Lifespan: The Revolutionary Science of Why We Age—and Why We Don't Have To

by David A. Sinclair

So prevalent is the combined problem of early mortality and morbidity that there is a statistic for it: the disability-adjusted life year, or DALY, which measures the years of life lost from both premature death and poor state of health. The Russian DALY is the highest in Europe, with twenty-five lost years of healthy life per person. In Israel, it is an impressive ten years. In the United States, the number is a dismal twenty-three.

The average age of death can vary rather significantly over time, and is affected by many factors, including the prevalence of obesity, sedentary lifestyles, and drug overdoses. Similarly, the very idea of poor health is both subjective and measured differently from place to place, and so researchers are divided on whether the DALY is rising or declining in the United States. But even the more optimistic assessments suggest that the numbers have largely been static in recent years. To me, that in itself is an indictment of the US system; like other advanced countries, we should be making tremendous progress toward reducing the DALY and other measures of morbidity, yet, at best, it seems we’re treading water.

One study found that 85-year-old men are diagnosed with an average of four different diseases, with women of that age suffering from five. Heart disease and cancer. Arthritis and Alzheimer’s. Kidney disease and diabetes. Most patients have several additional undiagnosed diseases, including hypertension, ischemic heart disease, atrial fibrillation, and dementia.

The combination of genetic and epigenetic changes induced by years of exposure to cigarette smoke increases the chances of developing lung cancer about fivefold.

But consider this: though smoking increases the risk of getting cancer fivefold, being 50 years old increases your cancer risk a hundredfold. By the age of 70, it is a thousandfold.

But being wrong has never stopped conventional wisdom from negatively impacting public policy. And because aging isn’t a disease by the commonly accepted definition, it doesn’t fit nicely into the system we’ve built for funding medical research, drug development, and the reimbursement of medical costs by insurance companies. Words matter. Definitions matter. Framing matters. And the words, definitions, and framing we use to describe aging are all about inevitability. We didn’t just throw in the towel before the fight began, we threw it in before we even knew there was a fight to be had.

I believe that aging is a disease. I believe it is treatable. I believe we can treat it within our lifetimes. And in doing so, I believe, everything we know about human health will be fundamentally changed.

I believe

Of course not. When we stay healthy and vibrant, as long as we feel young physically and mentally, our age doesn’t matter. That’s true whether you are 32, 52, or 92. Most middle-aged and older adults in the United States report feeling ten to twenty years younger than their age, because they still feel healthy. And feeling younger than your age predicts lower mortality and better cognitive abilities later in life.22 It’s a virtuous cycle, as long as you keep pedaling.

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.

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 often.

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.

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.

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.

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

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.

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.

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

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

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.

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.

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.

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

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.

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.

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.

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.)

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.

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.

Now that we know how life works and have the tools to change it at a genetic and epigenetic level, we can build upon this very old wisdom. And when it comes to the goal of extending healthy lifespans, the easiest measures to use are the various drugs that we already know can impact human aging.

It is for this reason that if you were to make a pilgrimage to Rapa Nui, you might come upon a small plaque at the site where S. hygroscopicus was discovered. “At this site,” the plaque reads in Portuguese, “soil samples were obtained in January 1965 that allowed the production of rapamycin, a substance that inaugurated a new era for patients who need organ transplants.” I suspect that a larger plaque may soon be in order, because the discovery of S. hygroscopicus set into motion a tremendous amount of research, much of which is still ongoing and some of which has the potential to prolong vitality for countless other people. Because in recent years it has become clear that rapamycin isn’t just an antifungal compound and it isn’t just an immune system suppressor; it’s also one of the most consistently successful compounds for extending life.

We know this from experiments on a diverse menagerie of model organisms in labs around the world. And much as my own research began with experiments with yeast, much of the initial work that has been done to understand rapamycin was completed on S. cerevisiae. If you put 2,000 normal yeast cells into a culture, a few will remain viable after six weeks. But if you feed those yeast cells rapamycin, in six weeks about half will still be healthy.7 The drug will also increase the number of daughter cells mothers can produce by stimulating the production of NAD.

If all metformin could do was reduce cancer incidence, it would still be worth prescribing widely. In the United States, the lifetime risk of being diagnosed with cancer is greater than 40 percent.24 But there’s a dividend beyond preventing cancer directly, a side effect of living longer that most people don’t consider: after age 90, your chances of dying of cancer drop considerably.25 Of course, people will still die of other conditions, but the tremendous pain and costs associated with cancer would be significantly mitigated.

The beauty of metformin is that it impacts many diseases. Through the power of AMPK activation, it makes more NAD and turns on sirtuins and other defenses against aging as a whole—engaging the survival circuit upstream of these conditions, ostensibly slowing the loss of epigenetic information and keeping metabolism in check, so all organs stay younger and healthier.

Among the people taking metformin—and leading the charge to evaluate its long-term effects on aging in humans—is Nir Barzilai, the Israeli American physician and geneticist who, along with his colleagues at Albert Einstein College of Medicine, discovered several longevity gene variants in the insulin-like growth hormone receptor that controls FOXO3, the cholesterol gene CETP, and the sirtuin SIRT6, all of which seem to help ensure that some lucky people with Ashkenazi Jewish ancestry remain healthy beyond 100.

he is fond of pointing out that even if we were never to extend lives past 120, we know that 120 is possible. “So for most of us,” he has told me, “there are 40 good years still on the table.”

