COLD ACTIVATES LONGEVITY GENES. Sirtuins are switched on by cold, which in turn activates protective brown fat in our back and shoulders. Image: The author enduring “cold therapy” at the Massachusetts Institute of Technology in 1999.
EVERY DAY I WAKE UP to an inbox full of messages from people from all over the world. The tide ebbs and flows but always takes the form of a flash flood in the wake of newly announced research from my team or others.
“What should I be taking?” they ask.
“Can you tell me what I need to do to get admitted into one of the human trials?” they implore.
“Can you extend the lifespan of my daughter’s hamster?” I kid you not.
Some of the letters are much sadder than others. One man recently wrote to offer to contribute a donation to my lab in honor of his mother, who had passed away after suffering terribly through many years of age-related illness. “I feel compelled to help, even in some small way, to prevent this from happening to someone else,” he wrote. The next day, a woman whose father had been diagnosed with Alzheimer’s wrote to ask if there were any way to get him admitted into a study. “I would do anything, take him anywhere, spend every last cent I have,” she pleaded. “He is the only family I have and I cannot bear the thought of what is about to happen to him.”
There is great reason for hope on the not-so-distant horizon, but those battling against the ravages of aging right now must do so in a world in which most doctors have never even thought about why we age, let alone how to treat aging.
Some of the medical therapies and life-extending technologies discussed in this book are already here. Others are a few years away. And there are more to discuss that are a decade or so down the road; we’ll get to those as well.
But even without access to this developing technology, no matter who you are, where you live, how old you are, and how much you earn, you can engage your longevity genes, starting right now.
That’s what people have been doing for centuries—without even knowing it—in centenarian-heavy places such as Okinawa, Japan; Nicoya, Costa Rica; and Sardinia, Italy. These are, you might recognize, some of the places the writer Dan Buettner introduced to the world as so-called Blue Zones starting in the mid-2000s. Since that time, the primary focus for those seeking to apply lessons from these and other longevity hot spots has been on what Blue Zone residents eat. Ultimately this resulted in the distillation of “longevity diets” that are based on the commonalities in the foods eaten in places where there are lots of centenarians. And overwhelmingly that advice comes down to eating more vegetables, legumes, and whole grains, while consuming less meat, dairy products, and sugar.
And that’s not a bad place to start—in fact, it’s a great place to start. There is widespread disagreement, even among the best nutritionists in the world, as to what constitutes the “best” diet for H. sapiens. That’s likely because there is no best diet; we’re all different enough that our diets need to be subtly and sometimes substantially different, too. But we’re also all similar enough that there are some very broad commonalities: more veggies and less meat; fresh food versus processed food. We all know this stuff, though applying it can be a challenge.
A big part of the reason so many people aren’t willing to face up to that challenge is because we’ve always thought of aging as an inevitable part of life. It might come a little earlier for some and a little later for others, but we’ve always been told that it’s coming for us all.
That’s what we used to say about pneumonia, influenza, tuberculosis, and gastrointestinal conditions, too. In 1900, those four illnesses accounted for about half of the deaths in the United States and—if you managed to live long enough—you could be virtually assured that one of them would get you eventually.
Today, deaths among people suffering from tuberculosis and gastrointestinal conditions are exceedingly rare. And pneumonia and influenza claim less than 10 percent of the lives taken by those conditions a little more than a century ago—with most of those deaths now among individuals weakened by aging.
What changed? In no small part it was framing. Advances in medicine, innovations in technology, and better information to guide our lifestyle decisions resulted in a world in which we didn’t have to accept the idea that these diseases were “just the way it goes.”
We don’t have to accept aging like that, either.
But even among those who will have the most immediate access to pharmaceuticals and technologies that will be emerging to offer longer and healthier lives in the next few decades, reaching an optimal lifespan and healthspan won’t be as easy as flipping a switch.
There will always be good and bad choices. And that starts with what we put into our bodies.
And what we don’t.
After twenty-five years of researching aging and having read thousands of scientific papers, if there is one piece of advice I can offer, one surefire way to stay healthy longer, one thing you can do to maximize your lifespan right now, it’s this: eat less.
This is nothing revolutionary, of course. As far back as Hippocrates, the ancient Greek physician, doctors have been espousing the benefits of limiting what we eat, not just by rejecting the deadly sin of gluttony, as the Christian monk Evagrius Ponticus counseled in the fourth century, but through “intentional asceticism.”
Not malnutrition. Not starvation. These are not pathways to more years, let alone better years. But fasting—allowing our bodies to exist in a state of want, more often than most of us allow in our privileged world of plenty—is unquestionably good for our health and longevity.
Hippocrates knew this. Ponticus knew this. So, too, did Luigi Cornaro, a fifteenth-century Venetian nobleman who could, and probably should, be considered the father of the self-help book.
The son of an innkeeper, Cornaro made a fortune as an entrepreneur and lavishly spent his money on wine and women. By his mid-30s, he was exhausted by food, drink, and sex—the poor guy—and resolved to limit himself in each regard. The historical record is a bit vague on the details of his sex life after that fateful decision,1 but his diet and drinking habits have been well documented: he ate no more than twelve ounces of food and drank two glasses of wine each day.
“I accustomed myself to the habit of never fully satisfying my appetite, either with eating or drinking,” Cornaro wrote in his First Discourse on the Temperate Life, “always leaving the table well able to take more.”2
Cornaro’s discourses on the benefits of la vita sobria might have fallen into obscurity had he not provided such compelling personal proof that his advice had merit: he published his guidance when he was in his 80s, and in exceptional health, no less, and he died in 1566 at nearly (and some sources say more than) 100 years old.
