Book	Outlive: The Science and Art of Longevity
Author	Peter Attia
Published	March 28, 2023

Healthspan is the new metric for health/ longevity in the 21st century and the future.

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. Assuming that you’re not someone who engages in ultrarisky behaviors like BASE jumping, motorcycle racing, or texting and driving, 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. 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

The future of medicine and health is preventative.

In every case, we are intervening at the wrong point in time, well after the disease has taken hold, and often when it’s already too late—when the eggs are already dropping. It gutted me every time I had to tell someone suffering from cancer that she had six months to live, knowing that the disease had likely taken up residence in her body several years before it was ever detectable. We had wasted a lot of time. While the prevalence of each of the Horsemen diseases increases sharply with age, they typically begin much earlier than we recognize, and they generally take a very long time to kill you. 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 logical conclusion is that we need to step in sooner to try to stop the Horsemen in their tracks—or better yet, prevent them altogether. 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.

Leading indicators of disease will become more important/ influential, and they won’t be binary.

I would argue that this is almost the exact wrong way to approach type 2 diabetes. As we will see in chapter 6, type 2 diabetes belongs to a spectrum of metabolic dysfunction that begins long before someone crosses that magical diagnostic threshold on a blood test. 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 pre-diabetes 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.

Risk = probability/ statistics = the quantitative sciences. Medicine/ health will become more and more analytical, and will ultimately be transformed by quantitative/ data/ computational science.

My detour into the world of consulting came to an end, but it opened my eyes to a huge blind spot in medicine, and that is the understanding of risk. In finance and banking, understanding risk is key to survival. Great investors do not take on risk blindly; they do so with a thorough knowledge of both risk and reward. The study of credit risk is a science, albeit an imperfect one, as I learned with the banks. While risk is obviously also important in medicine, the medical profession often approaches risk more emotionally than analytically.

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. Did you drive to Whole Foods to get it? Also risky. But on balance, that salad is probably good for you (or at least less bad than some other things you could eat).

Because I am a math guy, I like to visualize lifespan and healthspan in terms of a mathematical function, as in figure 2 on the following page—one of many graphs that I draw for my patients. The horizontal or x-axis of the graph represents your lifespan, how long you will live, while the vertical or y-axis represents a kind of sum total of your physical and cognitive function, the two age-dependent dimensions of healthspan. (Obviously, healthspan is not really quantifiable, but bear with my oversimplification.) The black line represents the natural trajectory of your life: You are born at time zero, and for purposes of our diagram, we’ll say your physical and cognitive health start out at 100 percent. You remain relatively robust until about the fifth decade of life, at which point your cognitive and physical health will likely begin a gradual but steady decline, until you die (healthspan = zero) sometime in your sixties or early seventies. This would have been a not untypical lifespan for someone born into a hunter-gatherer or primitive agrarian tribe, provided they managed to avoid early death thanks to infectious disease or another calamity.

The 3 vectors of healthspan deterioration: cognitive, physical and emotional.

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. Fortunately, most people don’t progress all the way to frank dementia, but many people experience some decline in their cognitive capacity as they age. Our objective is to minimize this. 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. At the same time, the inexorable progression of atherosclerotic disease might leave us gasping for breath when we walk to the end of the driveway to fetch the newspaper (if newspapers still exist when we are old). Or we could be living a relatively active and healthy life until we fall or suffer some unexpected injury, as Sophie did, that tips us into a downward spiral from which we never recover.

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. Surveys show that happiness tends to reach its nadir in our forties (age forty-seven, to be exact), but as I learned through painful experience, middle-aged distress often has its roots much earlier, in adolescence or childhood. And we may not recognize that we are in danger until we reach a crisis point, as I did. How we deal with it has a huge bearing on our physical health, our happiness, and our very survival.

Activities of daily living (ADL) score = checklist for assessing longevity and detoriation.

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.

Exercise is the most effective therapy for health and longevity.

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.

Limitations of traditional randomized controlled trials (RCTs) as it relates to healthspan and longevity:

A one-year clinical trial, or even a five-year study, will not tell us everything we need to know about disease processes that take decades to unfold. There will never be a clinical trial to guide a cardiovascular prevention strategy for a healthy forty-year-old. It would simply take too long to do the study. Furthermore, outside of pharmacology, the interventions are very complex, particularly if they involve exercise, nutrition, and sleep. 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, evidencebased prescription for maximizing lifespan and healthspan. But the obstacles to doing this are insurmountable, not least because it would require a century to complete.

Analogies between investing/ finance and health:

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.

