Outlive: The Science and Art of Longevity: The Million-Copy Bestseller

by Peter Attia

the odds are overwhelming that you will die as a result of one of the chronic diseases of aging that I call the Four Horsemen: heart disease, cancer, neurodegenerative disease, or type 2 diabetes and related metabolic dysfunction.

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

The typical cholesterol panel that you receive and discuss at your annual physical, along with many of the underlying assumptions behind it (e.g., “good” and “bad” cholesterol), is misleading and oversimplified to the point of uselessness.

One macronutrient, in particular, demands more of our attention than most people realize: not carbs, not fat, but protein becomes critically important as we age.

Exercise is by far the most potent longevity “drug.” No other intervention does nearly as much to prolong our lifespan and preserve our cognitive and physical function. But most people don’t do nearly enough—and exercising the wrong way can do as much harm as good.

Robert J. Gordon analyzed mortality data going back to 1900 (see figure 1) and found that if you subtract out deaths from the eight top infectious diseases, which were largely brought under control by the advent of antibiotics in the 1930s, overall mortality rates declined relatively little over the course of the twentieth century. That means that Medicine 2.0 has made scant progress against the Horsemen.

So we will break down this thing called exercise into its most important components: strength, stability, aerobic efficiency, and peak aerobic capacity.

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.

Studies of Scandinavian twins6 have found that genes may be responsible for only about 20 to 30 percent of the overall variation in human lifespan. The catch is that the older you get, the more genes start to matter. For centenarians, they seem to matter a lot.

This molecule, which came to be known as rapamycin, had also transformed transplant medicine, giving millions of patients a second chance at life. But that was not why we had traveled ten thousand miles to this remote spot. We had come because rapamycin had been demonstrated to do something that no other drug had ever done before: extend maximum lifespan in a mammal.

The job of mTOR3 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 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 nutrients14 (fuel), it activates, triggering a cascade of actions.

More importantly, AMPK works to inhibit the activity of mTOR, the cellular growth regulator. Specifically, it seems to be a drop in amino acids that induces mTOR to shut down, and with it all the anabolic (growth) processes that mTOR controls. Instead of making new proteins and undergoing cell division, the cell goes into a more fuel-efficient and stress-resistant mode, activating an important cellular recycling process called autophagy, which means “self-eating” (or better yet, “self-devouring”).

Autophagy is essential to life.15 If it shuts down completely, the organism dies. Imagine if you stopped taking out the garbage (or the recycling); your house would soon become uninhabitable. Except instead of trash bags, this cellular cleanup is carried out by specialized organelles called lysosomes, which package up the old proteins and other detritus, including pathogens, and grind them down (via enzymes) for reuse.

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

Metformin has been taken by millions of people for years. Over time, researchers noticed (and studies appeared to confirm) that patients on metformin appeared to have a lower incidence of cancer than the general population. One large 2014 analysis21 seemed to show that diabetics on metformin actually lived longer than nondiabetics, which is striking.

NAFLD and NASH are basically two stages of the same disease. 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.

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. This happens in about 11 percent of patients with NASH and is obviously far more serious. It now begins to affect the cellular architecture of the organ, making it much more difficult to reverse.

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)

If you meet three9 or more of these criteria, then you have the metabolic syndrome

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

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 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.

Individual fat-storage capacity seems to be influenced by genetic factors. This is a generalization, but people of Asian descent14 (for example), tend to have much lower capacity to store fat, on average, than Caucasians.

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.

Insulin resistance is a term that we hear a lot, but what does it really mean? Technically, it means that cells, initially muscle cells, have stopped listening to insulin’s signals, but another way to visualize it is to imagine the cell as a balloon being blown up with air. Eventually, the balloon expands to the point where it gets more difficult to force more air inside. You have to blow harder and harder.

The simplest explanation is likely that our metabolism, as it has evolved over millennia, is not equipped to cope with our ultramodern diet, which has appeared only within the last century or so. Evolution is no longer our friend, because our environment has changed much faster than our genome ever could.

The key factor here is that fructose is metabolized in a manner different from other sugars. When we metabolize fructose, along with certain other types of foods, it produces large amounts of uric acid, which is best known as a cause of gout but which has also been associated with elevated blood pressure.

more food and store more energy as fat.fn5 On a more macro level, consuming large quantities of liquid fructose simply overwhelms the ability of the gut to handle it; the excess is shunted to the liver, where many of those calories are likely to end up as fat. I’ve seen patients work themselves into NAFLD by drinking too many “healthy” fruit smoothies, for the same reason: they are taking in too much fructose, too quickly.

In the end, I still think excess calories matter the most.

But the first thing I look for, the canary in the coal mine of metabolic disorder, is elevated 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, or about twice as much sugar as in a regular Coca-Cola.fn6 We then measure the patient’s glucose and their insulin, every thirty minutes over the next two hours.

