost sixfold)—

It is beyond backwards that we do not treat hyperinsulinemia like a bona fide endocrine disorder of its own. I would argue that doing so might have a greater impact on human health and longevity than any other target of therapy.

And your “total cholesterol,” the first number that people offer up when we’re talking about heart disease, is only slightly more relevant to your cardiovascular risk than the color of your eyes.

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. All cells can synthesize their own cholesterol, but some 20 percent of our body’s (large) supply is found in the liver, which acts as a sort of cholesterol repository, shipping it out to cells that need it and receiving it back via the circulation.

Because cholesterol belongs to the lipid family (that is, fats), 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 LDL and HDL—which act like little cargo submarines. As their name suggests, these 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, respectively) 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.

When an HDL transfers its “good cholesterol” to an LDL particle, does that cholesterol suddenly become “bad”? The answer is no—because it’s not the cholesterol per se that causes problems but the nature of the particle in which it’s transported.

HDL particles are wrapped in a type of molecule called apolipoprotein A (or apoA), while LDL is encased in apolipoprotein B (or 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[* 1]—carries this apoB protein signature.

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. The vast majority of the cholesterol in our circulation is actually produced by our own cells.

The problem he recognized was that much 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.

Another very important job it does is to dilate and contract to allow increased or decreased blood flow, a process modulated by nitric oxide. Last, the endothelium regulates blood-clotting mechanisms, which can be important if you accidentally cut yourself. It’s a pretty important little structure.

This is what HDL particles generally do: particles tagged with apoA (HDL) can cross the endothelial barrier easily in both directions, in and out. LDL particles and other particles with the apoB protein are far more prone to getting stuck inside. This is what actually makes HDL particles potentially “good” and LDL particles potentially “bad”—not the cholesterol, but the particles that carry it. 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.

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. That number is much more relevant than the total quantity of cholesterol that these particles are carrying.

The macrophage, whose name means “big eater,” swallows up the aggregated or oxidized LDL, trying to remove it from the artery wall. But if it consumes too much cholesterol, then it blows up into a foam cell,

When enough foam cells gather together, they form a “fatty streak”—literally a streak of fat that you can see with your naked eye during an autopsy of a splayed-open coronary artery. The fatty streak is a precursor of an atherosclerotic plaque, and if you are reading this and are older than fifteen or so, there is a good chance you already have some of these lurking in your arteries. Yes, I said “fifteen” and not “fifty”—this is a lifelong process and it starts very early. Autopsy data from young people who died from accidents, homicides, or other noncardiovascular causes have revealed that as many as a third of sixteen-to twenty-year-olds already had actual atherosclerotic lesions or plaques in their coronary arteries when they died. As teenagers.

If an HDL particle arrives at our crime scene, with the foam cells and fatty streaks, it can suck the cholesterol back out of the macrophages in a process called delipidation. It then slips back across the endothelial layer and into the bloodstream, to deliver the excess cholesterol back to the liver and other tissues

Its role in this process of “cholesterol efflux” is one reason why HDL is considered “good,” but it does more than that. Newer research suggests that HDL has multiple other atheroprotective functions that include helping maintain the integrity of the endothelium, lowering inflammation, and neutralizing or stopping the oxidation of LDL, like a kind of arterial antioxidant.

My LDL-C tested at 110 to 120 mg/ dL, just slightly higher than normal but not a cause for concern, particularly in a younger person. My triglycerides were on the higher side, slightly north of 150 mg/ dL, but that did not set off any alarm bells either. I now know that these numbers almost certainly indicated a high concentration of atherogenic apoB particles—but no one bothered to test my apoB number, either.

Back then, nearly fifteen years ago, the apoB test (simply, measuring the concentration of apoB-tagged particles) was not commonly done. Since then, evidence has piled up pointing to apoB as far more predictive of cardiovascular disease than simply LDL-C, the standard “bad cholesterol” measure.

According to an analysis published in JAMA Cardiology in 2021, each standard-deviation increase in apoB raises the risk of myocardial infarction by 38 percent in patients without a history of cardiac events or a diagnosis of cardiovascular disease (i.e., primary prevention). That’s a powerful correlation. Yet even now, the American Heart Association guidelines still favor LDL-C testing instead of apoB. I have all my patients tested for apoB regularly, and you should ask for the same test the next time you see your doctor. (Don’t be waved off by nonsensical arguments about “cost”: It’s about twenty to thirty dollars.)

We are fortunate that many of these conditions can be modulated or nearly eliminated—including apoB, by the way—via lifestyle changes and medications. As we’ll discuss in the final section, 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.)

It turned out that the culprit was a little-known but very deadly type of particle called Lp( a) (pronounced “el-pee-little-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) for short (not to be confused with apolipoprotein A or apoA, the protein that marks HDL particles).

if you have a history of premature heart attacks in your family, you should definitely ask for an Lp( a) test. We test every single patient for Lp( a) during their first blood draw. Because elevated Lp( a) is largely genetic, the test need only be done once (and cardiovascular disease guidelines are beginning to advise a once-a-lifetime test for it anyway).

the only real treatment for elevated Lp( a) right now is aggressive management of apoB overall. Though we can’t reduce Lp( a) directly, beyond what a PCSK9 inhibitor can do, we can lower the remaining apoB concentration sufficiently that we can reduce a patient’s overall risk.[* 5]

Once you establish the central importance of apoB, the next question becomes, By how much does one need to lower it (or its proxy LDL-C) to achieve meaningful risk reduction? 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, provided there are no side effects from treatment. You want it as low as possible.

As Peter Libby, one of the leading authorities on cardiovascular disease, and colleagues wrote in Nature Reviews in 2019, “Atherosclerosis probably would not occur [emphasis mine] in the absence of LDL-C concentrations in excess of physiological needs (on the order of 10 to 20 mg/ dL).”

Many doctors, and in fact many of you reading this, might be shocked to see such a low LDL-C target: 10 to 20 mg/ dL? Most guidelines consider lowering LDL-C to 70 mg/ dL to be “aggressive,”

infants, who presumably require the most cholesterol, in order to meet the enormous demands of their rapidly growing central nervous system, have similarly low levels of circulating cholesterol, without any developmental impairment.

Our first order of business is to reduce the burden of apoB particles, primarily LDLs but also VLDLs, which can be dangerous in their own right. And do so dramatically, not marginally or incrementally. We want it as low as possible, sooner rather than later.