Dog Aging Project is an RCT on the effect of rapamycin on healthspan/ longevity (for dogs):

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. (Disclosure: I am a partial funder of this research.) The dogs in this study are also following a weekly, cyclical dosing schedule with rapamycin, similar to the protocol in the 2014 immune study in humans. If the results are positive, it would not surprise me if the use of rapamycin for longevity purposes becomes more common. A small but growing number of people, including me and a handful of my patients, already take rapamycin off-label for its potential geroprotective benefits. I can’t speak for everyone, but taking it cyclically does appear to reduce unwanted side effects, in my experience. Even so, the hurdles it would have to clear to gain approval for broader human use remain daunting. The vast majority of people who currently take rapamycin comprise transplant patients who already have serious health issues and multiple comorbidities. In populations like this, rapamycin’s side effects seem less significant than they might in healthier people. “There is a very low tolerance for side effects, by the public and by regulatory agencies, if you’re talking about treating a healthy person,” says Kaeberlein. “The intent is to slow aging in people before they get sick, to keep them healthy longer, so in many ways it is the opposite of the traditional biomedical approach, where normally we wait until people are sick and then we try to cure their diseases.” The real obstacle here is a regulatory framework rooted in Medicine 2.0, which does not (yet) recognize “slowing aging” and “delaying disease” as fully legitimate end points. This would represent a Medicine 3.0 use for this drug, where we would be using a drug to help healthy people stay healthy, rather than to cure or relieve a specific ailment. Thus, it would face much more scrutiny and skepticism. But if we’re talking about preventing the diseases of aging, which kill 80 percent of us, then it’s certainly worth having a serious conversation about what level of risk is and isn’t acceptable in order to achieve that goal. Part of my aim in writing this book is to move that conversation forward.

Criteria for metabolic syndrome. Also 20-40% of non-obese adults may be metabolically unhealthy!

In the 1980s, Reaven labeled this collection of related disorders “Syndrome X”—where the X factor, he eventually determined, was insulin resistance. 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 three or more of these criteria, then you have the metabolic syndrome—along with as many as 120 million other Americans, according to a 2020 article in JAMA. About 90 percent of the US population ticks at least one of these boxes. But notice that obesity is merely one of the criteria; it is not required for the metabolic syndrome to be diagnosed. Clearly the problem runs deeper than simply unwanted weight gain. This tends to support my view that obesity itself is not the issue but is merely a symptom of other problems. Studies have found that approximately one-third of those folks who are obese by BMI are actually metabolically healthy, by many of the same parameters used to define the metabolic syndrome (blood pressure, triglycerides, cholesterol, and fasting glucose, among others). At the same time, some studies have found that between 20 and 40 percent of nonobese adults may be metabolically unhealthy, by those same measures.

Individual fat-storage capacity seems to be influenced by genetic factors. This is a generalization, but people of Asian descent (for example), tend to have much lower capacity to store fat, on average, than Caucasians. There are other factors at play here as well, but this explains in part why some people can be obese but metabolically healthy, while others can appear “skinny” while still walking around with three or more markers of metabolic syndrome. It’s these people who are most at risk, according to research by Mitch Lazar at the University of Pennsylvania, because a “thin” person may simply have a much lower capacity to safely store fat. All other things being equal, someone who carries a bit of body fat may also have greater fat-storage capacity, and thus more metabolic leeway than someone who appears to be more lean.

Think of fat as acting like a kind of metabolic buffer zone, absorbing excess energy and storing it safely until it is needed. If we eat extra doughnuts, those calories are stored in our subcutaneous fat; when we go on, say, a long hike or swim, some of that fat is then released for use by the muscles. This fat flux goes on continually, and as long as you haven’t exceeded your own fat storage capacity, things are pretty much fine. But if you continue to consume energy in excess of your needs, those subcutaneous fat cells will slowly fill up, particularly if little of that stored energy is being utilized. When someone reaches the limit of their capacity to store energy in their subcutaneous fat, yet they continue to take on excess calories, all that energy still has to go somewhere. The doughnuts or whatever they might be eating are probably still getting converted into fat, but now the body has to find other places to store it. It’s almost as if you have a bathtub, and you’re filling it up from the faucet. If you keep the faucet running even after the tub is full and the drain is closed (i.e., you’re sedentary), water begins spilling over the rim of the tub, flowing into places where it’s not wanted or needed, like onto the bathroom floor, into the heating vents or down the stairs. It’s the same with excess fat.

Best practice / clinical guidelines are too short-sighted. The next age of medicine (“Medicine 3.0”) will think in decades, not years.

The fundamental problem, I believe, is classic Medicine 2.0: guidelines for managing cardiovascular risk are based on an overly short time horizon, compared to the time line of the disease. We need to begin treating it, and preventing it, much earlier. If we could get it right, the potential payoff would be huge: the high prevalence of male centenarians on the island of Sardinia, for example, has largely been attributed to their ability to avoid or delay circulatory disease. Fewer Sardinian men die from heart disease between the ages of eighty and one hundred than anywhere else in Italy.

