Published December 28, 2022
40 min read
Scientists are great at making mice live longer.
Rapamycin, widely prescribed to prevent organ rejection after a transplant, increases the life expectancy of middle-age mice by as much as 60 percent. Drugs called senolytics help geriatric mice stay sprightly long after their peers have died. The diabetes drugs metformin and acarbose, extreme calorie restriction, and, by one biotech investor’s count, about 90 other interventions keep mice skittering around lab cages well past their usual expiration date. The newest scheme is to hack the aging process itself by reprogramming old cells to a younger state.
“If you’re a mouse, you’re a lucky creature because there are a lot of ways to extend your life span,” says Cynthia Kenyon, a molecular biologist whose breakthrough work decades ago catalyzed what is now a research frenzy. “And long-lived mice seem very happy.”
What about us? How far can scientists stretch our life span? And how far should they go? Between 1900 and 2020, human life expectancy more than doubled, to 73.4 years. But that remarkable gain has come at a cost: a staggering rise in chronic and degenerative illnesses. Aging remains the biggest risk factor for cancer, heart disease, Alzheimer’s, type 2 diabetes, arthritis, lung disease, and just about every other major illness. It’s hard to imagine anyone wants to live much longer if it means more years of debility and dependence.
But if those mouse experiments lead to drugs that clean up the molecular and biochemical wreckage at the root of so many health problems in old age, or to therapies that slow—or, better yet, prevent—that messy buildup, then many more of us would reach our mid-80s or 90s without the aches and ailments that can make those years a mixed blessing. And more might reach what is believed to be the natural maximum human life span, 120 to 125 years. Few people get anywhere close. In industrialized nations, about one in 6,000 reaches the century mark and one in five million makes it past 110. The record holder, Jeanne Calment in France, died in 1997 at 122 years, 164 days.
Human biology, it seems, can be optimized for greater longevity. Unimaginable riches await whoever cracks the code. No wonder investors are pouring billions into trying. Google led the spending spree with the 2013 launch of Calico Life Sciences, where Kenyon is the vice president of aging research. Over the past few years, investment in the industry has come from tech tycoons, overnight crypto millionaires, and most recently Saudi royals. It seems everyone with cash to burn is placing a bet on aging’s next—or really, its first—big thing.
This work is powered by artificial intelligence, big data, cellular reprogramming, and an increasingly exquisite understanding of the zillions of molecules that keep our bodies humming. Some researchers even talk about “curing” aging.
Humans have chased dreams of eternal youth for centuries. But the study of aging and longevity was such a scientific backwater as recently as 30 years ago that Cynthia Kenyon had trouble recruiting young researchers to assist her in the experiments that would break the field open. Working then at the University of California, San Francisco, she altered one gene in tiny roundworms known as C. elegans and doubled their life span. The mutants acted younger, too, slithering friskily under the microscope while their unaltered peers lay about like lumps.
Kenyon’s startling discovery showed that aging was malleable—controlled by genes, cellular pathways, and biochemical signals. “The whole thing shifted from being out there in the nebulous world to familiar science that everyone understood,” she says. “And everyone could do it. So people just moved in.”
Delaying death in worms and mice, however, doesn’t mean it will work in humans. For a hot minute, senolytics, which kill damaging cells that accumulate with age, appeared poised to become the first antiaging therapy to make it through the regulatory gauntlet. But one of the first clinical trials, a highly anticipated study of an osteoarthritis treatment, found that it didn’t reduce swelling or joint pain any better than a placebo. Researchers and biotech companies are now testing senolytics to treat early onset Alzheimer’s, long COVID, chronic kidney disease, frailty in cancer survivors, and a complication of diabetes that can cause blindness. Clinical trials of other antiaging compounds are also under way. But so far, none of the experimental drugs that have had such dazzling effects in mice have made it to the market.
“There are lots of different approaches,” Kenyon says. “We don’t know if any of them will work. But maybe they’ll all work! Maybe combinations will be fabulous. The good news now is that people have literally accepted this kind of science as being real. They’re excited about the possibilities. We just have to try a lot of things. And that’s what people are doing.”