In my clinical experience, about a third to half of people who consume high amounts of saturated fats (which sometimes goes hand in hand with a ketogenic diet) will experience a dramatic increase in apoB particles, which we obviously don’t want.[* 8] Monounsaturated fats, found in high quantities in extra virgin olive oil, macadamia nuts, and avocados (among other foods), do not have this effect, so I tend to push my patients to consume more of these, up to about 60 percent of total fat intake. The point is not necessarily to limit fat overall but to shift to fats that promote a better lipid profile.

But for many patients, if not for most, lowering apoB to the levels we aim for—the physiologic levels found in children—cannot be accomplished with diet alone, so we need to use nutritional interventions in tandem with drugs.

Statins are far and away the most prescribed class of drugs for lipid management,

Typically our first line of defense (or attack), statins inhibit cholesterol synthesis, prompting the liver to increase the expression of LDLR, taking more LDL out of circulation. They may have other benefits too, including an apparent anti-inflammatory effect,

Atherosclerosis is with us, in some form, throughout our life course. Yet most doctors consider it “overtreatment” to intervene if a patient’s computed ten-year risk of a major adverse cardiac event (e.g., heart attack or stroke) is below 5 percent, arguing that the benefits are not greater than the risks, or that treatment costs too much. In my opinion, this betrays a broader ignorance about the inexorable, long-term unfolding of heart disease. Ten years is far too short a time horizon. If we want to reduce deaths from cardiovascular disease, we need to begin thinking about prevention in people in their forties and even thirties.

For context, most studies of statins used in primary prevention (that is, prevention of a first cardiac event) last about five years and typically find a “number needed to treat” (or NNT, the number of patients who need to take a drug in order for it to save one life) of between about 33 and 130, depending on the baseline risk profile of the patients. (Amazingly, the longest statin trials to date have lasted just seven years.) But looking at their risk reduction potential over a thirty-year time frame, as the Sniderman study did, reduces the NNT down to less than 7: For every seven people who are put on a statin at this early stage, we could potentially save one life. The reason for this is simple math: risk is proportional to apoB exposure over time. The sooner we lower apoB exposure, thus lowering risk, the more the benefits compound over time—and the greater our overall risk reduction.

Once you understand that apoB particles—LDL, VLDL, Lp( a)—are causally linked to ASCVD, the game completely changes. The only way to stop the disease is to remove the cause, and the best time to do that is now.

I advocate early, aggressive, and broad screening for my patients—such as colonoscopy (or other colorectal cancer screening) at age forty, as opposed to the standard recommendation of forty-five or fifty—because the evidence is overwhelming that it’s much easier to deal with most cancers in their early stages.

I am also cautiously optimistic about pairing these tried-and-true staples of cancer screening with emerging methods, such as “liquid biopsies,” which can detect trace amounts of cancer-cell DNA via a simple blood test.

What Is Cancer?

The Warburg effect, also known as anaerobic glycolysis, turns the same amount of glucose into a little bit of energy and a whole lot of chemical building blocks—which are then used to build new cells rapidly. Thus, the Warburg effect is how cancer cells fuel their own proliferation. But it also represents a potential vulnerability in cancer’s armor.[*

Obesity, especially when accompanied by accumulation of visceral fat (and other fat outside of subcutaneous storage depots), helps promote inflammation, as dying fat cells secrete an array of inflammatory cytokines into the circulation (see figure 4 in chapter 6). This chronic inflammation helps create an environment that could induce cells to become cancerous. It also contributes to the development of insulin resistance, causing insulin levels to creep upwards—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, which we talked about earlier in this chapter. 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 its 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.

I’m not suggesting that it’s possible to “starve” cancer or that any particular diet will magically make cancer go away; cancer cells always seem to be able to obtain the energy supply they need. What I am saying is that we don’t want to be anywhere on that spectrum of insulin resistance to type 2 diabetes, where our cancer risk is clearly elevated. To me, this is the low-hanging fruit of cancer prevention, right up there with quitting smoking.

New Treatments

From the day of her diagnosis, she had become obsessed with doing anything possible to stack the odds in her favor. She devoured everything she could read on the impact of nutrition on cancer, and she had concluded that a diet that reduced insulin and IGF-1 would aid in her treatment. So she worked out a regimen that consisted primarily of leafy vegetables, olive oil, avocados, nuts, and modest amounts of protein, mostly from fish, eggs, and poultry. The diet was just as notable for what it did not contain: added sugar and refined carbohydrates. All along, she underwent frequent blood tests to make sure her insulin and IGF-1 levels stayed low, which they did.

Work by Valter Longo of the University of Southern California and others has 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.

An immunotherapy is any therapy that tries to boost or harness the patient’s immune system to fight an infection or other condition (example: vaccines). The problem with trying to treat cancer this way is that while cancer cells are abnormal and dangerous, they are technically still our cells (“ self”).

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

With all diagnostic tests, there is a trade-off between sensitivity, or the ability of the test to detect an existing condition (i.e., its true positive rate, expressed as a percentage), and specificity, which is the ability to determine that someone does not have that condition (i.e., true negative rate). Together, these represent the test’s overall accuracy.

In short, the problem is not the tests themselves but how we use them. Prostate cancer screening provides an even better example. It’s no longer as simple as “Your PSA number is X or higher, and therefore we must biopsy your prostate, a painful procedure with many unpleasant possible side effects.” Now we know to look at other parameters, such as PSA velocity (the speed at which PSA has been changing over time), PSA density (PSA value normalized to the volume of the prostate gland), and free PSA (comparing the amount of PSA that is bound versus unbound to carrier proteins in the blood). When those factors are taken into account, PSA becomes a much better indicator of prostate cancer risk.

In my practice, we go further, typically encouraging average-risk individuals to get a colonoscopy by age forty—and even sooner if anything in their history suggests they may be at higher risk. We then repeat the procedure as often as every two to three years, depending on the findings from the previous colonoscopy. If a sessile (flat) polyp is found, for example, we’re inclined to do it sooner than if the endoscopist finds nothing at all. Two or three years might seem like a very short window of time to repeat such an involved procedure, but colon cancer has been documented to appear within the span of as little as six months to two years after a normal colonoscopy. Better safe than sorry.[* 8]

Why do I generally recommend a colonoscopy before the guidelines do? Mostly because, of all the major cancers, colorectal cancer is one of the easiest to detect, with the greatest payoff in terms of risk reduction. It remains one of the top five deadliest cancers in the United States, behind lung (# 1) and breast/ prostate (# 2 for women/ men), and just ahead of pancreas (# 4) and liver (# 5) cancers. Of these five, though, CRC is the one we have the best shot at catching early. As it grows in a relatively accessible location, the colon, we can see it without any need for imaging techniques or a surgical biopsy. Because it is so easily observed, we understand its progression from normal tissue to polyp to tumor. Finding it early makes a huge difference, since we can effectively eliminate polyps or growths on the spot.