In more recent times, Professor Alexandre Guéniot, the president of the Paris Medical Academy just after the turn of the twentieth century, was famed for living on a restricted diet. It is said that his contemporaries mocked him—for there was no science at that time to back his suspicion that hunger would lead to good health, just his gut hunch—but he outlived them, one and all. He finally succumbed at the age of 102.
The first modern scientific explorations of the lifelong effects of a severely restricted diet began during the last days of World War I. That’s when the longtime biochemical collaborators Lafayette Mendel and Thomas Osborne—the duo who had discovered vitamin A—discovered, along with researcher Edna Ferry, that female rats whose growth was stunted due to lack of food early in life lived much longer than those that ate plenty.3
Picking up on that evidence in 1935, a now-famous Cornell University professor named Clive McCay demonstrated that rats fed a diet containing 20 percent indigestible cellulose—cardboard, essentially—lived significantly longer lives than those that were fed a typical lab diet. Studies conducted over the next eighty years demonstrated again and again that calorie restriction without malnutrition, or CR, leads to longevity for all sorts of life-forms. Hundreds of mouse studies have been done since to test the effects of calories on health and lifespan, mostly on male mice.
Reducing calories works even in yeast. I first noticed this in the late 1990s. Cells fed with lower doses of glucose were living longer, and their DNA was exceptionally compact—significantly delaying the inevitable ERC accumulation, nucleolar explosion, and sterility.
If this happened only in yeast, it would merely be interesting. But because we knew that rodents also lived longer when their food was restricted—and later learned that this was the case for fruit flies, as well4—it was apparent that this genetic program was very old, perhaps nearly as old as life itself.
In animal studies, the key to engaging the sirtuin program appears to be keeping things on the razor’s edge through calorie restriction—just enough food to function in healthy ways and no more. This makes sense. It engages the survival circuit, telling longevity genes to do what they have been doing since primordial times: boost cellular defenses, keep organisms alive during times of adversity, ward off disease and deterioration, minimize epigenetic change, and slow down aging.
But this has, for obvious reasons, proven a challenge to test on humans in a controlled scientific setting. Sadly, it’s not hard to find instances in which humans have had to go without food, but those periods are generally times in which food insecurity results in malnutrition, and it would be a challenge to keep a test group of humans on the razor’s edge for the long periods of time that would be required for comprehensive controlled studies.
As far back as the 1970s, though, there have been observational studies that strongly suggested long-term calorie restriction could help humans live longer and healthier lives, too.
In 1978 on the island of Okinawa, famed for its large number of centenarians, bioenergetics researcher Yasuo Kagawa learned that the total number of calories consumed by schoolchildren was less than two-thirds of what children were getting in mainland Japan. Adult Okinawans were also leaner, taking in about 20 percent fewer calories than their mainland counterparts. Kagawa noted that not only were the lifespans of Okinawans longer, but their healthspans were, too—with significantly less cerebral vascular disease, malignancy, and heart disease.5
In the early 1990s, the Biosphere 2 research experiment provided another piece of evidence. For two years, from 1991 to 1993, eight people lived inside a three-acre, closed ecological dome in southern Arizona, where they were expected to be reliant on the food they were growing inside. Green thumbs they weren’t, though, and the food they farmed turned out to be insufficient to keep the participants on a typical diet. The lack of food wasn’t bad enough to result in malnutrition, but it did mean that the team members were frequently hungry.
One of the prisoners (and by “prisoners” I mean “experimental subjects”) happened to be Roy Walford, a researcher from California whose studies on extending life in mice are still required reading for scientists entering the aging field. I have no reason to suspect that Walford sabotaged the crops, but the coincidence was rather fortuitous for his research; it gave him an opportunity to test his mouse-based findings on human subjects. Because they were thoroughly medically monitored before, during, and after their two-year stint inside the dome, the participants gave Walford and other researchers a unique opportunity to observe the numerous biological effects of calorie restriction. Tellingly, the biochemical changes they saw in their bodies closely mirrored those Walford had seen in his long-lived calorie-restricted mice, such as decreased body mass (15 to 20 percent), blood pressure (25 percent), blood sugar level (21 percent), and cholesterol levels (30 percent), among others.6
In recent years, formal human studies have begun, but it has turned out to be quite difficult to get volunteer human subjects to reduce their food intake and maintain that level of consumption over long periods. As my colleagues Leonie Heilbronn and Eric Ravussin wrote in The American Journal of Clinical Nutrition in 2003, “the absence of adequate information on the effects of good-quality, calorie-restricted diets in nonobese humans reflects the difficulties involved in conducting long-term studies in an environment so conducive to overfeeding. Such studies in free-living persons also raise ethical and methodologic issues.”7 In a report published in The Journals of Gerontology in 2017, a Duke University research team described how it sought to limit 145 adults to a diet of 25 percent fewer calories than is typically recommended for a healthy lifestyle. People being people, the actual calorie restriction achieved was, on average, about 12 percent over two years. Even that was enough, however, for the scientists to see a significant improvement in health and a slowdown in biological aging based on changes in blood biomarkers.8
These days, there are many people who have embraced a lifestyle that permits significantly reduced caloric intake; about a decade ago, before fasting’s most recent revival, some of them visited my lab at Harvard.
“Isn’t it hard to do what you do?” I asked Meredith Averill and her husband, Paul McGlothin, at the time members of CR Society International and still very much advocates for calorie restriction, who limit themselves to about 75 percent of the calories typically recommended by doctors and sometimes quite a bit less than that. “Don’t you just feel hungry all the time?”
“Sure, at first,” McGlothin told me. “But you get used to it. We feel great!”