This encapsulates the fundamental difference between Medicine 2.0 and Medicine 3.0 when it comes to cardiovascular disease. The former views prevention largely as a matter of managing relatively short-term risk. Medicine 3.0 takes a much longer view—and more importantly seeks to identify and eliminate the primary causative agent in the disease process: apoB. This changes our approach to treatment completely. For example, a forty-five-year-old with elevated apoB has a lower ten-year risk than a seventy-five-year-old with low apoB. Medicine 2.0 would say to treat the seventy-five-year-old (because of their age), but not the forty-five-year-old. Medicine 3.0 says to disregard the ten-year risk and instead treat the causal agent in both cases—lowering the forty-fiveyear-old’s apoB as much 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).” Furthermore, the authors wrote: “If the entire population maintained LDL concentrations akin to those of a neonate (or to those of adults of most other animal species), atherosclerosis might well be an orphan disease.” Translation: if we all maintained the apoB levels we had when we were babies, there wouldn’t be enough heart disease on the planet for people to know what it was. Kind of like 3-hydroxyisobutyric aciduria. What, you haven’t heard of it? Well, that’s because there have been only thirteen reported cases. Ever. That is an orphan disease. I’m being a bit facetious, but my point is that atherosclerotic disease shouldn’t even be in the top ten causes of death, if we treated it more aggressively. Instead, we have over eighteen million cases of fatal atherosclerotic disease per year globally.

Overtesting and overdiagnosis may be the bigger challenges in the futuren though.

The situation with mammography illustrates why we need to be very strategic about who we are testing and what their risk profile might be, and to understand what our test can and can’t tell us. No single diagnostic test, for anything, is 100 percent accurate. So it is foolish to rely on just one test, not only for breast cancer but in many other areas as well. We need to think in terms of stacking test modalities—incorporating ultrasound and MRI in addition to mammography, for example, when looking for breast cancer. With multiple tests, our resolution improves and fewer unnecessary procedures will be performed. 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.

3 key questions for evaluating your nutrition/ exercise: nourishment, musculature and metabolic health.

Our two most complex tactical domains are nutrition and exercise, and I find that most people need to make changes in both—rarely just one or the other. When I evaluate new patients, I’m always asking three key questions: a. Are they overnourished or undernourished? That is, are they taking in too many or too few calories? b. Are they undermuscled or adequately muscled? c. Are they metabolically healthy or not?

The benefits/ power of exercise:

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. (It also has benefits in terms of emotional health, although those are harder to quantify.)

“Poor cardiorespiratory fitness carries a greater relative risk of death than smoking.” What?!

The higher someone’s VO2 max, the more oxygen they can consume to make ATP, and the faster they can ride or run—in short, the more they can do. 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. Consider this: 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. That’s only the beginning. Someone in the bottom quartile of VO2 max for their age group (i.e., the least fit 25 percent) is nearly four times likelier to die than someone in the top quartile—and five times likelier to die than a person with elite-level (top 2.3 percent) VO2 max. That’s stunning. These benefits are not limited to the very fittest people either; even just climbing from the bottom 25 percent into the 25th to 50th percentile (e.g., least fit to below average) means you have cut your risk of death nearly in half, according to this study.

This doesn’t just apply to cardiovascular fitness, but also strength. In general, the stronger you are, the longer your healthspan.

Strength may even trump cardiorespiratory fitness, at least one study suggests. Researchers following a group of approximately 1,500 men over forty with hypertension, for an average of about eighteen years, found that even if a man was in the bottom half of cardiorespiratory fitness, his risk of all-cause mortality was still almost 48 percent lower if he was in the top third of the group in terms of strength versus the bottom third. It’s pretty much the same story we saw with VO2 max: The fitter you are, the lower your risk of death. Again, there is no other intervention, drug or otherwise, that can rival this magnitude of benefit.

The concept of the “Centenarian Decathlon”. Feel like there’s some room for improvement on this list of events.

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. It creates a template for our training. I start by presenting my patients with a long list of physical tasks that might include some of the following: Hike 1.5 miles on a hilly trail. Get up off the floor under your own power, using a maximum of one arm for support. Pick up a young child from the floor. Carry two five-pound bags of groceries for five blocks. Lift a twenty-pound suitcase into the overhead compartment of a plane. Balance on one leg for thirty seconds, eyes open. (Bonus points: eyes closed, fifteen seconds.) Have sex. Climb four flights of stairs in three minutes. Open a jar. Do thirty consecutive jump-rope skips.

The significance of lactate levels and metabolic health:

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. It seems unjust, but the people who most need to burn their fat, the people with the most of it, are unable to unlock virtually any of that fat to use as energy, while the lean, well-trained professional athletes are able to do so easily because they possess greater metabolic flexibility (and healthier mitochondria).

Watts per kilogram is a good metric to track. A very fit person produces 3 watts/ kg on average during Zone 2 training.