Other cancers that are relatively easy to spot on visual examination include skin cancer and melanomas. The pap smear for cervical cancer is another well-established, minimally invasive test that I recommend my patients do yearly.

in our internal organs, things get trickier. We can’t see them directly, so we must rely on imaging technologies such as low-dose CT scans for lung cancer. These scans are currently recommended in smokers and former smokers, but (as always) I think they should be used more widely, because about 15 percent of lung cancers are diagnosed in people who have never smoked. Lung cancer is the #1 cause of cancer deaths overall, but lung cancer in never-smokers ranks seventh, all by itself.

I am cautiously optimistic about the emergence of so-called “liquid biopsies” that seek to detect the presence of cancers via a blood test.[* 11] These are used in two settings: to detect recurrences of cancer in patients following treatment and to screen for cancers in otherwise healthy patients, a fast-moving and exciting field called multicancer early detection.

The implications of this, I think, are seismic: if liquid biopsies deliver on their promise, we could completely flip the time line of cancer so that we are routinely intervening early, when we have a chance of controlling or even eliminating the cancer—rather than the way we typically do it now, coming in at a late stage, when the odds are already stacked against the patient, and hoping for a miracle.

The only modifiable risks that really stand out in the data are smoking, insulin resistance, and obesity (all to be avoided)—and maybe pollution (air, water, etc.), but the data here are less clear.

Stephanie’s labs revealed that she had the APOE e4 allele, which is associated with a greater risk of Alzheimer’s disease—and not just one copy, but two (e4/ e4), which meant her risk of developing Alzheimer’s disease was up to twelve times greater than that of someone with two copies of the common e3 allele. The e2 version of 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. Stephanie was unlucky.

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 thus its function) and becomes chemically stickier, prone to aggregating in clumps. This is amyloid-beta, and it is clearly bad stuff. Laboratory mice that have been genetically engineered to accumulate amyloid-beta (they don’t naturally) have difficulty performing cognitive tasks that are normally easy, such as finding food in a simple maze. At the same time, amyloid also triggers the aggregation of another protein called tau, which in turn leads to neuronal inflammation and, ultimately, brain shrinkage.

One important section of the cognitive testing evaluates the patient’s sense of smell. Can they correctly identify scents such as coffee, for example? Olfactory neurons are among the first to be affected by Alzheimer’s disease.

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

There is a parallel concept known as “movement reserve” that becomes relevant with Parkinson’s disease. People with better movement patterns, and a longer history of moving their bodies, such as trained or frequent athletes, tend to resist or slow the progression of the disease as compared to sedentary people. This is also why movement and exercise, not merely aerobic exercise but also more complex activities like boxing workouts, are a primary treatment/ prevention strategy for Parkinson’s. Exercise is the only intervention shown to delay the progression of Parkinson’s.

The evidence suggests that tasks or activities that present more varied challenges, requiring more nimble thinking and processing, are more productive at building and maintaining cognitive reserve. Simply doing a crossword puzzle every day, on the other hand, seems only to make people better at doing crossword puzzles.

dancing appears to be more effective than walking at delaying symptoms of Parkinson’s disease, possibly because it involves more complex movement.

In those experiments, he had restricted the amount of blood flowing to the rats’ brains, and over time they had developed symptoms remarkably similar to those of Alzheimer’s disease in humans: memory loss and severe atrophy of the cortex and hippocampus. Restoring blood flow could halt or reverse the damage to some extent, but it seemed to be more severe and more lasting in older animals than younger ones. The key insight was that robust blood flow seemed to be critical to maintaining brain health.

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.

His “barf bag theory,” as he jokingly called it, was that Alzheimer’s disease is primarily a vascular disorder of the brain. The dementia symptoms that we see result from a gradual reduction in blood flow, which eventually creates what he calls a “neuronal energy crisis,” which in turn triggers a cascade of unfortunate events that harms the neurons and ultimately causes neurodegeneration.

“We believed, and still do, that amyloid-beta is an important pathological product of neurodegeneration,” de la Torre wrote recently, “...[ but] it is not the cause of Alzheimer’s disease.”

Scientists and physicians have long noted a connection between Alzheimer’s disease and metabolic dysfunction. Having type 2 diabetes doubles or triples your risk of developing Alzheimer’s disease, about the same as having one copy of the APOE e4 gene.

Insulin seems to play a key role in memory function. Insulin receptors are highly concentrated in the hippocampus, the memory center of the brain. Several studies have found that spraying insulin right into subjects’ noses—administering it as directly as possible into their brains—quickly improves cognitive performance and memory, even in people who have already been diagnosed with Alzheimer’s disease. One study found that intranasal insulin helped preserve brain volume in Alzheimer’s patients. Clearly, it is helpful to get glucose into neurons; insulin resistance blocks this. As the authors wrote, “Several lines of evidence converge to suggest that central insulin resistance plays a causal role in the development and progression of Alzheimer’s disease.”

The Role of APOE e4

Even though the higher risk APOE e4 protein differs from the harmless e3 one by just one amino acid, it appears to be less efficient at moving cholesterol into and especially out of the brain. There is also some evidence that the APOE e4 protein may also cause early breakdown of the blood-brain barrier itself, making the brain more susceptible to injury and eventual degeneration.

Data from present-day populations with a high prevalence of e4 suggest that it may have been helpful for survival in environments with high levels of infectious disease: children carrying APOE e4 in Brazilian favelas are more resistant to diarrhea and have stronger cognitive development, for example. In environments where infectious disease was a leading cause of death, APOE e4 carriers may have been the lucky ones, in terms of longevity. This survival benefit may have been due to the role of APOE e4 in promoting inflammation, which can be beneficial in some situations (e.g., fighting infection) but harmful in others (e.g., modern life).