At lunch that day, McGlothin expounded upon the merits of eating organic baby food and slurped down something that looked to me like orange mush. I also noticed that both he and Averill were wearing turtlenecks. It wasn’t winter. And most folks in my lab are perfectly comfortable in T-shirts. But with so little fat on their bodies, they needed the extra warmth. Then in his late 60s, McGlothin showed no signs that his diet might slow him down. He was the CEO of a successful marketing company and a former New York State chess champion. He didn’t look much younger than his age, though; in large part, I suspect this was because a lack of fat exposes wrinkles, but his blood biochemistry suggested otherwise. On his 70th birthday, his health indicators, from blood pressure and LDL cholesterol to resting heart rate and visual acuity, were typical of those of a much younger person.9 Indeed, they resembled those seen in the long-lived rats on calorie restriction.
It’s true that what we know about the impact of lifelong calorie restriction in humans comes down to short-term studies and anecdotal experiences. But one of our close relatives has offered us insights into the longitudinal benefits of this lifestyle.
Since the 1980s, a long-term study of calorie restriction in rhesus monkeys—our close genetic cousins—has produced stunningly compelling results. Before the study, the maximum known lifespan for any rhesus monkey was 40 years. But of twenty monkeys in the study that lived on calorie-restricted diets, six reached that age, which is roughly equivalent to their reaching 120 in human terms.
To hit that mark, the monkeys didn’t need to live on a calorie-restricted diet for their entire lives. Some of the test subjects were started on a 30 percent reduction regimen when they were middle-aged monkeys.10
CR works to extend the lifespan of mice, even when initiated at 19 months of age, the equivalent of a 60- to 65-year-old human, but the earlier the mice start on CR, the greater the lifespan extension.11 What these and other animal studies tell us is that it’s hard to “age out” of the longevity benefits of calorie restriction, but it’s probably better to start earlier than later, perhaps after age 40, when things really start to go downhill, molecularly speaking.
That doesn’t make a CR diet a good plan for everyone. Indeed, even Rozalyn Anderson, a former trainee of mine who’s now a famous professor at the University of Wisconsin and a lead researcher in the rhesus study, says a 30 percent calorie-reduced diet for humans, long term, amounted in her mind to a “bonkers diet.”12
It’s certainly not bonkers for everyone, though, especially considering that calorie restriction hasn’t been demonstrated only to lengthen life but also to forestall cardiac disease, diabetes, stroke, and cancer. It’s not just a longevity plan; it’s a vitality plan.
It’s nonetheless a hard sell for many people. It takes strong willpower to avoid the fridge at home or snacks at work. There’s an adage in my field: if calorie restriction doesn’t make you live longer, it will certainly make you feel that way.
But it turns out that’s okay, because research is increasingly demonstrating that many of the benefits of a life of strict and uncompromising calorie restriction can be obtained in another way. In fact, that way might be even better.
To ensure a genetic response to a lack of food, hunger doesn’t need to be the status quo. Once we’ve grown accustomed to stress, after all, it’s no longer as stressful.
Intermittent fasting, or IF—eating normal portions of food but with periodic episodes without meals—is often portrayed as a new innovation in health. But long before my friend Valter Longo at the University of California, Los Angeles, began touting the benefits of IF, scientists had been studying the effects of periodic calorie restriction for the better part of a century.
In 1946, University of Chicago researchers Anton Carlson and Frederick Hoelzel subjected rats to periodic food restriction and found, when they did, that those that went hungry every third day lived 15 to 20 percent longer than their cousins on a regular diet.13
At the time it was believed that fasting provided the body with a “rest.”14 That’s very much the opposite of what we now know about what happens at a cellular level when we subject our bodies to the stress of going without food. Either way, Carlson and Hoelzel’s work provided valuable information on the long-term results of irregular calorie restriction.
It’s not clear whether the pair applied what they’d learned to their own lives, but both lived relatively long lives for their time. Carlson died at the age of 81. Hoelzel made it to 74, despite having subjected himself over the years to experiments that included swallowing gravel, glass beads, and ball bearings to study how long it would take for such objects to pass through his system. And people say I’m crazy.
Today, human studies are confirming that once-in-a-while calorie restriction can have tremendous health results, even if the times of fasting are quite transient.
In one such study, participants ate a normal diet most of the time but turned to a significantly restricted diet consisting primarily of vegetable soup, energy bars, and supplements for five days each month. Over the course of just three months, those who maintained the “fasting mimicking” diet lost weight, reduced their body fat, and lowered their blood pressure, too. Perhaps most important, though, the participants had lower levels of a hormone made primarily in the liver called insulin-like growth factor 1, or IGF-1. Mutations in IGF-1 and the IGF-1 receptor gene are associated with lower rates of death and disease and found in abundance in females whose families tend to live past 100.15
Levels of IGF-1 have been closely linked to longevity. The impact is so strong, in fact, that in some cases it can be used to predict—with great accuracy—how long someone will live, according to Nir Barzilai and Yousin Suh, who research aging at the Albert Einstein College of Medicine at Yeshiva University in New York.
Barzilai and Suh are geneticists whose research focuses on centenarians who have made it to 100—and beyond—without suffering from any age-related diseases. That unique population is a vital study group, because its members provide a model for aging the way most people say they want to age—not accepting that additional years of life need to come with additional years of misery.
When we find clusters of these people, we see that in some cases it doesn’t actually matter what they put into their bodies. They carry gene variants that seem to put them into a state of fasting no matter what they eat. As anyone who has ever known a centenarian can attest, it doesn’t take a lifetime of making 100 percent healthy decisions to reach 100. When Barzilai’s team studied nearly 500 Ashkenazi Jews over the age of 95, they saw that many engaged in the same sorts of behaviors doctors have long been telling us to shun: eating fried foods, smoking, and just sitting around and drinking a little too much. Barzilai once asked one of his centenarian study subjects why she hadn’t listened to her doctors over the years when they had strongly advised her to end her lifelong smoking habit. “I’ve had four doctors tell me smoking would kill me,” she said with a wry smile, “and well, all four are dead now, aren’t they?”