One way to track your progression in zone 2 is to measure your output in watts at this level of intensity. (Many stationary bikes can measure your wattage as you ride.) You take your average wattage output for a zone 2 session and divide it by your weight to get your watts per kilogram, which is the number we care about. 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.

V02 max training involves hard but not maximal intensity interval work.

If zone 2 represents a steady state, where you are kind of cruising along at a sustainable pace, VO2 max efforts are almost the opposite. This is a much higher level of intensity—a hard, minutes-long effort, but still well short of an all-out sprint. 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. Besides improving mitochondrial health and glucose uptake and metabolic flexibility, and all those other good things, zone 2 training also increases your VO2 max somewhat. But if you really want to raise your VO2 max, you need to train this zone more specifically. Typically, for patients who are new to exercising, we introduce VO2 max training after about five or six months of steady zone 2 work.

4-6 mins on, 4-6 mins off intervals = best way improve your V02 max.

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. I do these workouts on my road bike, mounted to a stationary trainer, or on a rowing machine, but running on a treadmill (or a track) could also work. 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.

V02 max declines over time/ with age…

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. These are not abstract numbers; they represent a profound decline in function. It’s the difference between walking easily up a flight of stairs versus struggling to even walk on an inclined surface. It’s a far cry from hiking in the Dolomites. 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.

But it’s trainable!

How trainable is VO2 max? The conventional wisdom, reflecting the bulk of the literature, suggests that it’s possible to improve elderly subjects’ aerobic capacity by about 13 percent over eight to ten weeks of training, and by 17 percent after twenty-four to fifty-two weeks, according to one review. That’s a good start, but I think it represents only the beginning of what is possible; as usual with Medicine 2.0, these studies are almost always too short.

It is not clear how much upside it is possible to achieve, but the literature suggests that sustained, diligent training can pay off. A small study of nine well-trained octogenarian endurance athletes (cross-country skiers) found that their average VO2 max was 38, versus 21 for a control group of untrained octogenarian men, a difference of more than 80 percent. That’s huge. The athletes had the aerobic capacity of people decades younger than them, while the men in the control group had declined so far that they were on the verge of losing their ability to live independently.

Improve V02 = become functionally younger.

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. If you are a man in your sixties and you are starting with a VO2 max of 30, you are more or less average for your age group (see figure 12). (Women typically have a somewhat lower average VO2 max by age, because of various factors, so an “average” woman in her sixties would be at about 25 ml/kg/min.) If you can boost that up to 35 via training, you will be squarely in the top 25 percent of your age group. Nice work. Now, here’s another way to look at it: In your sixties, you will have achieved the aerobic fitness of an average man in his fifties, a decade younger than you. If you can get it still higher, to 38 or 39, you will be the aerobic equivalent of an average thirty-something. This means you will have bought yourself a phase shift, like we talked about with the centenarians: you now have the fitness of someone decades younger than you.

The most common problem in nutrition: reduce energy intake while adding lean mass, which means consuming fewer calories while also increasing protein intake, and paring that with proper exercise.

What problem are we trying to solve here? What is our goal with Nutrition 3.0? I think it boils down to the simple questions that we posited in chapter 10: Are you undernourished, or overnourished? Are you undermuscled, or adequately muscled? Are you metabolically healthy or not? The correlation between poor metabolic health and being overnourished and undermuscled is very high. Hence, for a majority of patients the goal is to reduce energy intake while adding lean mass. This means we need to find ways to get them to consume fewer calories while also increasing their protein intake, and to pair this with proper exercise. This is the most common problem we are trying to solve around nutrition.

The PREDIMED study and its results:

The large Spanish study known as PREDIMED (PREvención con DIeta MEDiterránea) was elegant in its design: rather than telling the nearly 7,500 subjects exactly what they were supposed to eat, the researchers simply gave one group a weekly “gift” of a liter of olive oil, which was meant to nudge them toward other desired dietary changes (i.e., to eat the sorts of things that one typically prepares with olive oil). A second group was given a quantity of nuts each week and told to eat an ounce per day,

The study was meant to last six years, but in 2013 the investigators announced that they had halted it prematurely, after just four and a half years, because the results were so dramatic. The group receiving the olive oil had about a one-third lower incidence (31 percent) of stroke, heart attack, and death than the low-fat group, and the mixed-nuts group showed a similar reduced risk (28 percent). It was therefore deemed unethical to continue the low-fat arm of the trial. By the numbers, the nuts-or-olive-oil “Mediterranean” diet appeared to be as powerful as statins, in terms of number needed to treat (NNT), for primary prevention of heart disease—meaning in a population that had not yet experienced an “event” or a clinical diagnosis.

The number one food group in the standard American diet (SAD) is “grain-based desserts”. Simply by elimintating those foods, you’re better off than most Americans.

