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

by Peter Attia

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.

I know this, but it is a profound reminder anyway!

Perhaps my biggest takeaway was that modern medicine does not really have a handle on when and how to treat the chronic diseases of aging that will likely kill most of us. This is in part because each of the Horsemen is intricately complex, more of a disease process than an acute illness like a common cold. The surprise is that this is actually good news for us, in a way. Each one of the Horsemen is cumulative, the product of multiple risk factors adding up and compounding over time. Many of these same individual risk factors, it turns out, are relatively easy to reduce or even eliminate. Even better, they share certain features or drivers in common that make them vulnerable to some of the same tactics and behavioral changes we will discuss in this book.

The metabolic derangement that leads to type 2 diabetes also helps foster and promote heart disease, cancer, and Alzheimer’s disease. Addressing our metabolic health can lower the risk of each of the Horsemen. Almost all “diets” are similar: they may help some people but prove useless for most. Instead of arguing about diets, we will focus on nutritional biochemistry— how the combinations of nutrients that you eat affect your own metabolism and physiology, and how to use data and technology to come up with the best eating pattern for you. 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. Finally, as I learned the hard way, striving for physical health and longevity is meaningless if we ignore our emotional health. Emotional suffering can decimate our health on all fronts, and it must be addressed.

The first era, exemplified by Hippocrates but lasting almost two thousand years after his death, is what I call Medicine 1.0. Its conclusions were based on direct observation and abetted more or less by pure guesswork, some of which was on target and some not so much. Hippocrates advocated walking for exercise, for example, and opined that “in food excellent medicine can be found; in food bad medicine can be found,” which still holds up. But much of Medicine 1.0 missed the mark entirely, such as the notion of bodily “humors,” to cite just one example of many. Hippocrates’s major contribution was the insight that diseases are caused by nature and not by actions of the gods, as had previously been believed.

Medicine 2.0 arrived in the mid-nineteenth century with the advent of the germ theory of disease, which supplanted the idea that most illness was spread by “miasmas,” or bad air. This led to improved sanitary practices by physicians and ultimately the development of antibiotics.

Medicine 3.0, in my opinion, is not really about technology; rather, it requires an evolution in our mindset, a shift in the way in which we approach medicine. I’ve broken it down into four main points. First, Medicine 3.0 places a far greater emphasis on prevention than treatment. When did Noah build the ark? Long before it began to rain. Medicine 2.0 tries to figure out how to get dry after it starts raining. Medicine 3.0 studies meteorology and tries to determine whether we need to build a better roof, or a boat. Second, Medicine 3.0 considers the patient as a unique individual. Medicine 2.0 treats everyone as basically the same, obeying the findings of the clinical trials that underlie evidence-based medicine. These trials take heterogeneous inputs (the people in the study or studies) and come up with homogeneous results (the average result across all those people). Evidence-based medicine then insists that we apply those average findings back to individuals. The problem is that no patient is strictly average. Medicine 3.0 takes the findings of evidence-based medicine and goes one step further, looking more deeply into the data to determine how our patient is similar or different from the “average” subject in the study, and how its findings might or might not be applicable to them. Think of it as “evidence-informed” medicine. The third philosophical shift has to do with our attitude toward risk. In Medicine 3.0, our starting point is the honest assessment, and acceptan...

Medicine 2.0 focuses largely on lifespan, and is almost entirely geared toward staving off death, Medicine 3.0 pays far more attention to maintaining healthspan, the quality of life.

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.

Strategy without tactics is the slowest route to victory. Tactics without strategy is the noise before defeat. —SUN TZU

In this book, we will apply this three-part approach to longevity: objective → strategy → tactics.

Living longer means delaying death from all four of the Horsemen. The Horsemen do have one powerful risk factor in common, and that is age. As you grow older, the risk grows exponentially that one or more of these diseases has begun to take hold in your body. Unfortunately, there’s not much we can do about our chronological age—but what do we mean by “aging,” exactly? It’s not merely the passage of time, but what is happening inside us, beneath the surface, in our organs and our cells, as time passes. Entropy is working on us every single day. “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.”1 They continued: “This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases.”

