Never Say Die

Some people live far longer than others. If you could find out how, would you bottle it?


NIR BARZILAI IS 57 YEARS OLD. There are wrinkles at the corners of his eyes, and his hair is turning grey. As the director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx, Barzilai is more interested than most of us in the process of getting older. He studies ‘super-agers’, people between the ages of 95 and 112 who have never experienced any of the four most common diseases of aging: heart disease, diabetes, cancer and cognitive decline. But after years spent tracking how and why people age, he can’t help noticing the telltale changes taking place in his own body. “You’re bothered by subtle signs of aging in yourself, like rapidly recalling colleagues’ names, or changes in your sense of coordination while biking,” he says. “Your line of work makes you extra aware of these.” He’s trying to find ways to forestall aging and death, but his work seems to just make him more anxious about the process.

David Sinclair, a close friend of Barzilai’s who also studies aging—although in mice, worms and yeast instead of people—has a more acute version of the same problem. He says he’s been haunted by death since he was four years old, when he realized that everyone around him was going to die. First his pets, then his grandparents, then his parents. “The realization that the people around me would be gone, after I assumed that we’d always be together, was a shock,” says Sinclair, 43. He’s now a tenured professor at Harvard, but it’s still an issue for him. When she was four, his daughter asked if he would always be around. He told her that, regretfully, he would not. “It’s tragic that conscious animals like ourselves get to realize our own mortality,” says Sinclair.

You’d think that as modern-day scientists, they’d be more objective, more dispassionate about their subject—possibly even a little cold-blooded—but really they are just like everyone else: they want to delay death, not just to preserve their friends and loved ones, but also themselves.

Nothing can take away the knowledge that we all are destined to grow old and die. That awareness, and the desire to delay or circumvent death, has been part of human culture since ancient times: one of the earliest surviving works of literature, The Epic of Gilgamesh, is concerned in part with the quest for eternal life. As a species, we’ve experimented widely to find the answer, bathing in the blood of virgins and injecting crushed guinea-pig testes under our skin, basking in mineral springs and preserving our brains in subzero temperatures.

More recently, reputable scientists have entered the field, trying to break away from quackery and establish aging research as a disciplined, credible pursuit. It’s been a nonstop battle against persistent waves of pseudoscience, false anti-aging ‘therapies’, and creepy press about the extreme methods of some anti-aging advocates. One of the most famous is Ray Kurzweil, a prominent inventor and technologist who ingests up to 200 vitamins a day and receives intravenous injections of a compound he believes rejuvenates his tissues. Kurzweil, like Gilgamesh, plans to live forever. If he does so, it would be an historic achievement, to say the least.

Researchers like Barzilai and Sinclair have more modest goals. They apply rigorous scientific standards to painstakingly identify the molecular and genetic underpinnings of aging. And work like theirs may, for the first time, be the path to real, legitimate drugs to ward off the diseases of ageing that cause most of our untimely ends.

I always expected to live longer than my grandparents. My paternal grandfather died at 49 after a painful battle with colon cancer. He left behind eight young children and a widow, my grandmother. She died at age 94, when her heart gave out, after two years in a nursing home. My maternal grandparents are still alive, both now in their mid-eighties. He has had melanoma several times and currently has prostate cancer; she is suffering from brain degeneration.

Still, I was taught that I would outlast them, just like they’d outlasted their own parents and grandparents. This was for good reason: life expectancy soared in the United States over the last 50 years, thanks to better health care and expanded use of vaccines. Medicine today provides my generation with a carefully curated set of healthy-living guidelines: if I don’t smoke, and if I run two miles a day, eat more vegetables and less meat, get regular health screenings and drink a glass of red wine every night, I’ll have a real shot at dancing at the weddings of my great-grandchildren.