Walt Crompton, a retired biomedical engineer in Silicon Valley, is 69 years old. He has ample white hair, a white goatee, and a dark vision of growing older. “I’m at the age where I’m swirling around faster and faster at the bottom of the toilet,” he says. “You look around, more and more of your peers are dying, getting horrible diseases. You have little aches and pains, all of a sudden your knee hurts when you run, and blah, blah, blah. If it’s not one thing, it’s another.”
With a mindset like that, it’s no surprise Crompton became obsessed with aging and life-extension research. He read the mouse studies. He helped out at a longevity lab. He attended conferences where scientists spoke of the “hallmarks” of aging, the interconnected ways that biology goes awry over time.
Protective caps on chromosomes, called telomeres, shorten. The genome becomes unstable and cancer-causing DNA mutations increase. Changes occur in the epigenome—compounds that latch onto DNA and regulate the activity of genes. Some cells become senescent, meaning they stop functioning normally, but like zombies, they don’t die, and they secrete chemicals that cause inflammation. Disruptions occur in pathways that respond to nutrients, lipids, and cholesterol, throwing metabolism out of whack. And the list goes on. There’s no consensus on how these changes influence one another, or which is the most important to address.
At a conference, Crompton heard a scientist named Gregory Fahy explain his theory that immunological aging could be reversed by treating the thymus, a small gland in the chest that stimulates the development of disease-fighting T cells. Fahy was seeking volunteers to test his idea that injections of recombinant human growth hormone, a drug used for decades to treat children with short stature, could rejuvenate the thymus and the body’s waning defenses against disease. Fahy had injected himself with the stuff on and off for eight years, and with his thick dark brown hair and youthful enthusiasm, he appeared in enviable shape for a guy of Social Security age. Crompton signed up.
Fahy, the chief scientific officer of Intervene Immune, a California-based company, is well known as a cryobiologist who developed a technique to preserve kidneys by infusing them with ethylene glycol and storing them at minus 135°C (-211°F) until they can be transplanted. He created a stir by rewarming a rabbit brain in near-perfect condition, raising hopes a way will be found to allow mammalian brains, ours included, to survive cryopreservation. But Fahy has been fascinated by the thymus for decades, since he read a study by scientists who refreshed the immune systems of rats by implanting cells that make growth hormone. He believes most drugs that extend mice lives will disappoint us, because they “don’t do anything about keeping your immune system from going south.”
Recombinant human growth hormone is off patent, so repurposing it for antiaging won’t yield the financial bonanza of a new drug; it’s also associated with an elevated risk of some cancers. Fahy tried to get other scientists interested in doing a clinical trial and failed. “I took matters into my own hands and started regenerating my own thymus based on what I could glean from the rat study,” he says.
Because the drug can raise the risk of type 2 diabetes, he added two pills: metformin and dehydroepiandrosterone, or DHEA, a hormone that improves blood-sugar regulation. Both are also thought to mitigate the effects of aging, and they’re commonly used for that purpose. Metformin, which is taken for diabetes by 150 million people worldwide, may reduce the incidence of neurodegenerative diseases and cancer. U.S. researchers are planning a study to see if it prevents or delays major age-related illnesses. But some longevity scientists aren’t waiting: They pop metformin daily.
Crompton says he immediately felt the effects of Fahy’s regimen. “It seemed like I could leap tall buildings in a single bound.” He shed unwanted pounds without dieting. Another participant, Hank Pellissier, 70, tells me his hair, previously white, began growing in brown.
Tests showed that T cell production increased with the treatment, thymus fat disappeared, and kidney and prostate health improved. Most striking, the men lost an average of two and a half years of biological age, as measured by what’s known as an epigenetic clock. It uses blood to measure chemical changes to DNA that alter gene expression and mark the passage of time.
Fahy’s study, published in 2019 in the journal Aging Cell, was too small to prove anything, and it was not placebo controlled. Nevertheless, the experiment provided the tantalizing suggestion that a medical intervention might lower a person’s biological age. Steve Horvath, who developed the epigenetic clock that’s now a go-to tool in longevity research, was impressed. The 55-year-old geneticist and biostatistician is now a participant in the larger trial Fahy is conducting.