Some people are simply winners in the genetic lottery. The rest of us have some extra work to do. But the good news is that the epigenome is malleable. Since it’s not digital, it’s easier to impact. We can control the behavior of this analog element of our biology by how we live our lives.
The important thing is not just what we eat but the way we eat. As it turns out, there is a strong correlation between fasting behavior and longevity in Blue Zones such as Ikaria, Greece, “the island where people forget to die,” where one-third of the population lives past the age of 90 and almost every older resident is a staunch disciple of the Greek Orthodox church and adheres to a religious calendar that calls for some manner of fasting more than half the year.16 On many days, that means no meat, dairy products, or eggs and sometimes no wine or olive oil, either—for some Greeks, that’s just about everything. Additionally, many Greeks observe periods of total fasting before taking Holy Communion.17
Other longevity hot spots, such as Bama County in southern China, are places where people have access to good, healthy food but choose to forgo it for long periods each day.18 Many of the centenarians in this region have spent their lives eschewing a morning meal. They generally eat their first small meal of the day around noon, then share a larger meal with their families at twilight. In this way, they typically spend sixteen hours or more of each day without eating.
When we investigate places like this, and as we seek to apply research about fasting to our modern lives, we find that there are scores of ways to calorie restrict that are sustainable, and many take the form of what has come to be known as periodic fasting—not being hungry all the time but using hunger some of the time to engage our survival circuit.
Over time, some of these ways of limiting food will prove to be more effective than others. A popular method is to skip breakfast and have a late lunch (the 16:8 diet). Another is to eat 75 percent fewer calories for two days a week (the 5:2 diet). If you’re a bit more adventurous, you can try skipping food a couple of days a week (Eat Stop Eat), or as the health pundit Peter Attia does, go hungry for an entire week every quarter. The permutations of these various models for extending life and health are being worked out in animals and will be worked out in people, too. The short-term studies are promising. I suspect the long-term research will be, too. In the meantime, however, almost any periodic fasting diet that does not result in malnutrition is likely to put your longevity genes to work in ways that will result in a longer, healthier life.
It doesn’t take any money to eat this way. In fact, it saves money. Moreover, people who are not accustomed to being able to gorge themselves whenever they want might be in a better position to be successful at going a few days each month with a lot less food.
At least at this juncture in the evolution of our customs around food, though, for many people any form of fasting is a nonstarter.
I’ve tried calorie restriction. I can’t do it. Feeling hungry isn’t fun, and food is just too pleasurable. Lately, I have taken to periodic fasting—skipping a meal or two each day—but I admit that it’s mostly unintentional. I simply forget to eat.
So far, though, we’ve talked only about engaging the survival circuit by limiting how much we eat, but what we eat is also important.
We’d die quite quickly without amino acids, the organic compounds that serve as the building blocks for every protein in the human body. Without them—and in particular the nine essential amino acids that our bodies cannot make on their own—our cells can’t assemble the life-giving enzymes needed for life.
Meat contains all nine of the essential amino acids. That’s easy energy, but it doesn’t come without a cost. Actually, a lot of costs. Because no matter how you feel about the morals of the matter, meat is murder—on our bodies. So can we just avoid protein? Ironically, protein is what satiates us. Same for mice. Same for swarming locusts in need of nutrients, which is why they eat each other.19 It would appear that animal life can’t easily limit protein in the diet without some hunger pains.
There isn’t much debate on the downsides of consumption of animal protein. Study after study has demonstrated that heavily animal-based diets are associated with high cardiovascular mortality and cancer risk. Processed red meats are especially bad. Hot dogs, sausage, ham, and bacon might be gloriously delicious, but they’re ingloriously carcinogenic, according to hundreds of studies that have demonstrated a link between these foods and colorectal, pancreatic, and prostate cancer.20 Red meat also contains carnitine, which gut bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is suspected of causing heart disease.
That doesn’t mean a little red meat will kill you—the diet of hunter-gatherers is a mix of plants packed with fiber and nutrients, mixed with some red meat and fish in moderation21—but if you’re interested in a long and healthy life, your diet probably needs to look a lot more like a rabbit’s lunch than a lion’s dinner. When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly.22
From an energy perspective, the good news is that there isn’t a single amino acid that can’t be obtained by consuming plant-based protein sources. The bad news is that, unlike most meats, weight for weight, any given plant usually delivers limited amounts of amino acids.
From a vitality perspective, though, that’s great news. Because a body that is in short supply of amino acids overall, or any single amino acid for a spell, is a body under the very sort of stress that engages our survival circuits.
You’ll recall that when the enzyme known as mTOR is inhibited, it forces cells to spend less energy dividing and more energy in the process of autophagy, which recycles damaged and misfolded proteins. That act of hunkering down ends up being good for prolonged vitality in every organism we’ve studied. What we’re coming to learn is that mTOR isn’t impacted only by caloric restriction.23 If you want to keep mTOR from being activated too much or too often, limiting your intake of amino acids is a good way to start, so inhibiting this particular longevity gene is really as simple as limiting your intake of meat and dairy.
It’s also increasingly clear that all essential amino acids aren’t equal. Rafael de Cabo at the National Institutes of Health, Richard Miller at the University of Michigan, and Jay Mitchell at Harvard Medical School have found over the years that feeding mice a diet with low levels of the amino acid methionine works particularly well to turn on their bodily defenses, to protect organs from hypoxia during surgery, and to increase healthy lifespan by 20 percent.24 One of my former students, Dudley Lamming, who now runs a lab at the University of Wisconsin, demonstrated that methionine restriction causes obese mice to shed most of their fat—and fast. Even as the mice, which Lamming called “couch potatoes,” continued to eat as much as they wanted and shun exercise, they still lost about 70 percent of their fat in a month, while also lowering their blood glucose levels.25
We can’t live without methionine. But we can do a better job of restricting the amount of it we put into our bodies. There’s a lot of methionine in beef, lamb, poultry, pork, and eggs, whereas plant proteins, in general, tend to contain low levels of that amino acid—enough to keep the light on, as it were, but not enough to let biological complacency set in.