But that assumption turns out to be wrong. In America, life-expectancy increases have been slowing, according to a recent review of mortality data. In fact, some argue that life expectancy may have already hit its upper limit. “We have always assumed that each generation will be healthier and longer lived than the prior one,” said the study’s authors. In fact, they discovered that the amount of time that we spend sick with major diseases has actually increased, and age-related diseases are more, not less, prevalent than they used to be.

The truth is, I’m likely to die around age 81, the average life expectancy for a woman in the United States. What I eat and do will help get me there, hopefully without suffering from cancer or heart disease, but not much further than that. It turns out that reaching your 100th birthday doesn’t have much to do with lifestyle. It has to do with something over which we have no control — our genes.

According to a new way of thinking that’s emerging among aging experts, exceptional longevity isn’t a reward for healthy living; it’s more like a winning lottery ticket, coded into the genes of a lucky few — only 1.73 of every 10,000 people in the U.S. have it. The remarkable longevity of centenarians, in other words, is a fluke, the consequence of rare and unique gene combinations passed from parents to children to grandchildren.

That’s the bad news. The good news is that researchers like Barzilai and other colleagues have recently identified something else, something totally unexpected, in the cells of these oldest living humans, and it could radically transform old age for the rest of us.

Besse Cooper, U.S.,
116 years old

STUDIES OF CENTENARIANS are nothing new. But attempts to investigate why some people live longer don’t always pan out. In the early 1970s, Alexander Leaf, a physician at Massachusetts General Hospital, visited remote towns in the former Soviet Union, Pakistan and Ecuador, searching for people who reportedly lived for 140 years or more. He concluded that outdoor living and healthy diet were key factors, but later had to disavow the work when it turned out that most of the ‘centenarians’ were only in their nineties. In fact, life expectancy in the communities he visited was actually lower than in the U.S

In the 1970s, Makoto Suzuki, a cardiologist and geriatrician from Tokyo, met a centenarian on the Japanese island of Okinawa. When Suzuki visited the woman, he found her outside, cutting the grass in front of her home with a sickle. She didn’t think of herself as unusual. As proof, she gestured to the home directly opposite her, where another healthy centenarian lived.

Unlike Leaf’s studies, the ages of Okinawa’s residents could be verified because town registries had records of every citizen’s birth since 1879. Suzuki learned that the prevalence of centenarians, as well as the average life expectancy of the island’s people, was higher than in any other place in Japan. He began studying the population, and today the project has collected data on more than 900 Okinawan centenarians. In one of his first experiments, Suzuki hypothesized that since the elderly appeared to be protected against illness, they might have stronger immune systems than other people. So he performed the first genetic study of centenarians and looked at a set of immune-system genes called human leukocyte antigen (HLA) genes. He found that some variants of HLA — versions of the gene with specific changes in the sequence, like different flavors of the same sweet treats — were over-represented in the Okinawa centenarian population.

Unfortunately, his results proved hard to reproduce, and Suzuki ultimately concluded that though heritable factors like HLA do exist for healthy longevity, environmental factors — including the traditional Okinawan diet of low-fat, nutrient-rich foods such as sweet potatoes and fruits — were more important.

Since then, lifestyle became the focus of aging and longevity research, primarily because a majority of scientists believed it had the most significant impact. According to numerous twin studies of aging — in which researchers compare identical and fraternal twins — most of the variability in longevity comes from environmental factors, not genetics. These studies have found that among the general population, a maximum of about one-third of the ageing process is attributable to genetic factors. In other words, only 20 to 30 percent of your chances of living to 80 are due to the genes you inherited from your parents. What you ate and drank, where you lived, how you worked: these were the crucial environmental and lifestyle factors that determined how long you lived.

Additional evidence supporting this claim can be seen in the average life span of Seventh Day Adventists, an evangelical Christian denomination that believes the body is a temple and should be cared for accordingly. Because of their beliefs, Seventh Day Adventists are taught to exercise often, get plenty of rest, and refrain from meat, alcohol, tobacco and caffeine. Studies confirm that adhering to this lifestyle can add up to eight years of life.