I think about healthspan and its deterioration in terms of three categories, or vectors. The first vector of deterioration is cognitive decline. Our processing speed slows down. We can’t solve complex problems with the quickness and ease that we once did. Our memory begins to fade. Our executive function is less reliable. Our personality changes, and if it goes on for long enough, even our sentient self is lost.

The second vector of deterioration is the decline and eventual loss of function of our physical body. This may precede or follow cognitive decline; there is no predetermined order. But as we grow older, frailty stalks us. We lose muscle mass and strength, along with bone density, stamina, stability, and balance, until it becomes almost impossible to carry a bag of groceries into the house. Chronic pains prevent us from doing things we once did with ease.

No matter how ambitious your goals are for your later years, I suggest that you familiarize yourself with something called the “activities of daily living,” a checklist used to assess the health and functionality of elderly people. The list includes such basic tasks as preparing a meal for oneself, walking without assistance, bathing and grooming, using a phone, going to the grocery store, handling personal finances, and so on.

The third and final category of deterioration, I believe, has to do with emotional health. Unlike the others, this one is largely independent of age; it can afflict outwardly healthy young people in their twenties, or it can creep up on you in middle age, as it did with me. Or it can descend later in life.

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

The key difference between Medicine 2.0 and Medicine 3.0 has to do with how and when we apply our tactics. Typically, Medicine 2.0 steps in only when something is acutely wrong, like an infection or a broken bone, with short-term fixes for the immediate problem. In Medicine 3.0, our tactics must become interwoven into our daily lives. We eat, breathe, and sleep them—literally. 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.

Like “healthspan,” exercise is another one of those overly broad blanket terms that annoy me, because it can encompass everything from a walk in the park to a hard bike ride up a mountain pass, a set of tennis, or a session in the gym lifting heavy weights. These all count as “exercise,” but they obviously have very different effects (and risks, by the way). So we will break down this thing called exercise into its most important components: strength, stability, aerobic efficiency, and peak aerobic capacity. Increasing your limits in each of these areas is necessary if you are hoping to reach your limit of lifespan and healthspan. Again, my goal is not to tell you how to lose weight fast or improve the aesthetic quality of your midsection. We want to maintain physical strength, stamina, stability across a broad range of movements, while remaining free from pain and disability. This is another area where my thinking has changed over time. 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.

Our second domain is nutrition. I won’t be telling you to eat this, not that, or prescribing a specific diet that everyone should follow, and I’m definitely not taking sides in the pointless, never-ending diet wars

Next is sleep, which I and many others had ignored for far too long.

Finally, we will explore the importance of emotional health, which I believe is every bit as important a component of healthspan as the others.

Studying longevity itself in this way is almost impossible—unless we could somehow take a hundred thousand babies, randomize them to four or five different interventions, and follow them throughout their lifetimes. That would (hopefully) yield a rock-solid, evidence-based prescription for maximizing lifespan and healthspan. But the obstacles to doing this are insurmountable, not least because it would require a century to complete. Option B is to look at the different types of data that we do have and then develop a strategy that triangulates between them. This might not definitively solve the problem, but it can at least point us in the right direction. Our Option B strategy is based on combining insights from five different sources of data that, viewed separately, probably aren’t strong enough to act on. When taken together, however, they can provide a solid foundation for our tactics. But our supporting framework must shift, from exclusively evidence-based to evidence-informed, risk-adjusted precision medicine.

If we were epidemiologists from Saturn and all we had to go on was articles about centenarians in publications like USA Today and Good Housekeeping, we might conclude that the secret to extreme longevity is the breakfast special at Denny’s, washed down with Jim Beam and a good cigar. And perhaps this is so. Another possibility is that these celebrity centenarians are messing with the rest of us.

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.