The Preventive Plan

Because metabolism plays such an outsize role with at-risk e4 patients like Stephanie, 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 for someone like her would be to switch to a Mediterranean-style diet, relying on more monounsaturated fats and fewer refined carbohydrates, in addition to regular consumption of fatty fish. 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, their brain relies on a mix of ketones and glucose for fuel. Studies in Alzheimer’s patients find that while their brains become less able to utilize glucose, their ability to metabolize ketones does not decline. 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 in subjects with mild cognitive impairment and early-stage Alzheimer’s disease.

The precise role of alcohol in relation to Alzheimer’s disease remains somewhat controversial: some evidence suggests that alcohol may be slightly protective against Alzheimer’s, while other evidence shows that heavier drinking is itself a risk factor for the disease, and e4 carriers may be more susceptible to alcohol’s deleterious effects.

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

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

I now tell patients that exercise is, full stop and hands down, the best tool we have in the neurodegeneration prevention tool kit.

Sleep is also a very powerful tool against Alzheimer’s disease, as we’ll see in chapter 16. Sleep is when our brain heals itself; while we are in deep sleep our brains are essentially “cleaning house,” sweeping away intracellular waste that can build up between our neurons.

Studies have found that hearing loss is clearly associated with Alzheimer’s disease, but it’s not a direct symptom. Rather, it seems hearing loss may be causally linked to cognitive decline, because folks with hearing loss tend to pull back and withdraw from interactions with others. When the brain is deprived of inputs—in this case auditory inputs—it withers. Patients with hearing loss miss out on socializing, intellectual stimulation, and feeling connected; prescribing them hearing aids may help relieve some symptoms.

Another surprising intervention that may help reduce systemic inflammation, and possibly Alzheimer’s disease risk, is brushing and flossing one’s teeth. (You heard me: Floss.) There is a growing body of research linking oral health, particularly the state of one’s gum tissue, with overall health. 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. Even stranger, P. gingivalis has also shown up inside the brains of patients with Alzheimer’s disease, although scientists are not certain that this bacterium is directly causing dementia,

(Also, better oral health correlates strongly with better overall health, particularly in terms of cardiovascular disease risk, so I pay much more attention to flossing and gum health

The best interpretation I can draw from the literature suggests that at least four sessions per week, of at least twenty minutes per session, at 179 degrees Fahrenheit (82 degrees Celsius) or hotter seems to be the sweet spot to reduce the risk of Alzheimer’s by about 65 percent (and the risk of ASCVD by 50 percent).

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

Once dementia is diagnosed, it is extremely difficult to slow and maybe impossible to reverse (though we’re not certain of that). So we are forced to leave the familiar territory of the medicine that we know, with its promise of certainty, and embrace the Medicine 3.0 concepts of prevention and risk reduction.

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.

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

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.

OUR MOST POWERFUL TOOL FOR PREVENTING COGNITIVE DECLINE IS EXERCISE.

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. We can easily take in far more fructose calories than our bodies can safely handle.

We are open to changing our minds. For example, I used to recommend long periods of water-only fasting for some of my patients—and practiced it myself. But I no longer do so, because I’ve become convinced that the drawbacks (mostly having to do with muscle loss and undernourishment) outweigh its metabolic benefits in all but my most overnourished patients.

I’m not fond of the way we reduce these complex, nuanced, vitally important questions down to simple either-ors. Cardio or weights? Low-carb or plant-based? Olive oil or beef tallow? I don’t know. Must we really take sides?

More than any other tactical domain we discuss in this book, exercise has the greatest power to determine how you will live out the rest of your life. There are reams of data supporting the notion that even a fairly minimal amount of 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. Not only does it reverse physical decline, which I suppose is somewhat obvious, but it can slow or reverse cognitive decline as well.

Going from zero weekly exercise to just ninety minutes per week can reduce your risk of dying from all causes by 14 percent. It’s very hard to find a drug that can do that.

Study after study has found that regular exercisers live as much as a decade longer than sedentary people. Not only do habitual runners and cyclists tend to live longer, but they stay in better health, with less morbidity from causes related to metabolic dysfunction.

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. This is measured, naturally, while a person is exercising at essentially their upper limit of effort.

At rest, someone my size might require about 300 ml of oxygen per minute in order to generate enough ATP, the chemical “fuel” that powers our cells, to perform all the physiological functions necessary to stay alive and watch the movie.

Now, if I start running up a hill as fast as I can, my body’s oxygen demand will increase from there: 4,000 ml, 4,500 ml, even 5,000 ml or more depending on the pace and my fitness level. The fitter I am, the more oxygen I can consume to make ATP, and the faster I can run up that hill.

The amount of oxygen that I am using at this level of effort represents my VO2 max. (And not long after that, I will “fail,” meaning I am no longer able to continue running up the hill at that pace.) VO2 max is typically expressed in terms of the volume of oxygen a person can use, per kilogram of body weight, per minute. An average forty-five-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 thirties or forties, on the other hand, might score only in the high 20s on a VO2 max test,

This number is not just relevant to athletes; it turns out to be highly correlated with longevity. A 2018 study in JAMA that followed more than 120,000 people found that higher VO2 max (measured via a treadmill test) was associated with lower mortality across the board. The fittest people had the lowest mortality rates—by a surprising margin.

A person who smokes has a 40 percent greater risk of all-cause mortality (that is, risk of dying at any moment) than someone who does not smoke, representing a hazard ratio or (HR) of 1.40. This study found that someone of below-average VO2 max for their age and sex (that is, between the 25th and 50th percentiles) is at double the risk of all-cause mortality compared to someone in the top quartile (75th to 97.6th percentiles). Thus, poor cardiorespiratory 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 [emphasis mine]. Extremely high aerobic fitness was associated with the greatest survival.”

But I can say with a very high degree of certainty that having a higher VO2 max is better for your overall health and longevity than having a lower VO2 max. Period. Even better news, for our purposes, is that VO2 max can be increased via training.

Further analysis revealed that it’s not the mere muscle mass that matters but the strength of those muscles, their ability to generate force. It’s not enough to build up big pecs or biceps in the gym—those muscles also have to be strong. They have to be capable of creating force. Subjects with low muscle strength were at double the risk of death, while those with low muscle mass and/ or low muscle strength, plus metabolic syndrome, had a 3 to 3.33 times greater risk of all-cause mortality.

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

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. 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.

By age eighty, the average person will have lost eight kilograms of muscle, or about eighteen pounds, from their peak. But people who maintain higher activity levels lose much less muscle, more like three to four kilograms on average. While it’s not clear which direction the causation flows here, I suspect it’s probably both ways: people are less active because they are weaker, and they are weaker because they are less active.