Australian centenarians insist that a healthy outlook on life, including maintaining social networks and mental activity, kept them young. Tokyo’s centenarians, meanwhile, eat less meat, fish and oil than ordinary people. And American centenarians in Georgia consume more whole milk, more green vegetables and less yoghurt than the average.

If that seems like a confusing combination of advice, things get even more complex when you look at wider population samples. Studies of those aged 60 or more have consistently revealed additional factors that could slow aging. Older women who eat at least one serving of blueberries or two or more of strawberries each week delay cognitive decline by up to 2.5 years. Fibre reduces the risk of death from all causes — by as much as 22 percent — in both men and women. And for those at high risk for heart disease, the fabled Mediterranean diet can reduce the chances of developing it by 30 percent.

But for every study linking healthy lifestyle to longer life, there’s another that contradicts it. When nutrition researchers in Georgia reviewed everything we know about nutrition intake in centenarians, they concluded that there was no pattern across centenarian populations and no single diet that promoted exceptional longevity. In younger populations of healthy adults, taking vitamin E, vitamin C or multivitamin supplements doesn’t significantly reduce cardiovascular disease or decrease the risk of dementia, and increasing the amount of fruit and vegetables in their diet does not help prevent chronic illnesses like cardiovascular disease or cancer.

What’s worse, the single most promising technique for extending life span in laboratory animals doesn’t seem to work in humans. Caloric restriction, which entails reducing your daily calories by 30 to 40 percent, reliably extends life span in a range of organisms, including fish, mice, and dogs. Back in 2009, the conclusions from a 20-year-long experiment on rhesus monkeys seemed to show that if they were fed a reduced-calorie diet, they lived longer and delayed the onset of age-related diseases. But in 2012, a second long-term study of rhesus monkeys found that caloric restriction did not, in fact, lengthen lifespan.

Caloric restriction has yet to be tested in a human clinical trial, so we don’t know if it will make a difference for people. However, Roy Walford, an accomplished pathologist at the University of California, Los Angeles who studied caloric restriction in mice, did take the chance to test the idea on himself. For 30 years, Walford lived on a near-starvation diet of only 1,600 calories per day. He believed that caloric restriction could extend the human life span to 150 years — but died in 2004 at 79 from complications of motor neuron disease, rendering his personal experiment moot.

BARZILAI, IN HIS EAST BRONX LAB, didn’t buy into the lifestyle theory. His own doubts began in 1998, when he initiated the Longevity Genes Project at Einstein with just three centenarians. The old people he studied seemed to undermine all the usual arguments and theories. And the more centenarians he recruited, the more he began to observe a pattern of strong family histories of longevity. In fact, compared to those with no centenarian siblings, a brother of a centenarian is at least 17 times as likely to reach age 100, while a sister of one is eight times as likely. Clearly, family is a large component of longevity, which suggested to Barzilai that those who live exceptionally long have inherited, not earned it.

Something else bothered Barzilai. If consensus opinion was true, and two-thirds of aging was attributable to lifestyle and only one-third to genetics, then centenarians should have especially healthy lifestyles, trumping even that of Seventh Day Adventists. But whenever Barzilai asked one of his centenarians what she attributed her healthy longevity to, he’d get an answer like “I have chicken fat every day” or “I eat chocolate all the time.”

Jiroemon Kimura, Japan
116 years old

His centenarians’ answers didn’t add up. At 105 years old, Sarah Sampson ascribes her healthy longevity to simple living: “I was a quiet, obedient child. I like plain, unadulterated food. And I never ran around, if you know what I mean.” Others in Barzilai’s group credit exercise. Some believe it was good luck or spirituality. Pearl Cantrell, a 105-year-old Texas woman, says her secret is to eat several pieces of bacon a day; the oldest man ever, 116-year-old Jiroemon Kimura, who passed away June 12 this year, thought his longevity was from getting out of bed early.

