Outlive: The Science and Art of Longevity

by Peter Attia

Nor does longevity mean merely notching more and more birthdays as we slowly wither away.

Most of my patients instinctively get this. When they first come to see me, they generally insist that they don’t want to live longer, if doing so means lingering on in a state of ever-declining health. Many of them have watched their parents or grandparents endure such a fate, still alive but crippled by physical frailty or dementia. They have no desire to reenact their elders’ suffering.

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, and it is what Tithonus forgot to ask for. Healthspan is typically defined as the period of life when we are free from disability or disease, but I find this too simplistic.

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 my intent here is not to tell you exactly what to do; it’s to help you learn how to think about doing these things.

It’s not “preventive” medicine; it’s proactive medicine, and I believe it has the potential not only to change the lives of individuals but also to relieve vast amounts of suffering in our society as a whole.

While books like this always trumpet the fact that lifespans have nearly doubled since the late 1800s, the lion’s share of that progress may have resulted entirely from antibiotics and improved sanitation, as Steven Johnson points out in his book Extra Life. The Northwestern University economist 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.

Nearly all the money flows to treatment rather than prevention—and when I say “prevention,” I mean prevention of human suffering. Continuing to ignore healthspan, as we’ve been doing, not only condemns people to a sick and miserable older age but is guaranteed to bankrupt us eventually.

Medicine 3.0 demands much more from you, the patient: You must be well informed, medically literate to a reasonable degree, clear-eyed about your goals, and cognizant of the true nature of risk. You must be willing to change ingrained habits, accept new challenges, and venture outside of your comfort zone if necessary. You are always participating, never passive. You confront problems,

It’s one thing to break your femur in a skiing accident when you’re forty and still strong and resilient; it’s quite another to break it falling off a curb when you’re seventy-five and functioning at 25 percent of your capacity.

Here’s another way to think of it. Lifespan deals with death, which is binary: you’re alive, and then you’re dead. It’s final. But before that happens, sometimes long before, most people suffer through a period of decline that, I would argue, is like dying in slow motion.

The other key point is that lifespan and healthspan are not independent variables; they are tightly intertwined. If you increase your muscle strength and improve your cardiorespiratory fitness, you have also reduced your risk of dying from all causes by a far greater magnitude than you could achieve by taking any cocktail of medications.

Our tactics in Medicine 3.0 fall into five broad domains: exercise, nutrition, sleep, emotional health, and exogenous molecules, meaning drugs, hormones, or supplements.

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.

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.

Can we, through our behaviors, somehow reap the same benefits that centenarians get for “free” via their genes? Or to put it more technically, can we mimic the centenarians’ phenotype, the physical traits that enable them to resist disease and survive for so long, even if we lack their genotype? Is it possible to outlive our own life expectancy if we are smart and strategic and deliberate about it?

According to a large 2019 meta-analysis of seven separate longevity studies, with a total of nearly thirty thousand participants, 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 combination. Meanwhile, those with two copies of e4, one from each parent, were 81 percent less likely to live that long, according to the analysis. That’s a pretty big swing.

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

When nutrients are scarce, mTOR is suppressed and cells go into a kind of “recycling” mode, breaking down cellular components and generally cleaning house. Cell division and growth slow down or stop, and reproduction is put on hold to allow the organism to conserve energy.

a reasonable person could conclude that there was something good about turning down mTOR, at least temporarily—and that rapamycin may have potential as a longevity-enhancing drug.

modern experiments have demonstrated, over and over, that reducing the food intake of lab animals could lengthen their lives.

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, responding to the transient drop in nutrient levels. Just as you would change your itinerary if your fuel light came on, heading for the nearest gas station rather than Grandma’s house, AMPK prompts the cell to conserve and seek alternative sources of energy. It does this first by stimulating the production of new mitochondria, the tiny organelles that produce energy in the cell, via a process called mitochondrial biogenesis. Over time—or with disuse—our mitochondria become vulnerable to oxidative stress and genomic damage, leading to dysfunction and failure. Restricting the amount of nutrients that are available, via dietary restriction or exercise, triggers the production of newer, more efficient mitochondria to replace old and damaged ones. These fresh mitochondria help the cell produce more ATP, the cellular energy currency, with the fuel it does have. AMPK also prompts the body to provide more fuel for these new mitochondria, by producing glucose in the liver (which we’ll talk about in the next chapter) and releasing energy stored in fat cells.