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 increases29 in one’s risk of cancer (up to twelvefold), Alzheimer’s disease (fivefold), and death from cardiovascular disease (almost sixfold)—all of which underscores why addressing, and ideally preventing, metabolic dysfunction is a cornerstone of my approach to longevity.

When I was in medical school, my first-year pathology professor liked to ask a trick question: What is the most common “presentation” (or symptom) of heart disease? It wasn’t chest pain, left arm pain, or shortness of breath, the most common answers; it was sudden death. You know the patient has heart disease because he or she has just died from it.

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,

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,

Each lipoprotein particle is enwrapped by one or more large molecules, called apolipoproteins, that provide structure, stability, and, most importantly solubility to the particle. HDL particles are wrapped in a type of molecule called apolipoprotein A (or apoA), while LDL is encased in apolipoprotein B (or apoB). 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 othersfn1—carries this apoB protein signature.

“There’s no connection whatsoever between cholesterol in food and cholesterol in blood,”9 Keys said in a 1997 interview. “None. And we’ve known that all along. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.”

“What proportion of heart attacks occur in people younger than age sixty-five?” I guessed high, one in four, but I was way low. Fully half of all major adverse cardiovascular events11 in men (and a third of those in women), such as heart attack, stroke, or any procedure involving a stent or a graft, occur before the age of sixty-five. In men, one-quarter of all events occur before age fifty-four.

This isn’t a perfect analogy, but I think of atherosclerosis as kind of like the scene of a crime—breaking and entering, more or less. Let’s say we have a street, which represents the blood vessel, and the street is lined with houses, representing the arterial wall. The fence in front of each house is analogous to something called the endothelium, a delicate but critical layer of tissue that lines all our arteries and veins, as well as certain other tissues, such as the kidneys. Composed of just a single layer of cells, the endothelium acts as a semipermeable barrier between the vessel lumen (i.e., the street, where the blood flows) and the arterial wall proper, controlling the passage of materials and nutrients and white blood cells into and out of the bloodstream.

The street is very busy, with a constant flow of blood cells and lipoproteins and plasma and everything else that our circulation carries, all brushing past the endothelium. Inevitably, some of these cholesterol-bearing lipoprotein particles will penetrate the barrier, into an area called the subendothelial space—or in our analogy, the front porch. Normally, this is fine, like guests stopping by for a visit. They enter, and then they leave. This is what HDL particles generally do: particles tagged with apoA (HDL) can cross the endothelial barrier easily in both directions, in and out. LDL particles and other particles with the apoB protein are far more prone to getting stuck inside.

Now that it is lodged in the subendothelial space and oxidized, rendering it somewhat toxic, the LDL/apoB particle stops behaving like a polite guest, refusing to leave—and inviting its friends, other LDLs, to join the party. Many of these also are retained and oxidized. It is not an accident that the two biggest risk factors for heart disease, smoking and high blood pressure, cause damage to the endothelium. Smoking damages it chemically, while high blood pressure does so mechanically, but the end result is endothelial harm that, in turn, leads to greater retention of LDL.

the key factor here is actually exposure to apoB-tagged particles, over time. The more of these particles that you have in your circulation, not only LDL but VLDL and some others, the greater the risk that some of them will penetrate the endothelium and get stuck.

So to gauge the true extent of your risk, we have to know how many of these apoB particles are circulating in your bloodstream. That number is much more relevant than the total quantity of cholesterol that these particles are carrying.

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, a term that you may have heard—so named because under a microscope it looks foamy or soapy. When enough foam cells gather together, they form a “fatty streak”

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.

The atherosclerotic process moves very slowly. This may be partly because of the action of HDLs. 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

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.

the ever-growing number of foam cells begin to sort of ooze together into a mass of lipids, like the liquefying contents of a pile of trash bags that have been dumped on the front lawn. This is what becomes the core of our atherosclerotic plaque. And this is the point where breaking and entering tilts over into full-scale looting. In an attempt to control the damage, the “smooth muscle” cells in the artery wall then migrate to this toxic waste site and secrete a kind of matrix in an attempt to build a kind of barrier around it, like a scar. This matrix ends up as the fibrous cap on your brand-new arterial plaque.

Normally, however, most atherosclerotic plaques are fairly undramatic. They grow silently and invisibly, gradually occluding the blood vessel until one day the obstruction, due to the plaque itself or a plaque-induced clot, becomes a problem. For example, a sedentary person may not notice that she has a partially blocked coronary artery until she goes outside to shovel snow. The sudden demands on her circulatory system can trigger ischemia (decreased blood delivery of oxygen) or infarction (tissue death from no blood flow)—or, in layman’s terms, a heart attack or a stroke. It may seem sudden, but the danger was lurking all along.