In 2010, Barzilai decided to prove once and for all whether lifestyle was at the root of centenarians’ longevity. From his team’s home base in an old building at the Einstein, Barzilai and his research assistants reached out to over 500 centenarians, mostly in the New York City area, and questioned them about their lifestyles when they were 70. Questions ranged from their smoking history, physical activity and habits to more measurable details like weight and height. They then compared that data to information from 3,000 non-centenarians — people from the general public who completed a national nutrition survey in the early 1970s.

The results were unmistakable: centenarians have no better habits than the rest of us: they smoke, eat as poorly and are just as lazy as the general population. The finding contradicts twin studies, which aging researchers now realize had a flaw: they studied only twins in the general population — people who normally live to 80. Exceptional longevity, it turns out, is a whole different ballgame.

Barzilai’s study discounting the effects of lifestyle came out in 2011. The next year, Tom Perls at Boston University proved it was possible to accurately predict the likelihood of someone becoming a centenarian by looking at the person’s genetics alone. With biostatistician Paola Sebastiani, Perls scanned the whole genomes of control subjects, centenarians, and supercentenarians (those who live to 110 plus). They identified 281 markers of 130 genes associated with longevity: a genetic signature, a lucky combination that wins the longevity jackpot.

Using just that set of 130 genes, Perls can tell whether someone is a centenarian or not with 61 percent accuracy. And as the bar gets higher, so his accuracy increases: He can tell who is 102 or older with 73 percent accuracy, and who is 105 or older with 85 percent accuracy.

So, after all these years of thinking about aging as a force to be fought with exercise and diet, it turns out that — for super-agers at least — something else was going on. The clustering of longevity in families; the evidence that centenarians’ lifestyles are no healthier than those of the rest of us; and the fact that genes alone can be used to predict whether a person will live to be 100 or older; these have led to a new consensus. It’s now accepted that the one-third statistic doesn’t apply to super-agers. “In centenarians, it’s probably 80-20,” says Barzilai. That is: 80 percent genetics, 20 percent lifestyle. Exceptional longevity, it turns out, is all in the genes.

Jeanne Calment (France) was the oldest person on earth at 122 years old.

LILLY PORT PERCHES on the edge of her sofa at her home in Scarsdale, New York, as straight and poised as a finishing-school student. With pink nails, she picks a piece of lint from her red sweater, a souvenir from a recent trip to the ancient Peruvian mountaintop city of Machu Picchu.

Machu Picchu is more than a mile above sea level. Lilly hiked all the way to the top. She is 100 years old.

The year before her Peru trip, she visited Cambodia and Vietnam. Next year she was thinking about Iceland, but has decided on Hawaii instead. “I’m in perfect condition,” she says.

What is it in Lilly Port’s genome, hidden inside every cell in her body, that makes her the exception to the standard rules of mortality? One possibility is what geneticist Nicholas Schork characterizes as “healthy ageing by subtraction” — the idea that centenarians are at a lower risk for disease than the general population is. “They escape disease and live to a long age because they don’t have predisposing genes,” says Schork, who is based at the Scripps Research Institute, just north of San Diego, California. “In that way, it’s the absence of a bad thing.”

Schork doesn’t necessarily subscribe to this mode of thinking, and for good reason. Although it was the commonly held belief for the last decade or so, once again, it does not appear to be true. In 2010, researchers in the Netherlands showed that individuals aged between 80 and 100 have as many disease-risk gene variants as the rest of us. And when Perls and Sebastiani scanned the genomes of centenarians for their own genetic-signature study, the results matched those of the Dutch research. “Centenarians have as many of these disease-associated genes as everybody else,” says Boston University’s Tom Perls.

Faced with that evidence, researchers like Perls and Schork are now turning to a second hypothesis: instead of the absence of a bad thing, centenarians have the presence of a good thing. Perhaps centenarians are protected from age-related diseases by certain genes that act like guards. “Even if you have genes that aren’t so good for you, the protective genes kind of trump those,” says Perls.