This is why I place such an emphasis on weight training—and doing it now, no matter your age. It is never too late to start; my mom did not begin lifting weights until she was sixty-seven, and it has changed her life.

I will find a way to lift heavy weights in some way, shape, or form four times per week, no matter what else I am doing or where I might be traveling.

When was the last time your doctor tested your grip strength or asked you a detailed question about your strength training? Does your doctor know your VO2 max? Or have they offered training suggestions for how to improve it? I’m guessing that has happened precisely never—because none of what we’re covering here or in the nutrition chapters is even considered to rise to the level of “healthcare,” at least in our system.

Then I joined a boutique fitness chain that specializes in high-intensity interval training, or HIIT. I enjoyed the fast-paced workouts they offered, like treadmill sprints and thirty-second Burpee blocks, and it took a fraction of the time that cycling did, so I was happy about that. But I didn’t have a goal other than “exercising.”

But then it hit me: the only way that we would be able to fight this was to adopt the philosophy of a decathlete—and apply it to aging.

The Centenarian Decathlon is a framework I use to organize my patients’ physical aspirations for the later decades of their lives, especially their Marginal Decade. I know, it’s a somewhat morbid topic, thinking about our own physical decline. But not thinking about it won’t make it any less inevitable.

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 still others might reflect your own personal interests. I find it useful because it helps us visualize, with great precision, exactly what kind of fitness we need to build and maintain as we get older.

But now let’s do a little math. Let’s say the kid weighs twenty-five or thirty pounds. That’s basically the same as doing a squat while holding a thirty-pound dumbbell in front of you (i.e., a goblet squat). Can you do that now, at age forty? Most likely. But now let’s look into the future. Over the next thirty or 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. Can you do that?

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.

Together, we come up with a list of ten or fifteen events in their personal Centenarian Decathlon, representing their goals for their later decades. This then determines how they should be training.

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,” and it is what we want:

As fundamental as zone 2 training is for professional cyclists, however, San Millán believes that it’s even more important for nonathletes, for two reasons. First, it 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 is that he believes 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) is the first element of my Centenarian Decathlon training program.

In technical terms, San Millán describes zone 2 as 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 more efficient our mitochondrial “engine,” the more rapidly we can clear lactate, and the greater effort we can sustain while remaining in zone 2.

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 I’m working too hard, lactate levels will rise, so I’ll slow down. (It’s sometimes tempting to go too hard in zone 2, because the workout feels relatively “easy” on good days.) I make a point of this because lactate is literally what defines zone 2. It’s all about keeping lactate levels steady in this range, and the effort sustainable.

there are other ways to estimate your zone 2 range that are reasonably accurate. If you know your maximum heart rate—not estimated, but your actual maximum, the highest number you’ve ever seen on a heart rate monitor—your zone 2 will correspond to between approximately 70 and 85 percent of that peak number, depending on your fitness levels.

That’s a big range, so when starting people out, I prefer they rely on their rate of perceived exertion, or RPE, also known as the “talk test.” How hard are you working? How easy is it to speak? 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.

This pronounced difference comes back to the fact that the unhealthy subjects’ mitochondria—their engine( s)—were much less efficient than those of the athletes, so they very quickly switched over from aerobic respiration, burning fat and glucose in the mitochondria with oxygen, to the much less efficient glycolysis, an energy-producing pathway that consumes only glucose and produces loads of lactate

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 (or glycogen) for all their energy needs—and that they are totally unable to access their fat stores.

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 called mitophagy (which is like autophagy, touched on in chapter 5, but for mitochondria). 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.

This is another reason why zone 2 is such a powerful mediator of metabolic health and glucose homeostasis. Muscle is the largest glycogen storage sink in the body, and as we create more mitochondria, we greatly increase our capacity for disposing of that stored fuel, rather than having it end up as fat or remaining in our plasma. Chronic blood glucose elevations damage organs from our heart to our brain to our kidneys and nearly everything in between—even contributing to erectile dysfunction in men.

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.

I have one patient with type 1 diabetes, meaning he produces zero insulin, who keeps his glucose in check almost entirely by walking briskly for six to ten miles every day, and sometimes more. As he walks, his muscle cells are vacuuming glucose out of his bloodstream via NIMGU. He still needs to inject himself with insulin, but only a tiny fraction of the amount that he would otherwise require.

Based on multiple discussions with San Millán and other exercise physiologists, 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.

I am so persuaded of the benefits of zone 2 that it has become a cornerstone of my training plan. Four times a week, I will spend about an hour riding my stationary bike at my zone 2 threshold.

So if you weigh 60 kilos (about 132 pounds) and can generate 125 watts in zone 2, that works out to a bit more than 2 watts/ kg, which is about what one would expect from a reasonably fit person. These are rough benchmarks, but someone who is very fit will be able to produce 3 watts/ kg, while professional cyclists put out 4 watts/ kg and up. It’s not the number that matters, but how much you are improving over time.

As you improve, your zone 2 pace will get faster.)

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 the production of BDNF, brain-derived neurotrophic factor, which we touched on earlier.

Maximum Aerobic Output: VO2 Max

At VO2 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.

Even if you are not competing in high-level endurance sports, your VO2 max is an important number that you can and should know. Testing is widely available, even from some of the larger fitness chains. The bad news is that the VO2 max test is an unpleasant affair that entails riding an exercise bike or running on a treadmill at ever greater intensity, while wearing a mask designed to measure oxygen consumption and CO2 production. The peak amount of oxygen you consume, typically close to the point at which you “fail,” meaning the point where you just can’t keep going, yields your VO2 max.

Why is this important? Because our VO2 max is a pretty good proxy measure of our physical capability. It tells us what we can do—and what we cannot do.

Studies suggest that 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. We are planning for you to live for another thirty years, or forty. If you are only starting at 32 ml/ kg/ min now, at fifty, you can expect to be closer to 21 ml/ kg/ min at age eighty.

To arrive in her ninth decade with a sufficient level of fitness to achieve her goal, our fifty-year-old would need to have a VO2 max of about 45 to 49 right now. This is the top tier for her sex, but two decades younger.

Keep in mind, increasing your VO2 max by any amount is going to improve your life, not only in terms of how long you live but also how well you live, today and in the future. Improving your VO2 max from the very bottom quartile to the quartile above (i.e., below average) is associated with almost a 50 percent reduction in all-cause mortality, as we saw earlier.