If you don’t happen to have centenarian siblings, the next best option is to choose long-lived parents.

many of the oldest old die from pneumonia and other opportunistic infections, and that a few centenarians, such as Madame Calment, really do die of what used to be called old age. But the vast majority still succumb to diseases of aging—the Horsemen—just like the rest of us. The crucial distinction, the essential distinction, is that they tend to develop these diseases much later in life than the rest of us—if they develop them at all. We’re not talking about two or three or even five years later; we’re talking decades.

researchers have observed that centenarians tend to be in pretty good health overall—which, again, is not what most people expect. This doesn’t mean that everyone who lives that long will be playing golf and jumping out of airplanes, but Perls’s ninety-five-and-older study subjects scored very well on standard assessments of cognitive function and ability to perform those tasks of daily living we mentioned in chapter 3, such as cooking meals and clipping their own toenails,

women live longer but tend to be in poorer health.

supercentenarians and the “semisupercentenarians” (ages 105 to 109) actually tend to be in even better health than garden-variety hundred-year-olds. These are the super survivors, and at those advanced ages, lifespan and healthspan are pretty much the same.

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.

one individual gene, or even three dozen genes, is unlikely to be responsible for centenarians’ extreme longevity and healthspan. Broader genetic studies suggest that hundreds, if not thousands, of genes could be involved, each making its own small contribution—and that there is no such thing as a “perfect” centenarian genome.

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 FOXO314 that were strongly associated with healthy aging and longevity. Since then, several other studies15 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. FOXO3 belongs to a family of “transcription factors,” which regulate how other genes are expressed—meaning whether they are activated or “silenced.” I think of it as rather like the cellular maintenance department. Its responsibilities are vast, encompassing a variety of cellular repair tasks, regulating metabolism, caring for stem cells, and various other kinds of housekeeping, including helping with disposal of cellular waste or junk. But it doesn’t do the heavy lifting itself, like the mopping, the scrubbing, the minor drywall repairs, and so on. Rather, it delegates the work to other, more specialized genes—its subcontractors, if you will. 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 c...

We still have more questions than answers when it comes to the genetics behind extreme longevity, but this at least points in a more hopeful direction. While your genome is immutable, at least for the near future, gene expression can be influenced by your environment and your behaviors.

Most of us, obviously, cannot expect to get away with some of the centenarians’ naughty behaviors, such as smoking and drinking for decades. But even if we don’t (and in many cases, shouldn’t) imitate their “tactics,” the centenarians can nevertheless help inform our strategy. 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’re trying to attack heart disease, cancer, stroke, and Alzheimer’s one disease at a time, as if somehow these diseases are all unrelated to each other,” says S. Jay Olshansky, who studies the demography of aging at the University of Illinois–Chicago, “when in fact the underlying risk factor for almost everything that goes wrong with us as we grow older, both in terms of diseases we experience, and of the frailty and disability associated with it, is related to the underlying biological process of aging.”

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.

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. Cell division and growth slow down or stop, and reproduction is put on hold to allow the organism to conserve energy.

The authors of the study, published in Nature, speculated that rapamycin might extend lifespan “by postponing death from cancer, by retarding mechanisms of aging, or both.”6 The real headline here, however, was that no other molecule had been shown to extend lifespan in a mammal. Ever.

This idea goes all the way back to Hippocrates, but more modern experiments have demonstrated,12 over and over, that reducing the food intake of lab animals could lengthen their lives.

Studies dating back to the 1930s13 have found that limiting caloric intake can lengthen the lifespan of a mouse or a rat by anywhere from 15 to 45 percent, depending on the age of onset and degree of restriction. Not only that, but the underfed animals also seem to be markedly healthier for their age, developing fewer spontaneous tumors than normally fed mice.

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

CR’s usefulness remains doubtful outside of the lab; very lean animals may be more susceptible to death from infection or cold temperatures. And while eating a bit less worked for Luigi Cornaro, as well as for some of my own patients, long-term severe caloric restriction is difficult if not impossible for most humans to sustain. Furthermore, 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.

The real value of caloric restriction research lies in the insights it has contributed to our understanding of the aging process itself. CR studies have helped to uncover critical cellular mechanisms related to nutrients and longevity. 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 nutrients14 (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.

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.

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.

The FDA has given the green light for a clinical trial of another drug with potential longevity benefits, the diabetes medication metformin. This trial is called TAME (Targeting Aging with Metformin), and it came about in a very different way. 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.

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.

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.

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,fn1