By cleansing our cells of damaged proteins and other cellular junk, autophagy allows cells to run more cleanly and efficiently and helps make them more resistant to stress. But as we get older, autophagy declines. Impaired autophagy is thought to be an important driver of numerous aging-related phenotypes and ailments, such as neurodegeneration and osteoarthritis. Thus, I find it fascinating that this very important cellular mechanism can be triggered by certain kinds of interventions, such as a temporary reduction in nutrients (as when we are exercising or fasting)—and the drug rapamycin. (The Nobel Committee shares this fascination, having awarded the 2016 Nobel Prize in Physiology or Medicine to Japanese scientist Yoshinori Ohsumi for his work in elucidating the genetic regulation of autophagy.)

For the moment, though, let’s think about the fact that all of what we’ve talked about in this chapter, from mTOR and rapamycin to caloric restriction, points in one direction: that what we eat and how we metabolize it appear to play an outsize role in longevity.

three Horsemen diseases (cardiovascular disease, cancer, and Alzheimer’s disease). As we will see in the next few chapters, metabolic dysfunction vastly increases your risk for all of these. So you can’t fight the Horsemen without taking on metabolic dysfunction first.

“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 three or more of these criteria, then you have the metabolic syndrome—along

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.

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.

When insulin is chronically elevated, more problems arise. Fat gain and ultimately obesity are merely one symptom of this condition, known as hyperinsulinemia. I would argue that they are hardly even the most serious symptoms: as we’ll see in the coming chapters, insulin is also a potent growth-signaling hormone that helps foster both atherosclerosis and cancer. And when insulin resistance begins to develop, the train is already well down the track toward type 2 diabetes, which brings a multitude of unpleasant consequences.

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.

Thanks to the miracles of modern food technology, we are almost literally swimming in a sea of fructose, especially in the form of soft drinks, but also hidden in more innocent-seeming foods like bottled salad dressing and yogurt cups.[*4]

Thus, the almost infinite availability of liquid fructose in our already high-calorie modern diet sets us up for metabolic failure if we’re not careful (and especially if we are not physically active).

In my patients, I monitor several biomarkers related to metabolism, keeping a watchful eye for things like elevated uric acid, elevated homocysteine, chronic inflammation, and even mildly elevated ALT liver enzymes. Lipoproteins, which we will discuss in detail in the next chapter, are also important, especially triglycerides; I watch the ratio of triglycerides to HDL cholesterol (it should be less than 2:1 or better yet, less than 1:1), as well as levels of VLDL, a lipoprotein that carries triglycerides—all of which may show up many years before a patient would meet the textbook definition of metabolic syndrome. These biomarkers help give us a clearer picture of a patient’s overall metabolic health than HbA1c, which is not very specific by itself.

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.

Yet diabetes is only one danger: 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)—all of which underscores why addressing, and ideally preventing, metabolic dysfunction is a cornerstone of my approach to longevity.

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 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.

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

It took nearly two more decades before the advisory committee responsible for the US government dietary guidelines finally conceded (in 2015) that “cholesterol is not a nutrient of concern for overconsumption.”

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.

I was still in my thirties, yet I likely already had all three of the major prerequisites for heart disease: significant lipoprotein burden or apoB, LDL oxidation or modification (leading to the plaques that my calcium scan revealed), and a high level of background inflammation. None of these is enough to guarantee that someone will develop heart disease, but all three are necessary to develop it. 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.)

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.

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.

There are at least two reasons for this. First, it seems saturated fat contributes directly to the synthesis of excess cholesterol. Second, and more importantly, excess saturated fat causes the liver to reduce expression of LDL receptors, thereby reducing the amount of LDL removed from circulation.

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. Over the next few years, every other woman who was enrolled at her trial site had died. Every single one. The patients had been on state-of-the-art chemotherapy plus the PI3K inhibitor, yet their metastatic breast cancer had still overtaken them. The trial had to be stopped because it was clear that the drugs were not working. Except for Sandra. Why was she still alive, while hundreds of other women with the same disease, at the same stage, were not? Was she merely lucky? Or could her very strict diet, which likely inhibited her insulin and IGF-1, have played a role in her fate?

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.