Fahy, who is 72, enrolled as his own guinea pig and resumed his hormone injections. “I’m getting up there, unfortunately,” he says. “The clock is ticking. I have to do my work fast to save not only everybody else but myself as well.”
At 98, my mother, Dorothy, has outlived my father, her two younger sisters, and a late-life boyfriend. Her short gray bob is always salon perfect. She is thin and walks slowly, with a cane, but she stands straight. On most weekdays she goes to her neighborhood senior center, where she takes exercise classes, dances, and eats lunch with friends. She never forgets a birthday or a bill due.
Not much about her lifestyle would have predicted such healthy longevity. She escaped Nazi Germany as an adolescent, suffering more than her share of trauma, though I’ve never heard her use that word. She smoked cigarettes for decades. My father was a butcher, and we lived on red meat. On the plus side, she has always been physically active. She ran competitive track as a child, walked a few miles back and forth to work, and swam several times a week for years after she retired.
Scientists study healthy elders like my mother and track centenarians to figure out how they manage to defy the actuarial tables. Kristen Fortney, a 40-year-old biotech executive with a Ph.D. in medical biophysics, is putting big data and computational wizardry to the task. Most drug development for aging aims to fix something that goes wrong; Fortney is trying to understand what goes right.
“I’ve always approached it from the perspective of what’s going to have the greatest impact and what’s the low-hanging fruit,” Fortney says. “I’ve always believed that’s to copy what already works. There are already all these human examples of successful aging … individuals out there who are making it to a hundred and beyond, and their muscles still work, their brains still work, so we know it can be done.”
Fortney’s company, BioAge Labs in Richmond, California, analyzes blood and tissue stored in biobanks from Hawaii to Estonia. The specimens are linked to electronic medical records, so Fortney and her colleagues know the health outcomes of the people behind every vial of blood, and they search for biomarkers that distinguish those who’ve aged well. Machines measure each sample for up to tens of thousands of variables, including 7,000 proteins. (A decade ago, the best technology could pick out only a few hundred.) Using artificial intelligence, the scientists then identify possible targets for medication and search the reject piles of pharmaceutical companies for drugs that were developed for other purposes and shown to be safe but never released.
Fortney’s team has tested several dozen drug candidates in mice, and has two in clinical trials. One targets the immune system, and the other addresses muscle mass and strength. Because the U.S. Food and Drug Administration approves drugs only if they prevent or treat a disease, and the agency doesn’t consider aging a disease, trials such as Fortney’s investigate a drug’s effect on an age-related condition. But the researchers almost always have grander ambitions.
For example, Fortney is evaluating a compound, code-named BGE-117, for age-related muscle dysfunction because it acts on a pathway involved in tissue regeneration, remodeling blood vessels, and other critical processes. But the hope, the company explains, is to target “multiple diseases of aging with large unmet needs, high prevalence, and huge markets.”
It was feeding time when I visited Vera Gorbunova’s super-agers: 300 naked mole rats, give or take—a litter had been born four days earlier, and one pregnant female looked ready to burst. The refrigerator held bountiful options, including five pounds of apples, 18 ears of corn, two pounds of celery, three bags of romaine lettuce, purple grapes, bananas, white potatoes, sweet potatoes, and carrots, all of it organic.
Naked mole rats can live more than 40 years in captivity, 10 times longer than typical for a rodent their size. I couldn’t help thinking we’d all live longer if we just ate what these small, wrinkled, bucktoothed creatures do. Gorbunova and Andrei Seluanov, who are married and both biologists at the University of Rochester, study naked mole rats in hopes of stealing their longevity adaptations for us. “In every long-lived animal we find something new. Crazy things!” Gorbunova tells me.
The mystery of the phenomenal longevity of some animals has propelled studies around the globe. Researchers have endured Arctic storms and seasickness to catch, study, tag, and release Greenland sharks, which live at least 250 years and maybe even a few centuries more. Scientists dredging ocean quahog clams from the seabed north of Iceland hauled up a 507-year-old. University of Birmingham biologist João Pedro de Magalhães, seeking clues in DNA, sequenced the genome of the bowhead whale, a 120,000-pound behemoth thought to be the longevity champion of the mammalian world but endangered by pollution and other threats. He also worked with Gorbunova and Seluanov to investigate the naked mole rat genome.