The SAD disrupts the body’s metabolic equilibrium. It places enormous strain on our ability to control our blood glucose levels, and causes us to store fat when we should be utilizing it. 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.” If we consume a bunch of grain-based desserts in a Cheesecake Factory binge, our blood glucose levels will surge. And if we do it over and over and over again, as we saw in previous chapters, we will eventually overwhelm our ability to handle all those calories in a safe way. The SAD essentially wages war on our metabolic health.

The types of diets / nutritional strategies: caloric, dietary or time restrictions.

Once you strip away the labels and the ideology, almost all diets rely on at least one of the following three strategies to accomplish this: CALORIC RESTRICTION, or CR: eating less in total, but without attention to what is being eaten or when it’s being eaten DIETARY RESTRICTION, or DR: eating less of some particular element(s) within the diet (e.g., meat, sugar, fats) TIME RESTRICTION, or TR: restricting eating to certain times, up to and including multiday fasting

Caloric restriction wins.

From the standpoint of pure efficacy, CR or caloric restriction is the winner, hands down. This is how bodybuilders shed weight while holding on to muscle mass, and it also allows the most flexibility with food choices. The catch is that you have to do it perfectly—tracking every single thing you eat, and not succumbing to the urge to cheat or snack—or it doesn’t work. Many people have a hard time sticking with it. DR or dietary restriction is probably the most common strategy employed for reducing energy intake. It is conceptually simple: pick a type of food, and then don’t eat that food. It only works, obviously, if that food is both plentiful and significant enough that eliminating it will create a caloric deficit.

Feedback on the keygenic diet:

In the past, I was a huge proponent of ketogenic diets, finding them particularly useful to manage or prevent diabetes in patients like Eduardo. I also like that they have a strict definition, unlike “low carb” or “low fat.” A ketogenic diet means restricting carbohydrates to such an extent that the body begins metabolizing fat into “ketone bodies” that the muscles and brain can utilize as fuel. A ketogenic diet helped fix Not-Thin Peter, and it had likely saved Eduardo’s life. I thought it was the medicine that every metabolically unhealthy person needed. But my patients brought me back to earth, as they so often do. As a physician, one often receives feedback in a very direct, personal way. If I give someone a medication or a recommendation, I will find out pretty quickly whether it is working. It’s not “data” in the strict sense, but it can be equally powerful. I’ve had more than one patient for whom a ketogenic diet has completely failed. They didn’t lose weight, and their liver enzymes and other biomarkers failed to improve. Or they found it impossible to sustain. I’ve had other patients who were able to stick to the diet, but then their lipid numbers (especially their apoB) went through the roof, probably because of all the saturated fats they were eating.

Amount of required protein required to thrive: 1 g/ lb/ day.

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. The ideal amount can vary from person to person, but the data suggest that 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—nearly triple the minimal recommendation.

The literature suggests that the ideal way to achieve this is by consuming four servings of protein per day, each at ~0.25 g/lb of body weight. A six-ounce serving of chicken, fish, or meat will provide about 40 to 45 grams (at about 7 grams of actual protein per ounce of meat), so our hypothetical 180-pound person should eat four such servings a day.

Generally, the more protein we consume, the better.

Multiple studies suggest that the more protein we consume, in general, the better. A large prospective study called the Healthy Aging and Body Composition Study, with more than two thousand elderly subjects, found that those who ate the most protein (about 18 percent of caloric intake) kept more of their lean body mass over three years than those in the lowest quintile of protein consumption (10 percent of calories). The difference was significant: the lowprotein group lost 40 percent more muscle than the high-protein group.

Beyond its role in building muscle, protein may have beneficial effects on our metabolism. One study found that giving elderly people supplements containing essential amino acids (that is, mimicking some effects of increasing dietary protein) lowered their levels of liver fat and circulating triglycerides. Another study in men with type 2 diabetes found that doubling their protein intake from 15 to 30 percent of total calories, while cutting carbohydrates by half, improved their insulin sensitivity and glucose control. Eating protein also helps us feel satiated, inhibiting the release of the hunger-inducing hormone ghrelin, so we eat fewer calories overall.

Mono-unsaturated faty acids (MUFA) > poly-unsaturated fatty acids (PUFA) > saturated fatty acids.

As we discussed in the introduction to Medicine 3.0 and earlier in this chapter, any hope of using broad insights from evidence-based medicine is bound to fail when it comes to nutrition, because such population-level data cannot provide much value at the individual level when the effect sizes are so small, as they clearly are here. All Medicine 2.0 has to offer is broad contours: MUFA seems to be the “best” fat of the bunch (based on PREDIMED and the Lyon Heart study), and after that the meta-analyses suggest PUFA has a slight advantage over SFA. But beyond that, we are on our own.