Sarah Knauss, U.S.,
119 years old

This line of thinking can be traced, at least in part, to a day in January 1991 when two graduate students wandered into the lab of Lenny Guarente, a tall, soft-spoken biologist at the Massachusetts Institute of Technology. Their timing was perfect: he was itching to do something new and offbeat, something high risk and potentially high reward. After talking amongst themselves, the suggestion came up that they should look at aging in yeast. At the time, almost nobody studied the molecular biology of aging; even fewer believed it possible to tease out the genetic underpinnings of life span. It was considered fringe science. But Guarente thought it was an interesting problem. “Unsolved, important,” he recalls. He said yes.

By 1995, Guarente and his pupils, Nick Austriaco and Brian Kennedy, had identified a gene that, when crippled in yeast, increased its lifespan by a whopping 30 percent. Austriaco and Kennedy knew that the gene supplied the code, the blueprint, to build a type of protein called a sirtuin. As time went on, and the lab did more work, they started to understand what was happening: that almost all forms of life have sirtuin proteins in their cells: bacteria, for example, have one or two, while mammals have seven different versions. What they didn’t know was what the protein actually did.

A turning point came when David Sinclair, just arrived from Australia, joined Guarente’s lab. A newly minted scientist who seemed to have a million ideas, Sinclair quickly unraveled the chain of cause and effect behind the remarkable life extension that Austriaco and Kennedy had observed. At the heart of it was Sir2, a repairman gene that tackles the damage that accumulates in aging cells, ultimately helping those cells to live longer. Sir2, and its human equivalent, SIRT1, was one of the guard genes everyone was looking for.

Other “superstar” genes — single stretches of DNA that have big impacts on longevity — were soon identified. French scientists analyzing the DNA of more than 300 centenarians discovered that many of their subjects had a particular version of the APOE gene, which helps regulate cholesterol. In 2003, Barzilai added another to the list: a variant of a gene known as CETP, which he noticed was prevalent in the centenarian Ashkenazi Jews in his study. It too helps controls cholesterol, and it has since been shown to help ward off hypertension, cardiovascular disease and cognitive decline. Next was FOXO3, a gene that binds to and controls other genes. It looks like a butterfly, with two large loops where it attaches to DNA, and it is abundant in long-lived Japanese-Americans, as well as the French, Italians and Germans.

SIRT1, APOE, CETP, FOXO3: abundant evidence suggests that these are just some of the genes that can prevent age-related illnesses and promote longevity. It sounds like good news, but for most of us, it’s not.

“Everything we know about lifestyle —everything— is likely to get you above the age of 80, but not to 100,” says Barzilai. “For 100, you need more than that.” For 100, you need the guard genes, and chances are that you don’t have them.

But what if there was a way to distill the essence of this genetic lottery ticket? What if you could pop a pill that would give you the same protective benefits?

DAVID SINCLAIR’S LABORATORY is on the ninth floor of Harvard Medical School’s tall, sparkling research building. The walls leading to his office are lined with framed news articles, awards and photos that chronicle 15 years of research into sirtuins.

Sinclair typifies the new model for success in today’s anti-aging field, according to Jennifer Fishman, a professor in the biomedical ethics unit at McGill University in Montreal, Canada, where she studies the social and ethical dimensions of anti-aging science. And it is not just because of Sinclair’s Harvard pedigree or impressive publication record. Unlike the “old guard” of ageing researchers, like Guarente, Sinclair works with the pharmacy sales counter in mind. “He’s a model of what might be possible,” says Fishman. “He’s much more interested in translational science — developing compounds and getting them to market — than in basic biology.”

Sinclair disagrees with that assessment. While he is focused on making medicines, he argues that it would be impossible if he did not understand the underlying machinery. “My lab has proposed more basic mechanisms of ageing than most others I know,” he says. “Am I more interested in helping people, rather than simply adding a research paper to a library? Yes. But it’s only possible if you understand mechanisms.”