The rodent habitat in Rochester, New York, is 90 degrees, dark, and humid, like a burrow. Each colony—a queen, her consorts, and many generations of her minions—inhabits its own plexiglass dwelling. It has wide tubes connecting three large canisters, ostensibly for sleeping, eating, and excreting. If naked mole rats don’t like a meal, says Nancy Corson, who manages the colonies, “they’ll put it in the toilet.”
They look adorably social as they somersault over one another and huddle in piles like laundry, but they’re belligerently territorial. Researcher Rochelle Buffenstein, who once had more than 7,500 and now has 2,000 in her lab at the University of Illinois, Chicago, has found the old don’t die any more often than the young. “Many of them die because they fight,” Gorbunova says. “That is not age dependent.”
Gorbunova showed me the other residents in her lab: Damaraland mole rats; Chilean rodents called degus, a model for studying Alzheimer’s; and African spiny mice, which have almost mythical powers to regenerate skin and cartilage. A large freezer is packed with tissue from squirrels, rabbits, porcupines, beavers, wild mice, bats, and two dozen other species. She gets these specimens from exterminators, hunters, animal-control officers, state conservation employees. She also traps some. And Wolfy, the family German shepherd whose framed portrait is displayed in her office, deposits the occasional carcass on her doorstep. I winced at that. “They served science,” she assures me.
Bowhead whales have more than a thousand times the cells we do, which should dramatically increase their risk of a cancer-causing mutation. But they don’t get cancer. Studies have shown they are astonishingly efficient and accurate at repairing DNA and keeping cells healthy. Gorbunova has found that other long-lived animals, including naked mole rats, share this superpower.
Bats control inflammation so masterfully they can harbor viruses without getting sick, a feat that drew global attention after they were suspected as the source of the pandemic’s coronavirus. “We were interested in bats even before COVID,” Gorbunova says. Scientists estimate that chronic inflammation, which often progresses as we age, is a major factor in more than half of all deaths worldwide.
And naked mole rats? One of their antiaging marvels is hyaluronan, a gooey sugar secreted by connective tissue. We make the substance, too, and it’s a staple of “age defying” skin creams. But Gorbunova and Seluanov discovered that the naked-mole-rat version has a different, heavier, molecular structure from ours, it’s much more abundant, and it doesn’t degrade as much as ours does. (And she told me, to my disappointment, that it’s produced differently from the pricey products I slather on my face.) Hyaluronan in naked mole rats not only makes their skin supple enough to squeeze through cramped tunnels but also suppresses tumors, the biologists found.
Studying longevity inevitably makes scientists contemplate their own. Once they pass a certain age, many do something—or a lot of things—to stave off molecular damage. Gorbunova, who is 51, tells me she eats seaweed because it activates a protein, sirtuin 6, which aids DNA repair and genomic stability. It struck me as on-brand that a biologist whose ringtone is a barking dog, and who says she chose her specialty because “I like animals and everything you can learn from them,” would try to enhance her own longevity by consuming fish food.
Gorbunova doesn’t study humans, though we’re considered long-lived animals too. We outlive all other primates, and not only because they’re more likely to be eaten by lions. Within a generation, Gorbunova believes, we’ll have treatments that extend the human life span by a decade or two. To push beyond that would require fundamentally changing the human operating system, and that may not be as wild as it sounds. “I think it’s possible,” she says.
In 2006, Shinya Yamanaka, a stem cell researcher in Japan, figured out how to reprogram adult cells and return them to an embryonic-like state. The discovery revolutionized cell biology and the search for ways to treat human diseases, winning Yamanaka a Nobel Prize. Now researchers are determined to use the technique, called cellular reprogramming or epigenetic reprogramming, to reverse aging and eradicate the illnesses that come with it.
“The implications could be bigger than CRISPR,” says biologist David Sinclair, referring to the transformative gene-editing technology. “I’m going to get destroyed for saying that! It’s certainly the biggest thing since CRISPR in terms of the amount of money and people getting into it.”