The purported benefits of fasting:

There is no denying that some good things happen when we are not eating. Insulin drops dramatically because there are no incoming calories to trigger an insulin response. The liver is emptied of fat in fairly short order. Over time, within three days or so, the body enters a state called “starvation ketosis,” where fat stores are mobilized to fulfill the need for energy—yet at the same time, as I often noticed when I was undergoing regular lengthy fasts, hunger virtually disappears. This paradoxical phenomenon is likely due to the ultrahigh levels of ketones that this state produces, which tamp down feelings of hunger. Fasting over long periods also turns down mTOR, the pro-growth and proaging pathway we discussed in chapter 5. This would also be desirable, one might think, at least for some tissues. At the same time, lack of nutrients accelerates autophagy, the cellular “recycling” process that helps our cells become more resilient, and it activates FOXO, the cellular repair genes that may help centenarians live so long. In short, fasting triggers many of the physiological and cellular mechanisms that we want to see.

But it should be used carefully, so as not to negatively impact lean muscle mass.

I have become convinced that frequent, prolonged fasting may be neither necessary nor wise for most patients. The cost, in terms of lost lean mass (muscle) and reduced activity levels, simply does not justify whatever benefits it may bring. My rule of thumb for any eating pattern, in fact, is that you must eat enough to maintain lean mass (muscle) and longterm activity patterns. That is part of what makes any diet sustainable. If we are going to use a powerful tool like fasting, we must do so carefully and deliberately.

Bullish on exercise, bearish on nutrition.

I used to think that diet and nutrition were the one path to perfect health. Years of experience, with myself and my patients, have led me to temper my expectations a bit. Nutritional interventions can be powerful tools with which to restore someone’s metabolic equilibrium and reduce risk of chronic disease. But can they extend and improve lifespan and healthspan, almost magically, the way exercise does? I’m no longer convinced that they can.

Limitations of nutrition:

I once believed that diet and nutrition could cure almost all ills, but I no longer feel that strongly about it. Nutritional biochemistry is an important component of our tactics, but it is not the only path to longevity, or even the most powerful one. I see it more as a rescue tactic, particularly for patients like Eduardo and Tom, with really severe metabolic problems such as NAFLD and type 2 diabetes. It is also essential for older people who need to build or maintain muscle mass. But its power to leverage increased lifespan and healthspan is more limited. Bad nutrition can hurt us more than good nutrition can help us. If you’re already metabolically healthy, nutritional interventions can only do so much.

Wearing a cast on a broken bone will allow it to heal. Wearing a cast on a perfectly normal arm will cause it to atrophy. While this example is obvious, it’s amazing how many people fail to translate it to nutrition. It seems quite clear that a nutritional intervention aimed at correcting a serious problem (e.g., highly restricted diets, even fasting, to treat obesity, NAFLD, and type 2 diabetes) might be different from a nutritional plan calibrated to maintain good health (e.g., balanced diets in metabolically healthy people).

In the end, the best nutrition plan is the one that we can sustain. How you manipulate the three levers of diet—calorie restriction, dietary restriction, and time restriction—is up to you. Ideally, your plan improves or maintains all the parameters we care about—not only blood glucose and insulin but also muscle mass and lipid levels, and possibly even weight—while reducing your risk of your most proximate Horseman or Horsemen.

The impact of chronic sleep deprivation on metacolic health:

We now know that chronic sleep debt is a far more insidious killer than the acute sleep deprivation that results in falling asleep at stop signs. Many studies have found powerful associations between insufficient sleep (less than seven hours a night, on average) and adverse health outcomes ranging from increased susceptibility to the common cold to dying of a heart attack. Poor sleep dramatically increases one’s propensity for metabolic dysfunction, up to and including type 2 diabetes, and it can wreak havoc with the body’s hormonal balance.

This may come as a surprise to you, as it did to me, but poor sleep wreaks havoc on our metabolism. Even in the short term, sleep deprivation can cause profound insulin resistance. Sleep researcher Eve van Cauter of the University of Chicago subjected healthy young people to severely restricted sleep, just 4.5 hours a night, and found that after four days they had the elevated insulin levels of obese middle-aged diabetics and, worse yet, approximately a 50 percent reduction in their capacity for glucose disposal. This turns out to be one of the most consistent findings in all of sleep research. No fewer than nine different studies have found that sleep deprivation increases insulin resistance by up to a third. Very rarely in medicine do we see such consistent findings, with experimental evidence confirming the epidemiology so powerfully, so it’s worth paying attention.

This association between sleep and metabolic health seems puzzling at first, but I think the missing link here is stress. Higher stress levels can make us sleep poorly, as we all know, but poor sleep also makes us more stressed. It’s a feedback loop. Both poor sleep and high stress activate the sympathetic nervous system, which—despite its name—is the opposite of calming. It is part of our fight-or-flight response, prompting the release of hormones called glucocorticoids, including the stress hormone cortisol. Cortisol raises blood pressure; it also causes glucose to be released from the liver, while inhibiting the uptake and utilization of glucose in the muscle and fat tissues, perhaps in order to prioritize glucose delivery to the brain.