From the moment Sinclair discovered a gene that extends life span in yeast, he thought that the human version might do the same for people. Many scientists thought this unlikely; human and yeast cells are different, and the repair methods did not seem like they would translate between the two. But Sinclair disagreed. “Whatever causes a yeast cell to grow old, [sirtuins] prevent that. Whatever causes us to grow old, it might be different, but they’ll prevent that,” he says. “That’s their job, to protect organisms, to keep us healthy and survive.”

Today, scientists know that he is right: SIRT1 does indeed control DNA repair in mammals, just as it does in yeast. Sinclair did not wait for this confirmation, though. To make an anti-aging drug in his lifetime, he knew he had to start work right away on a drug that activated the appropriate human sirtuin. He couldn’t be sure what such a drug might do, but his bet was that it would slow aging.

In 2003, Sinclair exposed samples of the protein to thousands of different chemicals in a bid to see which affected the molecule’s activity. Of 20 that appeared to activate the protein, one topped the list: resveratrol. Sinclair had never heard of it. He sat down at his computer and googled the term. Then he picked up the phone and called an editor he knew at Nature, a major scientific journal. “I said, ‘Are you sitting down? We’ve got this molecule that activates this [anti-aging] pathway. It’s from red wine’.”

Sinclair’s team fed resveratrol to yeast, flies, worms and mice. In every case, the compound did exactly as Sinclair hoped — it extended life span. But a person would need to drink 100 glasses of red wine each day to get resveratrol’s anti-aging benefits, so Sinclair set out to design synthetic molecules that were up to 1,000 times more potent than the naturally-occurring version.

In 2004, he founded a biotechnology company called Sirtris to develop anti-aging drugs based on this idea. The media loved Sirtris, declaring that Sinclair was pursuing a “fountain-of-youth pill”. However, the U.S. Food and Drug Administration does not recognize ageing as a disease, so Sirtris opted to design drugs that would fight specific age-related diseases, including diabetes and cancer. Sirtris went public in 2007; within a year, pharmaceutical giant GlaxoSmithKline acquired the company for $720 million.

But Sirtris and GlaxoSmithKline’s first major drug candidate, called SRT-501, was a disappointment. In 2010, while being tested against a blood cancer, the drug caused unwanted side effects that may have exacerbated kidney failure in some patients. The trial was stopped, and the drug abandoned.

It was not the first such failure. In 2006, Barzilai made a visit to Pfizer’s sprawling research facility in Groton, Connecticut. He was consulting with the company, and interested to hear how the candidate for their cholesterol-lowering drug, a CETP protein inhibitor called torcetrapib, was progressing.

Marie-Louise Meilleur, Canada, 117 years old

At the time, most major pharmaceutical companies were racing to develop similar drugs. CETP is a long, curving molecule that works like a miniature tugboat in the blood, binding cholesterol and moving it to the liver. It had attracted the attention of pharmaceutical companies because scientists knew that when they blocked the protein in animals, they saw levels of fatty cholesterol fall. The companies hoped it would do the same in humans. In fact, Pfizer had spent $800 million dollars — 10 percent of its 2006 research-and-development budget — on this single experimental drug project, with CEO Jeff Kindler calling it “one of the most important compounds of our generation”. It was certainly important for Pfizer: if it succeeded, the drug would probably bring in billions of dollars.

The project interested Barzilai because he knew that healthy centenarians have low levels of the CETP protein. Blocking the molecule, he reasoned, might ward off aging. But nobody spoke with Barzilai about Pfizer’s drug on the day of his visit: in fact, they were in the process of abruptly shutting down the entire trial. During its final clinical phase, the last step before regulatory approval, the drug had been stopped in its tracks. Although it was intended to lower cholesterol and treat heart disease, it was actually increasing high blood pressure and heart failure and even causing deaths.

It is not unusual for a drug to fail in late-stage trials. Even when the workings of a protein are well understood, crafting a molecule that boosts or inhibits that process can be extremely difficult. Even the most powerful computer simulations cannot predict every side effect; that, after all, is why drugs go through clinical trials.