Barzilai is leading the charge to make metformin the first drug to be approved to delay the most common age-related diseases by addressing their root cause: aging itself. If Barzilai and his colleagues can show metformin has measurable benefits in the ongoing Targeting Aging with Metformin (TAME) study, the US Food and Drug Administration has agreed to consider aging as a treatable condition.

gave him a small vial of white, fluffy resveratrol powder—marked only with the letter R—to try on insects in his lab. He took it back to Rhode Island, mixed it with some yeast paste, and fed it to his fruit flies. A few months later, I got a call from him. “David!” he said. “What is this R stuff?” Under lab conditions, the fruit fly Drosophila melanogaster typically lives for an average of forty or so days. “We added a week to their lives and sometimes more than that,” Tatar told me. “On average, they’re living for more than fifty days.” In human terms, that’s an additional fourteen years.

And when we gave resveratrol to human cells in culture dishes, they became resistant to DNA damage.

Despite its limitations as a drug, it did serve as an important first proof that a molecule can give the benefits of calorie restriction without the subject having to go hungry, and it set off a global race to find other molecules that might delay aging. Finally, at least in scientific circles, slowing aging with a drug was no longer considered bonkers.

Meanwhile, on a parallel path, researchers, including us, were homing in on a chemical called nicotinamide mononucleotide, or NMN, a compound made by our cells and found in foods such as avocado, broccoli, and cabbage. In the body, NR is converted into NMN, which is then converted into NAD. Give an animal a drink with NR or NMN in it,40 and the levels of NAD in its body go up about 25 percent over the next couple of hours, about the same as if it had been fasting or exercising a great deal.

And back at Harvard, we found that NMN could give old mice the endurance of young mice and then some, leading to the Great Mouse Treadmill Failure of 2017, when we had to reset the tracking program on our lab’s miniature exercise machines because no one had expected that an elderly mouse, or any mouse, could run anywhere near three kilometers.

This molecule doesn’t just turn old mice into ultramarathoners; we have used NMN-treated mice in studies that tested their balance, coordination, speed, strength, and memory, too.

These anecdotal reports of restored menstruation and fertile horses are early but interesting indicators that NAD boosters might restore failing or failed ovaries. We also see that NMN is able to restore the fertility of old mice that have had all their eggs killed off by chemotherapy or have gone through “mousopause.” These results, by the way, even though they were done multiple times and reproduced in two different labs by different people, are so controversial that almost no one on the team voted to publish them. I was the exception. They remain unpublished, for now.

All of this is why early indicators of restored ovarian function in humans, anecdotal as they may be, are so fascinating. If true, the mechanisms that work to prolong, rejuvenate, and reverse aging in ovaries are pathways we can use to do the same thing in other organs.

By the time my mother died in 2014, my father’s health had also begun its seemingly inexorable decline. He had retired at 67 and was in his mid-70s, still fairly active. He liked to travel and garden. But he had passed the type 2 diabetes threshold, was losing his hearing, and his eyes were starting to go bad. He would tire fast. He repeated himself. He was grumpy. He was hardly a picture of exuberant life. He started taking metformin for his borderline type 2 diabetes. The next year he started taking NMN. My father has always been a skeptic. But he is also insatiably curious and was fascinated by what he heard from me about what was happening to the mice in my lab. NMN isn’t a regulated substance; it’s available as a supplement. So he tried it out, starting with small doses. He knew quite well, though, that there are very big differences between mice and humans. At first he would say to me and to anyone else who asked, “Nothing has changed. How would I know?” So the statement that came about six months into his NMN tryout was telling. “I don’t want to get carried away,” he said, “but something is happening.” He was feeling less tired, he told me. Less sore. More mentally aware. “I’m outpacing my friends,” he said. “They’re complaining about feeling old. They can’t even come for bushwalks with me anymore. I’m no longer feeling that way. I don’t have aches or pains. I’m beating much younger people at rowing exercises at the gym.” His doctor, meanwhile, was struck by the fac...

About his father taking Nmn

As I looked at Dad, standing with my family, I thought, “This is what longer life is all about—having your parents there for life’s important moments.” And as he stood there, he later told me, he thought, “This is what longer life is all about—being around for your children’s important moments.”

The successes of STACs, AMPK activators, and mTOR inhibitors are a tremendously powerful indicator that we’re working in an area of our biology that is upstream of every major aging-associated disease. The fact that these molecules have been shown to extend the lifespan of virtually every organism they’ve been tested on is further evidence that we’re engaging with an ancient and powerful program to prolong life.

Although the enzyme known as telomerase can extend telomeres—the discovery of which afforded Elizabeth Blackburn, Carol Greider, and Jack Szostak a Nobel Prize in 2009—it is switched off to protect us from cancer, except in stem cells. In 1997, it was a remarkable finding that if you put telomerase into cultured skin cells, they don’t ever senesce.

We already know that destroying senescent cells in mice can give them substantially healthier and significantly longer lives. It keeps their kidneys functioning better for longer. It makes their hearts more resistant to stress. Their lifespans, as a result, are 20 to 30 percent longer, according to research led by Mayo Clinic molecular biologists Darren Baker and Jan van Deursen.3 In animal models of disease, killing of senescent cells makes fibrotic lungs more pliable, slows the progression of glaucoma and osteoarthritis, and reduces the size of all sorts of tumors.