The same is true for arginine and the three branched-chain amino acids, leucine, isoleucine, and valine, all of which can activate mTOR. Low levels of these amino acids correlate with increased lifespan26 and in human studies, a decreased consumption of branched-chain amino acids has been shown to improve markers of metabolic health significantly.27
We can’t live without them, but most of us can definitely stand to get less of them, and we can do that by lowering our consumption of foods that many people consider to be the “good animal proteins,” chicken, fish, and eggs—particularly when those foods aren’t being used to recover from physical stress or injury.
All of this might seem counterintuitive; amino acids, after all, are often considered helpful. And they can be. Leucine, for instance, is well known to boost muscle, which is why it’s found in large quantities in the protein drinks that bodybuilders often chug before, during, and after workouts. But that muscle building is coming in part because leucine is activating mTOR, which essentially calls out to your body, “Times are good right now, let’s disengage the survival circuit.”28 In the long run, however, protein drinks may be preventing the mTOR pathway from providing its longevity benefits. Studies in which leucine is completely eliminated from a mouse’s diet have demonstrated that just one week without this particular amino acid significantly reduces blood glucose levels, a key marker of improved health.29 So a little leucine is necessary, of course, but a little goes a long way.
All of these findings may explain why vegetarians suffer significantly lower rates of cardiovascular disease and cancer than meat eaters.30 The reduction of amino acids—and thus the inhibition of mTOR—isn’t the only thing at play in that equation. The lower calorie content, increased polyphenols, and feeling of superiority over your fellow human beings are also helpful. All of these, except the last, are valid explanations for why vegetarians live longer and stay healthier.
Even if we eat a low-protein, vegetable-rich diet, we may live longer, but we won’t maximize our lifespans—because putting our bodies into nutritional adversity isn’t going to maximally trigger our longevity genes. We need to induce some physical adversity, too. If that doesn’t happen, we miss a key opportunity to trigger our survival circuits further. Like a beautiful sports car driven only a block and back on Sunday mornings, our longevity genes will go tragically underutilized.
With so much horsepower under the hood, we just have to fire up the engine and take it out for a spin.
There’s a reason why for centuries exercise has been the go-to prescription for vitality. But that reason isn’t what most people—or even many doctors—think.
In the nearly four hundred years since the English physician William Harvey discovered that blood flows around the body in an intricate network of tubes, doctors thought that exercise improves health by moving blood through the circulatory system faster, flushing out the buildup of plaque.
That’s not how it works.
Yes, exercise improves blood flow. Yes, it improves lung and heart health. Yes, it gives us bigger, stronger muscles. But more than any of that—and indeed, what is responsible for much of that—is a simple thing that happens at a much smaller scale: the cellular scale.
When researchers studied the telomeres in the blood cells of thousands of adults with all sorts of different exercise habits, they saw a striking correlation: those who exercised more had longer telomeres. And according to one study funded by the Centers for Disease Control and Prevention and published in 2017, individuals who exercise more—the equivalent of at least a half hour of jogging five days a week—have telomeres that appear to be nearly a decade younger than those who live a more sedentary life.31 But why would exercising delay the erosion of telomeres?
If you think about how our longevity genes work—employing those ancient survival circuits—this all makes sense. Limiting food intake and reducing the heavy load of amino acids in most diets aren’t the only ways to activate longevity genes that order our cells to shift into survival mode. Exercise, by definition, is the application of stress to our bodies. It raises NAD levels, which in turn activates the survival network, which turns up energy production and forces muscles to grow extra oxygen-carrying capillaries. The longevity regulators AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise, irrespective of caloric intake, building new blood vessels, improving heart and lung health, making people stronger, and, yes, extending telomeres. SIRT1 and SIRT6, for example, help extend telomeres, then package them up so they are protected from degradation. Because it’s not the absence of food or any particular nutrient that puts these genes into action; instead it is the hormesis program governed by the survival circuit, the mild kind of adversity that wakes up and mobilizes cellular defenses without causing too much havoc.
There’s really no way around this. We all need to be pushing ourselves, especially as we get older, yet only 10 percent of people over the age of 65 do.32 The good news is that we don’t have to exercise for hours on end. One recent study found that those who ran four to five miles a week—for most people, that’s an amount of exercise that can be done in less than 15 minutes per day—reduce their chance of death from a heart attack by 40 percent and all-cause mortality by 45 percent.33 That’s a massive effect.
In another study, researchers reviewed the medical records of more than 55,000 people and cross-referenced those documents with death certificates issued over fifteen years.34 Among 3,500 deaths, they weren’t particularly surprised to see that those who had told their doctors they were runners were far less likely to die of heart disease. Even when the researchers adjusted for obesity and smoking, the runners were less likely to have died during the years of the study. The big shock was that the health benefits were remarkably similar no matter how much running the people had done. Even about ten minutes of moderate exercise a day added years to their lives.35
There is a difference between a leisurely walk and a brisk run, however. To engage our longevity genes fully, intensity does matter. Mayo Clinic researchers studying the effects of different types of exercise on different age groups found that although many forms of exercise have positive health effects, it’s high-intensity interval training (HIIT)—the sort that significantly raises your heart and respiration rates—that engages the greatest number of health-promoting genes, and more of them in older exercisers.36
You’ll know you are doing vigorous activity when it feels challenging. Your breathing should be deep and rapid at 70 to 85 percent of your maximum heart rate. You should sweat and be unable to say more than a few words without pausing for breath. This is the hypoxic response, and it’s great for inducing just enough stress to activate your body’s defenses against aging without doing permanent harm.37
We’re still working to understand what all of the longevity genes do, but one thing is already clear: many of the longevity genes that are turned on by exercise are responsible for the health benefits of exercise, such as extending telomeres, growing new microvessels that deliver oxygen to cells, and boosting the activity of mitochondria, which burn oxygen to make chemical energy. We’ve known for a long time that these bodily activities fall as we age. What we also know now is that the genes most impacted by exercise-induced stress can bring them back to the levels associated with youth. In other words: exercise turns on the genes to make us young again at a cellular level.