A group of high-profile tech entrepreneurs, including Jeff Bezos, shook the tight-knit world of aging research in early 2022 with the launch of a three-billion-dollar reprogramming venture, Altos Labs. Yamanaka signed on as an adviser, and other superstar scientists were lured from prestigious academic posts. Depending on your point of view, the massive investment in a technology that is itself embryonic either epitomizes Silicon Valley hubris or marks a shrewd bet on the future of medicine. “People will not invest serious money unless the science is believable,” says Steve Horvath, who retired recently from the University of California, Los Angeles to join Altos. “So the question is, will you and I benefit?”
Yamanaka used four proteins known as transcription factors, which initiate and regulate gene expression, to erase the identity of mature cells—essentially rewinding them to their original state. The leap to apply it to aging came from Juan Carlos Izpisua Belmonte, a biologist studying organ regeneration. He wanted to use the Yamanaka factors to turn back time only partway, restoring the youthful resilience of cells while maintaining their identity and function.
He and his team at the Salk Institute for Biological Studies in La Jolla, California, experimented with mice for several frustrating years until they hit upon a protocol that rejuvenated the animals instead of killing them. They used partial reprogramming to extend the lives of prematurely aged mice and to accelerate healing in normally aged old mice with muscle injuries. At the time, Izpisua Belmonte said the experiments demonstrated that aging “may not have to proceed in one single direction.”
Now, as a scientific director at Altos, he no longer talks publicly about turning aging into a two-way street. The company insists it is not in the business of reversing aging but of reversing disease. Maybe the backers want to distance themselves from the long, dubious history of antiaging snake oil, or they have their sights on what the FDA will approve: treatments for diseases, not for aging. But I was not the only one to puzzle over their distinction.
“What’s the difference?” Sinclair says, rolling his eyes.
Sinclair, a professor of genetics and co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, makes no secret of his mission to thwart aging, including his own. He has founded and invested in more than a dozen companies to commercialize longevity technologies and molecules. At 53, he takes metformin and sprinkles resveratrol on his breakfast. “I try things once, at least, that people are talking about,” he says. “I’m curious. I like to be an experimenter.” He lifts weights to keep his hormone levels up—he posted on Instagram that his testosterone is high. He recently adopted a vegan diet. “It’s not as boring as I thought it would be,” he tells me. He closely monitors his biological age through InsideTracker, a company he advises that analyzes 43 biomarkers.
When I visited his office, he offered to show me his results. We looked at the graphs on a computer screen. First up: C-reactive protein, an indicator of inflammation. “I’m way below what a 20-year-old would have,” he says. He scrolled through more data, concluding, “I’m way off the chart for youth.”
Sinclair modified the Yamanaka formula, eliminating one transcription factor that has been implicated in cancer, and then used partial reprogramming in mice to regrow crushed optic nerves. “That was great,” he says, “but I thought if this is really age reversal, we should be able to reverse age-related disease.” So he tried it in mice with a glaucoma-like condition, and their vision returned. But they weren’t very old, so Sinclair decided to reprogram cells of geriatric mice experiencing age-related vision loss. A colleague who is an ophthalmology researcher bet him it wouldn’t work.
“And guess what?” Sinclair says. “It did.”
Since publishing the results in Nature in December 2020, Sinclair has continued the studies and says the benefits appear long-lasting. Meanwhile, he and the researchers in his lab are doing mind-bending back-to-the-future experiments in which they speed up aging in mice, turning them wizened and sluggish, or accelerate aging in just one organ or in all of them. By switching aging on, they hope to learn how to shut it off.
Sinclair targeted the optic nerve because it’s one of the first places affected by aging. Shortly after birth, we lose the ability to regenerate cells there. He believes his studies offer a game-changing model for treating spinal cord injuries and disorders of the central nervous system. If turning back cellular age can recapture lost vision, he says, why not also the ability to walk or remember?
Nobody knows when, or whether, a moon-shot technology like cellular reprogramming will do for humans what it accomplishes so marvelously in mice. But in the meantime, we can do plenty to take on aging. Researchers at the Harvard T.H. Chan School of Public Health looked at decades of data from 123,219 adults in the U.S. and found that five habits may increase life expectancy by 14 years in women and 12 years in men: good diet, regular exercise, healthy weight, not smoking, and not drinking too much.