How much sleep is enough: 7.5 - 8.5 hours per night.

How long do we need to sleep? This question is tricky, because our sleep cycles are powerfully influenced by external cues such as sunlight, noise, and artificial lighting, not to mention our own emotions and stresses. Also, we are quite good at adapting to inadequate sleep, at least for a while. But many, many studies have confirmed what your mother told you: We need to sleep about seven and a half to eight and a half hours a night. There is even some evidence, from studies conducted in dark caves, that our eight-ish-hour sleep cycle may be hardwired to some extent, suggesting that this requirement is non-negotiable. Getting significantly less sleep than this, or significantly more, will almost inevitably cause problems in the long run.

Why is sleep so important? It affects brain/ cognitive health, the first of the three pillars of healthspan.

What is really striking about most of what we’ve discussed so far in this chapter—the crucial role that sleep plays in metabolic health and cardiovascular health—is how much of this effect is mediated through the brain. Sleep plays a major role in brain health, especially as we get older, not only in terms of daily cognitive function but also in terms of our long-term cognitive health, a crucial pillar of healthspan.

One easy way to improve sleep quality: reduce alcohol consumption.

The first thing I tell my patients who are having difficulty sleeping is to cut back on alcohol— or better yet, give it up entirely. It’s counterintuitive, because alcohol initially acts as a sedative, so it can help us fall asleep more quickly. But as the night wears on, alcohol turns from friend of sleep to foe, as it is metabolized into chemicals that impair our ability to sleep.

Other drawbacks of alcohol consumption:

The effects of alcohol on memory and cognition are apparent even in moderate drinkers. Studies have found that young people who drink heavily are more likely to forget even basic tasks like locking the door or mailing a letter. Students who averaged nine drinks per week (not much, by collegiate standards) performed worse on a word-based memory test. And, in a finding that will surprise no one, students who drank more slept later and felt sleepier in the daytime, as well as performing worse on tests. More alarming is the finding that students who drank heavily two days after a bout of learning or study forgot or failed to retain most of what they had learned.

Improve sleep by cultivating “sleep pressure”:

This concept of sleep pressure, our need or desire for sleep, is key to many of our sleep tactics. We want to cultivate sleep pressure, but in the right amounts, at the right times—not too much, not too little, and not too soon. This is why one of the primary techniques that doctors use to treat patients with insomnia is actually sleep restriction, limiting the hours when they are “allowed” to sleep to six, or less. This basically makes them tired enough that they fall asleep more easily at the end of the day, and (hopefully) their normal sleep cycle is restored. Their sleep pressure builds up to the point where it overwhelms whatever is causing their insomnia. But this also helps explain why napping can be counterproductive. Taking a nap during the day, while sometimes tempting, can also relieve too much of that sleep pressure, making it harder to fall back asleep at night.

Exercise, particularly Zone 2 training, increases sleep pressure:

Another way to help cultivate sleep pressure is via exercise, particularly sustained endurance exercise (e.g., zone 2), ideally not within two or three hours of bedtime. My patients often find that a thirty-minute zone 2 session can do wonders for their ability to fall asleep.

His best advice/ tactics for improving sleep:

Don’t drink any alcohol, period—and if you absolutely, positively must, limit yourself to one drink before about 6 p.m. Alcohol probably impairs sleep quality more than any other factor we can control. Don’t confuse the drowsiness it produces with quality sleep. Don’t eat anything less than three hours before bedtime—and ideally longer. It’s best to go to bed with just a little bit of hunger (although being ravenous can be distracting.) Abstain from stimulating electronics, beginning two hours before bed. Try to avoid anything involving a screen if you’re having trouble falling asleep. If you must, use a setting that reduces the blue light from your screen. For at least one hour before bed, if not more, avoid doing anything that is anxiety-producing or stimulating, such as reading work email or, God help you, checking social media. These get the ruminative, worry-prone areas of our brain humming, which is not what you want. For folks who have access, spend time in a sauna or hot tub prior to bed. Once you get into the cool bed, your lowering body temperature will signal to your brain that it’s time to sleep. (A hot bath or shower works too.) The room should be cool, ideally in the midsixties. The bed should be cool too. Use a “cool” mattress or one of the many bed-cooling devices out there. These are also great tools for couples who prefer different temperatures at night, since both sides of the mattress can be controlled individually. Darken the room completely. Make it dark enough that you can’t see your hand in front of your face with your eyes open, if possible. If that is not achievable, use an eye shade. I use a silky one called Alaska Bear that costs about $8 and works better than the fancier versions I’ve tried.

Fix your wake-up time—and don’t deviate from it, even on weekends. If you need flexibility, you can vary your bedtime, but make it a priority to budget for at least eight hours in bed each night.