The payoff is that increasing your VO2 max makes you functionally younger. One study found that boosting elderly subjects’ VO2 max by 6 ml/ kg/ min, or about 25 percent, was equivalent to subtracting twelve years from their age.

The beauty of this is that VO2 max can always be improved by training, no matter how old you are.

Even if we are not out to set world records, the way we train VO2 max is pretty similar to the way elite athletes do it: by supplementing our zone 2 work with one or two VO2 max workouts per week.

Where HIIT intervals are very short, typically measured in seconds, VO2 max intervals are a bit longer, ranging from three to eight minutes—and a notch less intense.

The tried-and-true formula for these 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 one hundred beats per minute. Repeat this four to six times and cool down.[* 4]

You want to make sure that you get as close to fully recovered as possible before beginning the next set. If you fail to recover sufficiently between sets, you will not be able to reach your peak effort in the working sets and you’ll consequently miss the desired adaptation.

The good news, I suppose, is that you don’t need to spend very much time in the pain cave. Unless you are training to be competitive in elite endurance sports like cycling, swimming, running, triathlon, or cross-country skiing, a single workout per week in this zone will generally suffice. You’ll pretty quickly find that it boosts your performance across the rest of your exercise program as well—and, more importantly, in the rest of your life.

The sad fact is that our muscle mass begins to decline as early as our thirties. An eighty-year-old man will have about 40 percent less muscle tissue (as measured by cross section of the vastus lateralis, aka the “quad” muscle of the thigh) than he did at twenty-five.

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

In its most extreme form, this muscle loss is called sarcopenia, as noted in chapter 11. Someone with sarcopenia will have low energy, feelings of weakness, and problems with balance. Sarcopenia is a prime marker for a broader clinical condition called frailty, where a person meets three of these five criteria: unintended weight loss; exhaustion or low energy; low physical activity; slowness in walking; and weak grip strength

Regaining that muscle, once we’ve gotten to this state, is no easy task. One study looked at sixty-two frail seniors (average age seventy-eight) who engaged in a program of strength training and found that even after six months of pure strength training, half of the subjects did not gain any muscle mass. They also didn’t lose any muscle mass, likely thanks to the weight training, but the upshot is, it is very difficult to put on muscle mass later in life.

The fact is that bone density diminishes on a parallel trajectory to muscle mass, peaking as early as our late twenties before beginning a slow, steady decline. For women, this decline happens much more quickly once they hit menopause, if they are not on HRT (yet another reason we heavily favor HRT), because estrogen is essential for bone strength—in both men and women.

The takeaway for readers here is that your BMD is important, demanding at least as much attention as muscle mass, so you should at least check your BMD every few years. (Particularly if your primary sports are nonweight-bearing, like cycling or swimming.)

think of strength training as a form of retirement saving. 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.

I’ve always been a fan of carrying heavy objects with my hands. As a teenager working on a construction site over the summers, I always volunteered to haul tools and materials across the site, and today I still incorporate some kind of carrying, typically with dumbbells, kettlebells, or sandbags, into most of my workouts. I’ve also become semiobsessed with an activity called rucking, which basically means hiking or walking at a fast pace with a loaded pack on your back. Three or four days a week, I’ll spend an hour rucking around my neighborhood, up and down hills, typically climbing and descending several hundred feet over the course of three or four miles.

The fifty-to sixty-pound pack on my back makes it quite challenging, so I’m strengthening my legs and my trunk while also getting in a solid cardiovascular session. The best part is that I never take my phone on these outings; it’s just me, in nature, or maybe with a friend or a family member or a houseguest

I was introduced to this pastime by Michael Easter in his eye-opening book The Comfort Crisis. His intriguing thesis is that because we have removed all discomfort of any kind from modern life, we have lost touch with the fundamental skills (not to mention the frequent suffering) that once defined what it meant to be human. Carrying stuff over long distances is one of these skills; our ancestors likely had to range far and wide to hunt food for their families and then carry their kills back to camp to feed everyone.

“Carrying shaped our species,” he says. “Our ancestors carried often. It gave them robust functional strength and endurance that was likely very protective. But we’ve engineered carrying out of our lives, just as we have many other forms of discomfort. Rucking is a practical way to add carrying back into our lives.”

Going uphill gives me a chance to push my VO2 max energy system; first-time ruckers are amazed at how taxing it is to walk up a 15 percent grade with even twenty pounds on your back—and then walk back down. (A good goal is to be able to carry one-quarter to one-third of your body weight once you develop enough strength and stamina.

Fundamentally I structure my training around exercises that improve the following: Grip strength, how hard you can grip with your hands, which involves everything from your hands to your lats (the large muscles on your back). Almost all actions begin with the grip. Attention to both concentric and eccentric loading for all movements, meaning when our muscles are shortening (concentric) and when they are lengthening (eccentric). In other words, we need to be able to lift the weight up and put it back down, slowly and with control. Rucking down hills is a great way to work on eccentric strength, because it forces you to put on the “brakes.” Pulling motions, at all angles from overhead to in front of you, which also requires grip strength (e.g., pull-ups and rows). Hip-hinging movements, such as the deadlift and squat, but also step-ups, hip-thrusters, and countless single-leg variants of exercises that strengthen the legs, glutes, and lower back.

I focus on these four foundational elements of strength because they are the most relevant to our Centenarian Decathlon—and also to living a fulfilling and active life in our later decades. 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.

I put grip strength first because it’s something that most people don’t really think about. Even I was surprised to discover that there is an enormous body of literature linking better grip strength in midlife and beyond to decreased risk of overall mortality.[* 5] The data are as robust as for VO2 max and muscle mass, in fact.

Training grip strength is not overly complicated. One of my favorite ways to do it is the classic farmer’s carry, where you walk for a minute or so with a loaded hex bar or a dumbbell or kettlebell in each hand. (Bonus points: Hold the kettlebell up vertically, keeping your wrist perfectly straight and elbow cocked at ninety degrees, as though you were carrying it through a crowded room.)

One of the standards we ask of our male patients is that they can carry half their body weight in each hand (so full body weight in total) for at least one minute, and for our female patients we push for 75 percent of that weight. This is, obviously, a lofty goal—please don’t try to do it on your next visit to the gym. Some of our patients need as much as a year of training before they can even attempt this test.

The most important tip is to keep your shoulder blades down and back, not pulled up or hunched forward. If you are new to strength training, start with light weights, even as low as ten to fifteen pounds, and work up from there.