“I think the one that gives you the most bang for your buck, if you’re only going to do one—which I don’t recommend—is exercise,” said Matt Kaeberlein, a professor of laboratory medicine and pathology and the director of the Healthy Aging and Longevity Research Institute at the University of Washington.
He’s a hard-core scientist, not a fitness guru. His lab developed a robotics platform called WormBot, which collects data simultaneously from hundreds of parallel experiments to tease out the factors that influence the life span of the roundworm C. elegans. He’s also testing rapamycin in dogs. But no matter how busy he gets, three days a week Kaeberlein, 51, heads to the makeshift gym in his garage and cycles through bench presses, squats, dead lifts, and shoulder lifts to maintain muscle mass. “For most people over 50, loss of muscle mass due to a sedentary lifestyle usually is one of the most important predictors of poor health outcomes later on,” he says.
Fitness experts argue endlessly about which exercise regimen best maximizes health and strength late in life. Similarly, nutrition experts disagree about the optimal diet—time-restricted eating, intermittent fasting, keto, vegan, Mediterranean, you name it.
Animal studies provide compelling evidence that severe calorie restriction increases life span. Whether that’s true for people has been notoriously difficult to determine. The National Institute on Aging initiated a large study two decades ago to measure the effects of a diet that cut calories by 25 percent. But even though participants received counseling, software to track what they ate, and meals for a while, they shaved calories by only 12 percent. I was reminded of the doctor who told me the best healthy diet is the one you’ll follow.
Becca Levy, a professor of epidemiology and psychology at Yale University, points to another important, controllable influence on healthy longevity: our beliefs about aging. In one study, which has been replicated around the world, Levy found that people in their 30s and 40s who had positive expectations for old age—they equated it with wisdom, for example, instead of decrepitude—were more likely to be in good health decades later. In another study, she showed that older people who have positive views of aging are much more likely to recover fully from a disabling injury. And in yet another, she found that positive views of old age were associated with a lower risk of Alzheimer’s. Levy has found that people with the brightest beliefs about aging live an average of seven and a half years longer than those with the gloomiest.
Reading research by scientists trying to unravel the mysteries of aging can make it hard to feel good about growing older. The idea of “curing” aging casts it as pathology. Published studies start, relentlessly, with bad news. “Aging is a degenerative process that leads to tissue dysfunction and death,” begins a typical paper. As I learned more about the science, I grew excited about the possibilities for breakthroughs but distressed about my own prospects as I approached 68.
Steve Horvath offered to run an epigenetic clock on me, a test with the anxiety-producing name of GrimAge. I sent him two vials of my blood. A while later I opened the report: My biological age was 3.3 years lower than my chronological age. The report offered a cheerful “congrats” and said, “You are already beating the clock!” But I felt let down. I certainly wasn’t in league with David Sinclair in bucking the tempest of time.
Then I thought about my mother, still enjoying life in her late 90s. Becca Levy’s research convinced me that my mom’s outlook at least partly explains her vitality. I’ve never heard her grumble about her birthday or say she can’t do something because she’s too old, a complaint I’m starting to hear from friends my age.
“No,” she says, when I point this out. “I’m not too old. I might do it slower, and I might do less of it. But I’m not too old to dance or walk or do anything I like to do.”
She pauses. “Well, I wouldn’t swim anymore.”
“Because you haven’t done it in a long time?”
“Because I don’t like the way I look in a bathing suit.”
Fran Smith, a regular contributor to the magazine, lives near New York City and specializes in stories about health. Four National Geographic Society Explorers photographed this story: Jasper Doest from Rotterdam, Netherlands; David Guttenfelder from Minneapolis; Nichole Sobecki from Nairobi, Kenya; and Melanie Wenger from Paris. Learn more about the Society’s support of its Explorers.
Watch Limitless With Chris Hemsworth, a series on human potential and combating aging by National Geographic, streaming now on Disney+.
This story appears in the January 2023 issue of National Geographic magazine.
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