Often I’m asked, “Can I just eat what I want and run off the extra calories?” My answer is “Unlikely.” When you give rats a high-calorie diet and allow them to burn off the energy, lifespan extension is minimal. Same for a CR diet. If you make food filling but not as calorific, some of the health benefits are lost. Being hungry is necessary for CR to work because hunger helps turn on genes in the brain that release longevity hormones, at least according to a recent study by Dongsheng Cai at the Albert Einstein College of Medicine.38
Would a combination of fasting and exercise lengthen your lifespan? Absolutely. If you manage to do both these things: congratulations, you are well on your way.
But there is plenty more you can do.
Before arriving in Boston in my early 20s, I’d spent my whole life in Australia. Culturally, everything worked out just fine. Within a week, I’d figured out which markets carried Vegemite, the black yeast spread that some might say requires some pretty significant epigenetic programming as a child to enjoy as an adult. It took a bit longer to track down the best places for meat pies, Violet Crumble, Tim Tams, and musk sticks, but eventually I figured out how to get all of those tastes of home, too. And it didn’t take long before I stopped caring that folks in the United States seem to have a hard time differentiating between Australian and British accents. (It’s not that hard; Aussie accents are sexier.)
The toughest part was the cold.
As a boy, I thought I knew what cold was. When the temperature at Observatory Hill, Sydney’s official weather station for more than a century, approached freezing (it hasn’t actually fallen below freezing in modern history), that was cold.
Boston was a whole different world. A really frigid one.
I invested in coats, sweaters, and long underwear and spent a lot of time indoors. Like a lot of postdoctoral fellows, I often worked through the night. I truly was committed to my work, but the truth is that part of the calculus for not going home, on many nights, was that I didn’t want to go outside.
These days I wish I’d taken a different approach. I wish I’d just told myself to tough it out. To take a walk in the bitter cold. To dip my toes into the Charles River in the middle of January. Because as it turns out, exposing your body to less-than-comfortable temperatures is another very effective way to turn on your longevity genes.
When the world takes us out of the thermoneutral zone—the small range of temperatures that don’t require our bodies to do any extra work to stay warm or cool off—all sorts of things happen. Our breathing patterns shift. The blood flow to and through our skin—the largest organ in our body—changes. Our heart rates speed up or slow down. These reactions aren’t happening just “because.” All of these reactions have genetic roots dating back to M. superstes’s fight for survival all those billions of years ago.
Homeostasis, the tendency for living things to seek a stable equilibrium, is a universal biological principle. Indeed, it is the guiding force of the survival circuit. And thus we see it everywhere we look—especially on the low end of the thermometer.
As scientists have increasingly turned their attention to the impacts of reduced food intake on the human body, it has quickly become clear that calorie restriction has the effect of reducing core body temperature. It wasn’t at first clear whether this contributed to prolonged vitality or was simply a by-product of all of the changes happening in the bodies of organisms exposed to this particular sort of stress.
Back in 2006, though, a team from the Scripps Research Institute genetically engineered some lab mice to live their lives a half degree cooler than normal—a feat they accomplished by playing a trick on the mice’s biological thermostat. The team inserted copies of the mouse UCP2 gene into the mice’s hypothalamus, which regulates the skin, sweat glands, and blood vessels. UCP2 short-circuited mitochondria in the hypothalamus so they produced less energy but more heat. That, in turn, caused the mice to cool down about half a degree Celsius. The result was a 20 percent longer life for female mice, the equivalent of about seven additional healthy human years, while male mice got an extension of 12 percent.39
COLD ACTIVATES LONGEVITY GENES. Sirtuins are switched on by cold, which in turn activates protective brown fat in our back and shoulders. Image: The author enduring “cold therapy” at the Massachusetts Institute of Technology in 1999.
The gene involved—which has a human analog—wasn’t just a piece of the complex machinery that tricked the hypothalamus into thinking the mice’s bodies were warmer than they were. It was also a gene that has been connected time and time again to longevity. Five years earlier, a joint team of researchers from Beth Israel Deaconess Medical Center and Harvard Medical School showed that mice age faster when their UCP2 gene is nullified.40 And in 2005, Stephen Helfand and his team, then at the University of Connecticut Health Center, had demonstrated that targeted upregulation of an analogous gene could extend the lifespans of fruit flies by 28 percent in females and 11 percent in males.41 Then, in 2017, the connection between the UCP2 gene and aging came full circle, thanks to researchers from Université Laval in Quebec: not only could UCP2 make mice “run cold,” the Canadian team demonstrated, but colder temperatures could change the way the gene operated, too—through its ability to rev up brown adipose tissue.42
Also known as “brown fat,” this mitochondria-rich substance was, until recently, thought to exist only in infants. Now we know that it is found in adults, too, although the amount of it decreases as we age. Over time, it becomes harder and harder to find; it mingles with white fat and is spread out even more unevenly across the body. It “hangs out” in different areas in different people, sometimes in the abdomen, sometimes across the upper back. That makes researching it in humans a bit of a challenge: it generally takes a PET scan—which requires the injection of radioactive glucose—to locate it. Rodent studies, however, have provided significant insights into the correlation between brown fat and longevity.
