Outlive: The Science and Art of Longevity

by Peter Attia

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

Nor does longevity mean merely notching more and more birthdays as we slowly wither away. This is what happened to a hapless mythical Greek named Tithonus, who asked the gods for eternal life. To his joy, the gods granted his wish. But because he forgot to ask for eternal youth as well, his body continued to decay. Oops.

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

In 1900, life expectancy hovered somewhere south of age fifty, and most people were likely to die from “fast” causes: accidents, injuries, and infectious diseases of various kinds. Since then, slow death has supplanted fast death. The majority of people reading this book can expect to die somewhere in their seventies or eighties, give or take, and almost all from “slow” causes.

the Four Horsemen: heart disease, cancer, neurodegenerative disease, or type 2 diabetes and related metabolic dysfunction. To achieve longevity—to live longer and live better for longer—we must understand and confront these causes of slow death.

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.

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

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

The standard-of-care treatment guidelines of the American Diabetes Association specify that a patient can be diagnosed with diabetes mellitus when they return a hemoglobin A1c (HbA1c) test result[*1] of 6.5 percent or higher, corresponding to an average blood glucose level of 140 mg/dL (normal is more like 100 mg/dL, or an HbA1c of 5.1 percent).

Type 2 diabetes is merely the last stop on the line. The time to intervene is well before the patient gets anywhere near that zone; even prediabetes is very late in the game. It is absurd and harmful to treat this disease like a cold or a broken bone, where you either have it or you don’t; it’s not binary. Yet too often, the point of clinical diagnosis is where our interventions begin. Why is this okay?

Medicine’s biggest failing is in attempting to treat all these conditions at the wrong end of the timescale—after they are entrenched—rather than before they take root. As a result, we ignore important warning signs and miss opportunities to intervene at a point where we still have a chance to beat back these diseases, improve health, and potentially extend lifespan.

More broadly, longevity demands a paradigm-shifting approach to medicine, one that directs our efforts toward preventing chronic diseases and improving our healthspan—and doing it now, rather than waiting until disease has taken hold or until our cognitive and physical function has already declined. 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.

a huge blind spot in medicine, and that is the understanding of risk. In finance and banking, understanding risk is key to survival.

Risk is not something to be avoided at all costs; rather, it’s something we need to understand, analyze, and work with. Every single thing we do, in medicine and in life, is based on some calculation of risk versus reward. Did you eat a salad from Whole Foods for lunch? There’s a small chance there could have been E. coli on the greens.

Consider the case of poor Ignaz Semmelweis, a Hungarian obstetrician who was troubled by the fact that so many new mothers were dying in the hospital in Vienna where he worked. He concluded that their strange “childbed fever” might somehow be linked to the autopsies that he and his colleagues performed in the mornings, before delivering babies in the afternoons—without washing their hands in between. The existence of germs had not yet been discovered, but Semmelweis nonetheless believed that the doctors were transmitting something to these women that caused their illness. His observations were most unwelcome. His colleagues ostracized him, and Semmelweis died in an insane asylum in 1865.

The shift from Medicine 1.0 to Medicine 2.0 was prompted in part by new technologies such as the microscope, but it was more about a new way of thinking. The foundation was laid back in 1628, when Sir Francis Bacon first articulated what we now know as the scientific method.

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.

Another, related issue is that longevity itself, and healthspan in particular, doesn’t really fit into the business model of our current healthcare system. There are few insurance reimbursement codes for most of the largely preventive interventions that I believe are necessary to extend lifespan and healthspan. Health insurance companies won’t pay a doctor very much to tell a patient to change the way he eats, or to monitor his blood glucose levels in order to help prevent him from developing type 2 diabetes. Yet insurance will pay for this same patient’s (very expensive) insulin after he has been diagnosed. Similarly, there’s no billing code for putting a patient on a comprehensive exercise program designed to maintain her muscle mass and sense of balance while building her resistance to injury. But if she falls and breaks her hip, then her surgery and physical therapy will be covered. 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.

Which brings us to perhaps the most important difference between Medicine 2.0 and Medicine 3.0. In Medicine 2.0, you are a passenger on the ship, being carried along somewhat passively. 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, even uncomfortable or scary ones, rather than ignoring them until it’s too late. You have skin in the game, in a very literal sense. And you make important decisions.

The point is that the tactics are what you do when you are actually in the ring. The strategy is the harder part, because it requires careful study of one’s opponent, identifying his strengths and weaknesses, and figuring out how to use both to your advantage, well before actually stepping in the ring. In this book, we will apply this three-part approach to longevity: objective → strategy → tactics.

“Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death,” wrote the authors of an influential 2013 paper describing what they termed the “hallmarks of aging.” They continued: “This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases.” The very process

Without an understanding of the strategy, and the science that informs it, our tactics will not mean much, and you’ll forever ride the merry-go-round of fad diets and trendy workouts and miracle supplements. You’ll be stuck in a Medicine 2.0 mentality, seeking a quick fix to your problems. The only way to become an adroit tactician is to shift your mindset to Medicine 3.0, which requires becoming a master strategist first.

Medicine 2.0 relies on two types of tactics, broadly speaking: procedures (e.g., surgery) and 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.

in biology we can rarely “prove” anything definitively the way we can in mathematics. Living systems are messy, and confounding, and complex, and our understanding of even fairly simple things is constantly evolving. The best we can hope for is reducing our uncertainty. A good experiment in biology only increases or decreases our confidence in the probability that our hypothesis is true or false. (Although we can feel fairly certain about some things, such as the evidence supporting the idea that your doctor should wash her hands and put on sterile gloves before operating on you.)