If you find yourself lying awake in bed, unable to get back to sleep, my advice is to stop fighting it. Get up, go into another room and do something relaxing. Fix a cup of tea (noncaffeinated, obviously), and read a (preferably boring) book until you feel sleepy again. The key, says Vikas Jain, is to find something that is relaxing and enjoyable but that serves no function; you never want to give your insomnia a purpose, such as doing work or paying bills, because if you do, your brain will make sure to wake you up for it on a regular basis. Keep in mind, too, that you might not actually have insomnia; you might simply be a night-owl chronotype, thinking you “should” go to bed much earlier than your brain or your body is ready for. So adjust your bedtime and waking time, if possible.

Mental health issues lead to health issues, which lead to longevity issues:

Middleaged white men and women, in particular, are succumbing to drug and alcohol overdoses, liver disease, and suicide at unprecedented rates, as Anne Case and Angus Deaton first observed in 2015. The substance-abuse crisis has created a longevity crisis, because it is really a mental health crisis in disguise.

It took me a while to recognize this, but feeling connected and having healthy relationships with others, and with oneself, is as imperative as maintaining efficient glucose metabolism or an optimal lipoprotein profile. It is just as important to get your emotional house in order as it is to have a colonoscopy or an Lp(a) test, if not more so. It’s just a lot more complicated.

Mental health encompasses disease-like states such as clinical depression and schizophrenia, which are complex and difficult to treat but do present with recognizable symptoms. Here, we are more interested in emotional health, which incorporates mental health but is also much broader—and less easy to codify and categorize. Emotional health has more to do with the way we regulate our emotions and manage our interpersonal relationships. I did not have a mental illness, per se, but I did have serious issues with my emotional health that impaired my ability to live a happy, well-adjusted life—and potentially did put my life in danger. Medicine 2.0 has a harder time dealing with situations such as this.

4 branches of the trauma tree:

The most important thing about childhood trauma is not the event itself but the way the child adapts to it. Children are remarkably resilient, and wounded children become adaptive children. The problems begin when these adaptive children grow up to become maladaptive, dysfunctional adults. This dysfunction is represented by the four branches of the trauma tree: (1) addiction, not only to vices such as drugs, alcohol, and gambling, but also to socially acceptable things such as work, exercise, and perfectionism (check); (2) codependency, or excessive psychological reliance on another person; (3) habituated survival strategies, such as a propensity to anger and rage (check); (4) attachment disorders, difficulty forming and maintaining connections or meaningful relationships with others (check). These branches are often fairly obvious and easy to spot; the tricky part is digging down to the roots and beginning to disentangle them. All of this is highly individual; everyone responds and adapts to trauma in a unique way. And it’s not as if there is some sort of pill that can make someone’s trauma, or their adaptations to it, simply go away. It requires hard work—and, as I would come to understand, it can also take a very long time.

Dialectical behavior therapy (DBT) and how it works:

One thing I like about DBT is that it is backed up by evidence: clinical trials have found it to be effective in helping suicidal and self-harming patients stop their dangerous behavior. Another thing that draws me to DBT is that it is skills-based, not just theoretical. Practicing DBT means literally working through a workbook with a DBT therapist, doing exercises every day. I’m better at doing than thinking sometimes. The practice of DBT is predicated on learning to execute concrete skills, repetitively, under stress, that aim to break the chain reaction of negative stimulus → negative emotion → negative thought → negative action. DBT consists of four pillars joined by one overarching theme. The overarching theme is mindfulness, which gives you the ability to work through the other four: emotional regulation (getting control over our emotions), distress tolerance (our ability to handle emotional stressors), interpersonal effectiveness (how well we make our needs and feelings known to others), and selfmanagement (taking care of ourselves, beginning with basic tasks like getting up in time to go to work or school).

Simply put, I experience less pain because I am able to recognize when the source of that pain is inside my own head. This was not an original insight, but it was nevertheless profound. I was about 2,500 years behind the Buddha, who said that “your worst enemy cannot harm you as much as your own unguarded thoughts.” Seneca improved on that in the first century AD, observing that “we suffer more often in imagination than in reality.” And later, in the sixteenth century, Shakespeare’s Hamlet noted, “There is nothing either good or bad, but thinking makes it so.”

DBT teaches a variety of techniques to enable people to maintain and improve their distress tolerance, and to recognize and cope with their emotions —and not be controlled by them, as I had been for so long. One simple tactic that I use to cope with mounting emotional distress is inducing an abrupt sensory change—typically, by throwing ice water on my face or, if I’m really struggling, taking a cold shower or stepping into an ice bath. This simple intervention stimulates an important cranial nerve, the vagus nerve, which causes our heart rate and respiratory rate to slow and switches us into a calm, parasympathetic mode (and out of our fight-or-flight sympathetic mode). Interventions like these are often enough to help refocus and think about a situation more calmly and constructively. Another technique I have grown very fond of is slow, deep breathing: four seconds to inhale, six seconds to exhale. Repeat. As the breath goes, the nervous system follows.