One study of genetically engineered Ames dwarf mice, for instance, demonstrated that the function of brown fat is enhanced in these remarkably long-lived animals.43 Other studies have shown that animals with abundant brown fat or subjected to shivering cold for three hours a day have much more of the mitochondrial, UCP-boosting sirtuin, SIRT3, and experience significantly reduced rates of diabetes, obesity, and Alzheimer’s disease.44
That is why we need to learn more about how to chemically substitute for brown adipose tissue thermogenesis.45 Chemicals called mitochondrial uncouplers can mimic the effects of UCP2, allowing protons to leak through mitochondrial membranes, like drilling holes in a dam at a hydroelectric plant. The result is not cold but heat as a by-product of the mitochondrial short circuit.
The sweet-smelling mitochondrial uncoupler called 2,4-dinitrophenol (DNP) was used for making explosives in the First World War, and it soon became apparent that employees exposed to the chemical were rapidly losing weight, with one employee even dying from overexposure.46 In 1933, doctors Windsor Cutting and Maurice Tainter, from the Stanford University School of Medicine, summarized a series of their papers showing that DNP markedly increases metabolic rate.47 That same year, despite Tainter and Cutting’s warnings about “certain potential dangers,” twenty companies started selling it in the United States, as did others in Great Britain, France, Sweden, Italy, and Australia.
It worked well—too well, in fact.
Just one year later, speaking before the American Public Health Association, Tainter said, “The interest in and enthusiasm for this product were so great that its wide-spread use has become a matter of some concern in public health. The total amount of the drug being used is astonishing.”
Moments later he dropped a bombshell: “during the past year, the Stanford Clinics have supplied . . . over 1,200,000 capsules of dinitrophenol of 0.1 gm. each.”48
Over 1 million capsules? From one university? In one year? That is astonishing. And that was in 1933, when California had an eighth of its present population. Three pounds of weight per person per week were reportedly being shed. The public was relieved—something finally worked. Obesity was going to be a thing of the past.
But the metabolic party didn’t last long. People began to die from overdoses, and other long-term side effects showed up. DNP was declared “extremely dangerous and not fit for human consumption” in the United States Federal Food, Drug, and Cosmetic Act of 1938. As a curious aside, the legislation was written by Senator Royal Copeland, a homeopathic physician who, only days before he died, entrenched protections for natural supplements that today fuel a largely unregulated industry with revenues of $122 billion.
The act rightly banned a dangerous substance but dashed hopes that obesity would be a thing of the past.49 Anecdotally, DNP continued to be prescribed to Russian soldiers during World War II to keep them warm,50 and today some unscrupulous people sell it on the internet. But they do so at their peril. In 2018, Bernard Rebelo was sentenced to seven years in prison for the death of a woman to whom he sold DNP. In the United States, there have been sixty-two documented deaths since 1918, though there were likely many more than that.51
One thing is clear: DNP is extremely dangerous. Eating less at each meal, moving more, and focusing on plant-based foods are much safer options.
Another thing you can try is activating the mitochondria in your brown fat by being a bit cold. The best way to do this might be the simplest—a brisk walk in a T-shirt on a winter day in a city such as Boston will do the trick. Exercising in the cold, in particular, appears to turbocharge the creation of brown adipose tissue.52 Leaving a window open overnight or not using a heavy blanket while you sleep could help, too.
This hasn’t gone unnoticed by the health and wellness industry. Being cold is hot right now. Cryotherapy—a few minutes in a box superchilled to −110°C or −166°F—is an increasingly popular method of inducing a helping of this sort of stress to our bodies, although the research is still a ways away from being conclusive as to how, why, and even whether it truly works.53 That didn’t stop me from accepting an invitation from Joe Rogan, the media mogul and comedian, to go with him to a cryotherapy spa. Three minutes standing in my underwear at Mars temperatures may have activated my brown fat and all the great health benefits that go with that. At the very least, it left me invigorated and grateful to be alive.
As with most things in life, it’s probably best to change your lifestyle when you are young, because making brown fat becomes harder as you get older. If you choose to expose yourself to the cold, moderation will be key. Similar to fasting, the greatest benefits are likely to come for those who get close to, but not beyond, the edge. Hypothermia is not good for our health. Neither is frostbite. But goose bumps, chattering teeth, and shivering arms aren’t dangerous conditions—they’re simply signs that you’re not in Sydney. And when we experience these conditions often enough, our longevity genes get the stress they need to order up some additional healthy fat.
What happens on the other side of the thermostat? The picture is a bit less clear, but we have some promising leads from our friend S. cerevisiae. We know from work in my lab that raising the temperature of yeast—from 30°C to 37°C, just below the limits of what those single-celled organisms can sustain—turns on the PNC1 gene and boosts their NAD production, so their Sir2 proteins can work that much harder. What’s fascinating is not so much that these temperature-stressed cells lived 30 percent longer but that the mechanism was the same as that evoked by calorie restriction.
Is heat good for human bodies, too? Possibly, but not exactly in the same way. Because we are warm-blooded animals, our enzymes haven’t evolved a tolerance for large changes in temperature. You can’t just raise your core body temperature and expect to live longer. But as my northern German wife, Sandra, likes to point out, there are a lot of benefits to exposing your skin and lungs to high temperatures, at least temporarily.
Continuing an ancient Roman tradition, many northern and eastern Europeans regularly partake in “sauna bathing” for relaxation and health reasons. The Finns are the most dedicated, with the majority of men reporting using a sauna once a week, year round. Sandra tells me it’s pronounced “ZOW-na” not “saw-nah,” and that no home should be without one. I’m sticking with saw-nah to avoid sounding like a snicklefritz, but when it comes to housing construction, Sandra may be on to something.