In the absence of multiple, repeated, decades-long randomized clinical trials that might answer our questions with certainty, we are forced to think in terms of probabilities and risk. In a sense it’s a bit like charting an investment strategy: we are seeking the tactics that are likeliest, based on what we know now, to deliver a better-than-average return on our capital, while operating within our own individual tolerance for risk. On Wall Street, gaining an advantage like this is called alpha, and we’re going to borrow the idea and apply it to health. I propose that with some unorthodox but very reasonable lifestyle changes, you can minimize the most serious threats to your lifespan and healthspan and achieve your own measure of longevity alpha. My aim here is to equip you with a set of tools that you can apply to your own specific situation—whether

Studies of Scandinavian twins 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. Being the sister of a centenarian makes you eight times more likely to reach that age yourself, while brothers of centenarians are seventeen times as likely to celebrate their hundredth birthday, according to data from the one-thousand-subject New England Centenarian Study, which has been tracking extremely long-lived individuals since 1995 (although because these subjects grew up in the same families, with presumably similar lifestyles and habits, this finding could be due to some environmental factors as well). If you don’t happen to have centenarian siblings, the next best option is to choose long-lived parents. This is part of why I place so much importance on taking a detailed family history from my patients: I need to know when your relatives died and why. What are your likely “icebergs,” genetically

In mathematical terms, the centenarians’ genes have bought them a phase shift in time—that is, their entire lifespan and healthspan curve has been shifted a decade or two (or three!) to the right. Not only do they live longer, but these are people who have been healthier than their peers, and biologically younger than them, for virtually their entire lives. When they were sixty, their coronary arteries were as healthy as those of thirty-five-year-olds. At eighty-five, they likely looked and felt and functioned as if they were in their sixties. They seemed like people a generation younger than the age on their driver’s license. This is the effect that we are seeking to mimic.

People are sicker for longer before they die. Their Marginal Decade is spent largely as a patient. 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. This is why I test all my patients for their APOE genotype, as we’ll discuss in chapter 9. The e2 variant of APOE, on the other hand, seems to protect its carriers against dementia—and it

Researchers have identified two other cholesterol-related genes, known as CETP and APOC3, that are also correlated with extreme longevity (and may explain why centenarians rarely die from heart disease).

Put another way, if we want to outlive our life expectancy and live better longer, we will have to work hard to earn it—through small, incremental changes.

One other possible longevity gene that has emerged, in multiple studies of centenarians worldwide, also provides some possible clues to inform our strategy. These are variants in a particular gene called FOXO3 that seem to be directly relevant to human longevity.

genetic analysis of Spanish centenarians found that they displayed extremely youthful patterns of gene expression, more closely resembling a control group of people in their twenties than an older control group of octogenarians. Precisely how these centenarians achieved this is not clear, but it may have something to do with FOXO3—or some other, as yet unknown, governor of gene expression.

Their superpower is their ability to resist or delay the onset of chronic disease by one or two or even three decades, while also maintaining relatively good healthspan.

We need to think about very early disease-specific prevention, which we will explore in detail in the next few chapters dedicated to the Horsemen diseases. And we need to think about very early general prevention, targeting all the Horsemen at once, via common drivers and risk factors.

David Sabatini was one of a handful of scientists who picked up the baton from Sehgal, seeking to explain this phenomenon. Understanding rapamycin became his life’s work.

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

The results were especially convincing because the experiment had been run by three different teams of researchers in three separate labs, using a total of 1,901 genetically diverse animals, and the results had been consistent across the board. Even better, other labs quickly and readily reproduced these results, which is a relative rarity, even with much-ballyhooed findings.

Caloric restriction without malnutrition, commonly abbreviated as CR, is a precise experimental method where one group of animals (the controls) are fed ad libitum, meaning they eat as much as they want, while the experimental group or groups are given a similar diet containing all the necessary nutrients but 25 or 30 percent fewer total calories (more or less). The restricted animals are then compared against the controls.

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, 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.

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.)

But all that started to change in late December 2014 with the publication of a study showing that the rapamycin analog everolimus actually enhanced the adaptive immune response to a vaccine in a group of older patients.

It seems odd that giving different doses of the same drug could have such disparate effects, but it makes sense if you understand the structure of mTOR, which is actually composed of two separate complexes, called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The two complexes have different jobs, but (at risk of oversimplifying) the longevity-related benefits seem to result from inhibiting complex 1. Giving the drug daily, as is typically done with transplant patients, appears to inhibit both complexes, while dosing the drug briefly or cyclically inhibits mainly mTORC1, unlocking its longevity-related benefits, with fewer unwanted side effects.

Kaeberlein is doing a large clinical trial of rapamycin in companion (pet) dogs, which are not a bad proxy for humans—they’re large, they’re mammals, they share our environment, and they age in ways similar to us. In a preliminary phase of this study, which he calls the Dog Aging Project, Kaeberlein found that rapamycin actually seemed to improve cardiac function in older animals. “One thing that’s been surprising to me,” he says, “is the different ways that rapamycin not only seems to delay the decline but seems to make things better. There clearly seems to be, at least in some organs, a rejuvenating function.”

The main phase of the Dog Aging Project, involving some 600 pet dogs, is now under way; results from this larger clinical trial are expected in 2026.

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.

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)

One of the liver’s many important jobs is to convert this stored glycogen back to glucose and then to release it as needed to maintain blood glucose levels at a steady state, known as glucose homeostasis. This is an incredibly delicate task: an average adult male will have about five grams of glucose circulating in his bloodstream at any given time, or about a teaspoon. That teaspoon won’t last more than a few minutes, as glucose is taken up by the muscles and especially the brain, so the liver has to continually feed in more, titrating it precisely to maintain a more or less constant level. Consider that five grams of glucose, spread out across one’s entire circulatory system, is normal, while seven grams—a teaspoon and a half—means you have diabetes. As I said, the liver is an amazing organ.

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.