So, despite the failures of these previous efforts, work on the products of the superstar genes continues. Barzilai now advises Merck, one of several companies that has kept faith in the CETP protein. He remains convinced that a drug that successfully and safely inhibits the protein will protect against not only high cholesterol and heart disease but also diabetes and cognitive decline, just as it does in his centenarians.

Several more years of trials are required, but if Merck’s drug is approved, it would be the first time something like this reaches the market. Of course, neither the drug company nor the FDA would label it so — in fact, representatives are at pains to stress that it is not an anti-aging drug — but wide use would allow us to see if it actually slows aging across a large, diverse population. That means creative follow-up studies are likely to happen. If, say, the drug hits the market and 10,000 people over age 60 start to take it, then in less than a decade we should be able to see if those people live longer and remain in better health than those not taking the drug — and not just because of improved vascular health.

Yet still the questions persist. These drugs are being pushed forward by a mix of medical need, the quest for personal longevity and huge potential profits, and often without much focus on the actual causes of aging.

In the 10 years since Sinclair first identified resveratrol as a potential anti-aging compound, many researchers have attempted to translate laboratory findings into anti-aging medications, despite having only rudimentary knowledge about how and why humans age. Many of this “new generation” of scientists, as Fishman calls them, are driven by personal passions — some might say obsessions — that sway them toward clinical applications. Yet their drug-development efforts have been hindered by that same limited knowledge about the actual mechanisms of these genes, often forcing the drug developers to slow down, change direction, or pause to gather more information about the new compounds and their effects.

Somehow, though, that hasn’t stymied anyone’s enthusiasm.

“This is coming,” says Brian Kennedy, once a graduate student in Guarente’s lab and now the president and CEO of the Buck Institute for Research on Aging in California. “We’re starting to find them, [molecules] that slow aging and extend health span.”

Misao Okawa is still alive at 116 years old.

SITTING IN HIS CRAMPED office at Boston University’s School of Medicine, the path inside littered with box after box of data, Tom Perls adjusts a faded red tie and crosses his scuffed black shoes. Like Barzilai and Sinclair, Perls is convinced that genetics plays a major role in achieving extraordinary longevity. But he disagrees with their approach. Perls argues that longevity is complex, a feature that is governed by many, many genes rather than a handful of superstar ones. He believes that scientists should be more focused on trying to understand the pathways and mechanisms governed by those genes than on trying to develop drugs based on them.

“I don’t think the aim, whether it be Sirtris or any other company, should be — nor do I think they’ll be successful at — coming up with a drug that will slow or reverse aging,” he says. “Aging is far too complex a process with way too many processes that contribute to it. Far better for everyone to stop smoking, exercise, avoid red meat, and be at healthy weights.”

As Perls speaks, he looks up at some framed photos of supercentenarians on his wall. There is Angeline Strandal, who at 104 still cared for her 77-year-old mentally disabled son; and here is Sarah Knauss, who lived to 119 and was the world’s oldest person at her death in 1999. James and Florence Hanlon, ages 106 and 101, were married for 81 years. These super-agers, Perls says, can help us understand aging — but not because of one or two special genes they may be lucky enough to possess.

In the last three years, Perls has moved away from the traditional single-gene approach and focuses his work instead on genome-wide association studies of centenarians. He is scanning every single DNA base in hundreds of genomes, using advanced DNA microarray chips and supercomputers to sift through the data.

Last year, after scanning the genomes of 801 centenarians and supercentenarians, he and his colleague Paola Sebastiani published the first fruit of their efforts. Besides the 281 versions of 130 genes associated with longevity mentioned earlier, they also identified 27 different genetic signatures — patterns of genes switched on or off — into which 90 percent of the super-agers studied could be grouped. Such findings could lead us to a much broader understanding of the major pathways that slow down ageing, or decrease risks for age-related diseases, and even someday help predict what age-related diseases an individual is at risk for.