A 2018 study conducted in Helsinki found that “physical function, vitality, social functioning, and general health were significantly better among sauna users than non-users,” although the researchers were correct to point out that part of the effect could be due to the fact that those who are sick or disabled don’t go to the sauna.54
A more convincing study followed a group of more than 2,300 middle-aged men from eastern Finland for more than twenty years.55 Those who used a sauna with great frequency—up to seven times a week—enjoyed a twofold drop in heart disease, fatal hearts attacks, and all-cause mortality events over those who heat bathed once per week.
None of the sauna studies dug deep enough to tell us why temporary heat exposure may be so good for us. If yeast is any guide, NAMPT, the gene in our bodies that recycles NAD, may be in on the act. NAMPT is turned on by a variety of adversity triggers, including fasting and exercise, which makes more NAD so the sirtuins can work hard at making us healthier.56 We have never tested if NAMPT is turned on by heat, but that would be something to do. Either way, one thing is clear: it does us little good to spend our entire lives in the thermoneutral zone. Our genes didn’t evolve for a life of pampered comfort. A little stress to induce hormesis once in a while likely goes a long way.
But dealing with biological adversity is one thing. Overwhelming genetic damage is another.
A bit of adversity or cellular stress is good for our epigenome because it stimulates our longevity genes. It activates AMPK, turns down mTOR, boosts NAD levels, and activates the sirtuins—the disaster response teams—to keep up with the normal wear and tear that comes from living on planet Earth.
But “normal” is the operative word, because when it comes to aging, “normal” is bad enough. When our sirtuins have to respond to many disasters—especially those that cause double-strand DNA breaks—these epigenetic signalers are forced to leave their posts and head to other places on the genome where DNA breaks have occurred. Sometimes they make their way back home. Sometimes they don’t.
We can’t prevent all DNA damage—and we wouldn’t want to because it’s essential for the function of the immune system and even for consolidating our memories57—but we do want to prevent extra damage.
And there’s a lot of extra damage to be had out there.
Cigarettes, for starters. There aren’t many legal vices out there that are worse for your epigenome than the deadly concoction of thousands of chemicals smokers put into their bodies every day. There’s a reason why smokers seem to age faster: they do age faster. The DNA damage that results from smoking keeps the DNA repair crews working overtime, and likely the result is the epigenetic instability that causes aging. And although I’m not likely to be the first person you’ll hear this from, it nonetheless bears repeating: smoking is not a private, victimless activity. The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke.58 If you do smoke, it is worth trying to quit.
Don’t smoke? That’s great, but even without smoke there’s fire. In much of the developed world—and increasingly in the developing world as well—we’re practically bathing in DNA-damaging chemicals. In some places—cities with lots of people and lots of cars, especially—the simple act of breathing is enough to do extra damage to your DNA. But it would also be wise to be wary of the PCBs and other chemicals found in plastics, including many plastic bottles and take-out containers.59 (Avoid microwaving these; it releases even more PCBs.) Exposure to azo dyes, such as aniline yellow, which is used in everything from fireworks to the yellow ink in home printers, can also damage our DNA.60 And organohalides—compounds that contain substituted halogen atoms and are used in solvents, degreasers, pesticides, and hydraulic fluid—can also wreak havoc on our genomes.
Nobody in his right mind would purposefully ingest solvents, degreasers, pesticides, and hydraulic fluid, of course, but there’s plenty of damage to be had in some of the things we do intentionally eat and drink. We’ve known for more than half a century that N-nitroso compounds are present in food treated with sodium nitrite, including some beers, most cured meats, and especially cooked bacon. In the decades since, we’ve learned that these compounds are potent carcinogens.61 What we’ve also come to understand is that cancer is just the start of our nitrate-treated woes, because nitroso compounds can inflict DNA breakage as well62—sending those overworked sirtuins back to work some more.
Then there’s radiation. Any source of natural or human-inflicted radiation, such as UV light, X-rays, gamma rays, and radon in homes (which is the second most frequent cause of lung cancer besides smoking63) can cause additional DNA damage, necessitating the call-up of an epigenetic fix-it team. As someone who flies a lot for work, I think about this quite a bit—every time I go through security, in fact. Most of the research on the current versions of airport scanners suggests that they probably don’t do tremendous damage to our DNA, but there’s been little attention given to their long-term impact on our epigenome and the aging process. No one has ever tested what a mouse looks like two years after being repeatedly exposed to these devices. The ICE mice tell us that chromosome tickling is all that’s needed to accelerate aging. I’m aware the radiation exposure from millimeter-wave scanners is lower than that from previous scanners. The security attendants at the machine tell travelers the exposure is about the “same as the flight.” But with millions of flight miles under my belt, why would I want to double the damage? Whenever possible, I take the pre-check line or ask for a pat down instead.
If all of this makes you feel as if it’s impossible to completely avoid DNA breaks and the epigenetic consequences of those breaks, well, that’s true. The natural and necessary act of replicating DNA causes DNA breaks, trillions of them throughout your body every day. You can’t avoid radon particles or cosmic rays unless you live in a lead box at the bottom of the ocean. And even if you were to move to a desert island, the fish you’d have to eat would likely contain mercury, PCBs, PBDEs, dioxins, and chlorinated pesticides, all of which can damage your DNA.64 In our modern world, even with the most “natural” lifestyle you can follow, this sort of DNA damage is inevitable.
No matter how old you are, even if you are a teenager, it is already happening to you.65 DNA damage has accelerated your clock, with implications at all stages of life. Embryos and babies experience aging. What, then, of people in their 60s, 70s, and 80s? What of those individuals who are already frail and cannot restrict their calories, go for a run, or make snow angels in the dead of winter? Is it too late for them?
Not at all.
But if we’re all going to live longer and healthier lives—regardless of how much epigenetic drift and aging we have experienced at this moment in time—we might need some additional help.