Another way to test your grip is by dead-hanging from a pull-up bar for as long as you can. (This is not an everyday exercise; rather, it’s a once-in-a-while test set.) You grab the bar and just hang there, supporting your body weight. This is a simple but sneakily difficult exercise that also helps strengthen the critically important scapular (shoulder) stabilizer muscles, which we will talk about in the next chapter. Here we like to see men hang for at least two minutes and women for at least ninety seconds at the age of forty. (We reduce the goal slightly for each decade past forty.)

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. It’s really important to keep us safe from falls and from orthopedic injuries. When we can eccentrically load our muscles, it also prevents our joints from taking excess stress, especially our knees.

Training eccentric strength is relatively simple. Big picture, it means focusing on the “down” phase of lifts ranging from pull-ups or pull-downs to deadlifts to rows; rucking downhill, carrying a weighted pack, is a great way to build both eccentric strength as well as spatial awareness and control, which are important parts of stability training (next chapter). It also helps protect against knee pain. You don’t need to do this for every rep of every set. Sometimes you just want to focus on moving the weight quickly or moving a heavier load, but make sure at some point in each workout that you are taking the time to cue the eccentric phase of your lifts.

Pulling motions are how we exert our will on the world, whether we are hoisting a bag of groceries out of the car trunk or climbing El Capitan. It is an anchor movement. In the gym, it typically takes the form of rows, where you’re pulling the weight toward your body, or pull-ups. A rowing machine, something I love to use for VO2 max training, is another simple and effective way to work on pulling strength.

The final foundational element of strength is hip-hinging, which is what it sounds like: You bend at the hips—not the spine—to harness your body’s largest muscles, the gluteus maximus and the hamstrings. (I repeat: Do not bend your spine.) It is a very powerful move that is essential to life. Whether you are launching off an Olympic ski jump, picking up a lucky penny off the sidewalk, or simply getting up out of a chair, you are hip-hinging.

The hard part is knowing how to eccentrically load the glutes and hamstrings before you hinge, and how to feel your feet pushing into the floor evenly across the full surface of your foot.

Stability is tricky to define precisely, but we intuitively know what it is. A technical definition might be: 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.

Short for dynamic neuromuscular stabilization, DNS sounds complicated, but it is based on the simplest, most natural movements we make: the way we moved when we were babies.

in my practice, we don’t like to push much strength training, including many of the assessments I’ve discussed, such as dead hangs and weighted step-ups, until we have established some modicum of stability. We don’t think it’s worth the risk.

Yet breathing is also important to stability and movement, and even to strength. Poor or disordered breathing can affect our motor control and make us susceptible to injury, studies have found.

It’s extremely subtle, but the way in which someone breathes gives tremendous insight to how they move their body and, more importantly, how they stabilize their movements.

One simple test that we ask of everyone, early on, looks like this: lie on your back, with one hand on your belly and the other on your chest, and just breathe normally, without putting any effort or thought into it. Notice which hand is rising and falling—is it the one on your chest, or your belly, or both (or neither)?

The idea behind breath training is that proper breathing affects so many other physical parameters: rib position, neck extension, the shape of the spine, even the position of our feet on the ground.

The easiest way to start this process is to get on your hands and knees and go through an extremely slowed-down, controlled Cat/ Cow sequence, similar to the basic yoga poses of the same names.[* 4] The difference is that you have to really, really slow down, moving so slowly and deliberately from one end of your spine to the other that you can feel each individual vertebra changing position, all the way from your tailbone up to your neck, until your spine is bent like a sway-backed cow. Then reverse the movement, tilting your pelvis forward and bending your spine one vertebra at a time until your back is arched again, like a really scared cat. (Note: Inhale on Cow, exhale on Cat.)

Beth taught me a simple exercise to help understand the importance of scapular positioning and control, a movement known as Scapular CARs, for controlled articular rotations: Stand with your feet shoulder-width apart and place a medium to light resistance band under your feet, one handle in each hand (a very light dumbbell also works). Keeping your arms at your sides, raise your shoulder blades, and then squeeze them back and together; this is retraction, which is where we want them to be when under load. Then drop them down your back. Finally, bring them forward to the starting point. We start out moving in squares like this, but the goal is to learn enough control that we can move our scapulae in smooth circles.

I would urge you to film yourself working out from time to time, to compare what you think you are doing to what you are actually doing with your body. I do this daily—my phone on the tripod is one of my most valuable pieces of equipment in the gym. I film my ten most important sets each day and watch the video between sets, to compare what I see to what I think I was doing. Over time, that gap has been narrowing.

The leading source of calories that Americans consume is a category called “grain-based desserts,” like pies, cakes, and cookies, according to the US Department of Agriculture. That is our number one “food group.”

The Wisconsin animals ate an off-the-shelf commercial monkey chow that was “semipurified,” meaning its ingredients were highly processed and rigorously titrated. The NIH monkeys were fed a diet that was similar in its basic macronutrient profile, but their chow was “natural” and less refined, custom formulated from whole ingredients by an in-house primate nutritionist at NIH. The most glaring contrast: while the NIH monkey chow contained about 4 percent sugar, the Wisconsin diet comprised an astonishing 28.5 percent sucrose, by weight. That is a greater proportion of sugar than you’ll find in vanilla Häagen-Dazs ice cream.

This could suggest that caloric restriction was eliminating early deaths because of the bad Wisconsin diet more than it was actually slowing aging—which is still useful information, as avoiding diabetes and related metabolic disorders is important to our strategy.

Taken together, then, what do these two monkey studies have to tell us about nutritional biochemistry? Avoiding diabetes and related metabolic dysfunction—especially by eliminating or reducing junk food—is very important to longevity. There appears to be a strong link between calories and cancer, the leading cause of death in the control monkeys in both studies. The CR monkeys had a 50 percent lower incidence of cancer. 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. 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.

Interestingly, the post facto analyses also revealed that the NIH control monkeys naturally consumed about 10 percent fewer calories per day than the Wisconsin controls, likely because their higher-quality diet left them feeling less hungry. The researchers speculated that even this very slight degree of caloric reduction may have been significant—

One reason carbohydrate restriction is so effective for many people is that it tends to reduce appetite as well as food choices. But some people have a harder time maintaining it than others. (Even I am pretty sure I could never go back to a ketogenic diet for more than a few days.)

Any form of DR that restricts protein, for example, is probably a bad idea for most people, because it likely also impairs the maintenance or growth of muscle.