Perls is vehement in his pursuit of this broader approach. Researchers still studying one gene at a time are “cavemen”, he says, while those like Sebastiani, who apply biostatistics to analyze whole genomes, are “astronauts”. Genomics provides light where there is only scrabbling in the dark.

“I don’t think anyone now believes that a single gene has a pronounced effect on longevity,” he says. “Rather, what we need to do is to take into account simultaneously the effects of many genetic variants with individually modest benefits, which together have a dramatic influence.”

Tom Kirkwood, associate dean for aging and director of the Newcastle Initiative on Changing Age at Newcastle University in the UK, agrees. Kirkwood likens the hunt for longevity genes to searching for a needle in a haystack — but instead of just one needle, there are hundreds or thousands of them. “We ought to be able to find them, but working out what they all do together is a challenge,” says Kirkwood. “You don’t go into a career in science because you’re not up for a fight.”

Gil Atzmon, a geneticist who works with Barzilai at Einstein, also admits that the field is moving toward whole-genome rather than single-gene approaches.

Atzmon calls finding the initial longevity superstars, including CETP, which he helped discover, “beginner’s luck”. Whole-genome approaches are not easy, he says — it is like “shooting in the dark” — but they are the next step in determining how some people are genetically predisposed to age better.

“When we started, we had a puzzle of 100 pieces, and we found one. But the minute we found one, we realized it’s a 1,000-piece puzzle. Then we found another; it grew to 10,000. Now we’re working with a puzzle of 3 billion pieces — the whole genome.”

Atzmon doesn’t share some of his colleagues’ anxiety that it may take too long to make progress in a 3-billion-piece puzzle, though maybe he doesn’t need to: he has exceptional longevity on both sides of his family, with multiple relatives who have lived to 99 and 100.

AGING SCIENCE IS A CURIOUS business, and it will probably remain so regardless of whether progress is made by studying single genes or genome scans. It is rare that the potential outcome of a line of research is tied so intimately to the future of those that pursue it. A successful physicist may, in a sense, live on through the advances he or she makes; the advances made by a successful ageing researcher may literally allow that person to live on.

This mixing of the personal and professional is not hard to understand, of course. Very few of us would say no to extra decades of healthy life. Nonetheless, the field feels marked by it. Fishman, for instance, says Sinclair is pushing the boundaries. “He’s not only an owner, but a customer — he wants to practice what he preaches,” she says. “He’s a true believer in his product.”

“We all have an extremely short time on the planet, and there’s no time to waste,” says Sinclair in his office at Harvard. A nondescript brown box the size of a microwave tilts precariously on a high shelf above his head. A white label on the side depicts two hexagons connected by three crooked lines — the chemical symbol for resveratrol.

Starting eight years ago, Sinclair began experimenting on himself, following the example of Albert Hofmann, the Swiss chemist who synthesized and ingested LSD to see what it might do to his mind, and Austrian physician Karl Landsteiner, who drew his own blood to prove the existence of blood types (for which he won the 1930 Nobel Prize in medicine).

Sinclair is treating himself with concentrated doses of resveratrol supplements. He admits there is no assurance that resveratrol is safe for long-term use in humans. “That’s why I never recommend it to anybody. It’s still an unknown. I might be the person that’s been taking it the longest” of anyone on the planet, he says.

There is a pause. “I’m still alive, though.”

Barzilai feels some of the same urgency that drives Sinclair. Neither of his parents lived long, and both were sick for the last few years of their lives. He has begun doing some whole-genome sequencing of his centenarians, and is now convinced it is the best way to pinpoint rare longevity genes. Those genes, he says, are the keys to making anti-ageing drugs, and making them soon.

“I think we can do it,” says Barzilai, “I think we have to.”

This story was written by Megan Scudellari, edited by Mark Horowitz, fact-checked by Audrey Quinn, and copy-edited by Georgia Cool. Illustrations courtesy of Ed Tucker. Pilar Uribe narrated the audio version.

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