A more significant issue with DR is that everyone’s metabolism is different. Some people will lose tremendous amounts 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 diets yield very different outcomes, depending on the individual.

if you drink, try to be mindful about it. You’ll enjoy it more and suffer fewer consequences. Don’t just keep drinking because they’re serving it on the plane. I strongly urge my patients to limit alcohol to fewer than seven servings per week, and ideally no more than two on any given day,

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 socked 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.

Now we have a tool to help us understand our own individual carbohydrate tolerance and how we respond to specific foods. This is called continuous glucose monitoring, or CGM, and it has become a very important part of my armamentarium in recent years.[* 2] The device consists of a microscopic filament sensor that is implanted in the upper arm, attached to a fingertip-sized transmitter that sends data[* 3] to the patient’s phone in real time. As its name suggests, CGM gives continuous, real-time information on blood glucose levels, which is extraordinary: the patient can see, moment by moment, how their blood sugar levels are responding to whatever they eat, whether a doughnut, a steak, or a handful of Raisinets.

At the moment, CGM is available only by prescription and is most commonly worn by patients diagnosed with type 1 or type 2 diabetes, who need to monitor their glucose levels from moment to moment. For these people, CGM is an essential tool that can protect them from life-threatening swings in blood glucose. But I think nearly every adult could benefit from it, at least for a few weeks, and it will likely be available to consumers without a prescription in the not-too-distant future.[* 4] It’s currently fairly easy for a nondiabetic to obtain a CGM from one of several online metabolic health start-ups.

Typically, my healthy patients need to use CGM only for a month or two before they begin to understand what foods are spiking their glucose (and insulin) and how to adjust their eating pattern to obtain a more stable glucose curve.

From these studies, it seems quite clear that we want to lower average blood glucose and reduce the amount of variability from day to day and hour to hour. CGM is a tool that can help us achieve that. We use it in healthy people in order to help them stay healthy. That shouldn’t be controversial.

Almost always, patients are stunned to see how some of their favorite foods send their glucose soaring, then crashing back to earth. This leads to the second phase, which is what I call the behavior phase. Here you mostly know how your glucose is going to respond to that bag of potato chips, and that knowledge is what prevents you from mindlessly eating it. I’ve found that CGM powerfully activates the Hawthorne effect, the long-observed phenomenon whereby people modify their behavior when they are being watched.

The real beauty of CGM is that it allows me to titrate a patient’s diet while remaining flexible. No longer do we need to try to hit some arbitrary target for carbohydrate or fat intake and hope for the best. Instead, we can observe in real time how their body handles the food they are eating. Is their average blood glucose a little bit high? Are they “spiking” above 160 mg/ dL more often than I would like? Or could they perhaps tolerate a little bit more carbohydrate in their diet? Not everyone needs to restrict carbohydrates; some people can handle more than others,

Overall, I like to keep average glucose at or below 100 mg/ dL, with a standard deviation of less than 15 mg/ dL.[* 5] These are aggressive goals: 100 mg/ dL corresponds to an HbA1c of 5.1 percent, which is quite low. But I believe that the reward, in terms of lower risk of mortality and disease, is well worth it given the ample evidence in nondiabetics and diabetics alike.

Also, 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.

Also, sleep disruption or reduction dramatically impairs glucose homeostasis over time. 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.

Another surprising thing I’ve learned thanks to CGM is about what happens to a patient’s glucose levels during the night. If she goes to bed at, say, 80 mg/ dL, but then her glucose ramps up to 110 for most of the night, that tells me that she is likely dealing with psychological stress. Stress prompts an elevation in cortisol, which in turn stimulates the liver to drip more glucose into circulation. This tells me that we need to address her stress levels and probably also her sleep quality.

He was gaming his CGM, but he had also unwittingly discovered another rule of nutrition, which is that timing is important: 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 (think dinner roll, potato chips), the faster and higher the glucose spike. Less processed carbohydrates and those with more fiber, on the other hand, blunt the glucose impact. I try to eat more than fifty grams of fiber per day.

Rice and oatmeal are surprisingly glycemic (meaning they cause a sharp rise in glucose levels), despite not being particularly refined; more surprising is that brown rice is only slightly less glycemic than long-grain white rice.

Timing, duration, and intensity of exercise matter a lot. In general, aerobic exercise seems most efficacious at removing glucose from circulation, while high-intensity exercise and strength training tend to increase glucose transiently, because the liver is sending more glucose into the circulation to fuel the muscles. Don’t be alarmed by glucose spikes when you are exercising.

control. All things equal, it appears that sleeping just five to six hours (versus eight hours) accounts for about a 10 to 20 mg/ dL (that’s a lot!) jump in peak glucose response, and about 5 to 10 mg/ dL in overall levels.

Stress, presumably, via cortisol and other stress hormones, has a surprising impact on blood glucose, even while one is fasting or restricting carbohydrates.

Nonstarchy veggies such as spinach or broccoli have virtually no impact on blood sugar. Have at them.

Simply tracking my glucose has a positive impact on my eating behavior. I’ve come to appreciate the fact that CGM creates its own Hawthorne effect, a phenomenon where study subjects change their behavior because they are being observed. It makes me think twice when I see the bag of chocolate-covered raisins in the pantry,

The first thing you need to know about protein is that the standard recommendations for daily consumption are a joke. Right now the US recommended dietary allowance (RDA) 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. There is ample evidence showing that we require more than this—and that consuming less leads to worse outcomes. More than one study has found that elderly people consuming that RDA of protein (0.8 g/ kg/ day) end up losing muscle mass, even in as short a period as two weeks. It’s simply not enough.

How much protein do we actually need? It varies from person to person. In my patients I typically set 1.6 g/ kg/ day as the minimum, which is twice the RDA.

for active people with normal kidney function, one gram per pound of body weight per day (or 2.2 g/ kg/ day) is a good place to start—

mass. 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

more. Older people in particular should try to keep track of their lean mass, such as via a body-composition-measuring scale (or better yet, DEXA scan), and adjust their protein intake upwards if lean mass declines.

Do you need to eat meat, fish, and dairy to get sufficient protein? No. But if you choose to get all 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.

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 (from dairy) is richer in available amino acids than soy protein isolate. So if you forgo protein from animal sources, you need to do the math on your protein quality score. In truth, this can get pretty complicated pretty quick, because you get wrapped around the axle of something called the Digestible Indispensable Amino Acid Score (DIAAS) and the Protein Digestibility-Corrected Amino Acid Score (PDCAAS).

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

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