Why are babies born young? The most natural phenomenon on earth is actually hard to explain — at least on a cellular level. Consider this problem: The components of conception are old. When a woman gets pregnant, she has been carrying her egg cells since birth. The sperm that joins with the egg to form a zygote might have been just a few months in the making, but it inherits markers of age from the man who produced it. It only follows that the zygote would also show signs of age — and at first it does.
But then a mysterious metamorphosis begins: The cells of the zygote begin to reverse that damage, shaking off the metaphorical dust that the parents accumulated on their DNA. After two weeks, the cells of the embryo are back to a kind of ground zero of youth. Only then are they as young as they will ever be. To understand this process, which was discovered only recently and is known as “natural rejuvenation,” is to contemplate a mind-bending truth: We don’t start out young; we work our way back to it.
Many scientists now believe that mastering cellular rejuvenation may be the key to transforming how long and how well we live. Some hope that they might eventually be able to harness the process to cure hundreds of diseases, extend life by decades and even fend off aging entirely.
Over the past 20 years, they have learned how to trigger rejuvenation in the lab, achieving a series of breakthroughs that have made that future feel tantalizingly close. Scientists have taken skin cells from 90-year-olds and restored them to youth in a petri dish. They have rejuvenated diseased mice, turning their gray hair back to black and strengthening their muscles. They have taken failing kidneys out of rats, rejuvenated them in a lab and successfully reimplanted them; they are now moving on to pigs. In March, the first safety trials to test rejuvenation therapy on humans began with an attempt to reverse disease in the eyes and cure glaucoma.
Rejuvenation is one of the newest and most promising developments in longevity research, a field that began in earnest in 1993 when a scientist at the University of California, San Francisco, proved that she could double the life span of a roundworm simply by tweaking a single gene. Since then, research devoted to how we age has exploded, developing alongside a booming longevity industry led by entrepreneurs and even some scientists pushing unproven products. Peptides, supplements, laser therapies, electric suits, collagen powders, cryotherapies, blood infusions and other offerings claiming to slow aging now constitute a $20 trillion global market.
Fueling this industry are some of the wealthiest men in the world, who are trying to finance their way to longer life, either by biohacking their own health or pouring money into the research. Major figures in Silicon Valley, including Peter Thiel, Larry Ellison and Sam Altman, have collectively invested billions in biotech companies and research centers devoted to slowing the aging process.
Rejuvenation sounds just as sci-fi as any of the ideas coming out of the longevity field, and yet there’s widespread agreement among scientists that the research has extraordinary potential. The most vehement disagreements are not over whether cellular aging can be reversed, but how far scientists can push it. Will it work in humans? Will its use be limited to targeted interventions that cure specific diseases? Or could it ever be safe enough to enable full-body rejuvenation — to help humans look and feel younger, or to stop them from aging in the first place?
Some of the answers to those questions are likely to come from Altos Labs, a secretive biotech company reportedly backed by Jeff Bezos and the investor Yuri Milner. With $3 billion in investment at its founding in 2022, Altos is thought to have been the single largest biotech start-up launch. A would-be Manhattan Project for longevity science, Altos is responsible for one of the biggest migrations of academics to industry in recent years, luring marquee names in the field with million-dollar salaries and the promise of near-unlimited funding. Among its competitors, Altos has earned a reputation as a black box. “They don’t share what they do,” one researcher told me. Its scientists rarely publish papers, and they don’t speak to journalists about their work — that is, until this March, when I was invited inside.
Altos’s main campus is in Redwood City, Calif., just north of Palo Alto, but much of its work on rejuvenation takes place in San Diego, under the direction of Juan Carlos Izpisua Belmonte. A scientist of great interest among his peers, Izpisua Belmonte set off an ethical debate in 2019 when he worked with scientists in China to create what’s known as a chimera: In this case, they made embryos that were part monkey, part human. (They destroyed any that survived after 20 days.) Last year, at a conference in Boston, so many scientists went to hear him speak that the police were called in to manage the jostling overflow.
Raised in poverty in Spain, where he briefly played professional soccer, Izpisua Belmonte is still a dramatic presence at age 65: tall, with a striking bald head and a tendency to speak almost in a whisper. His air was casual as he led me on a tour of the light-infused San Diego labs, but the energy of the young researchers we stopped to talk to was nervous, as if their high school principal, who happened to be Albert Einstein, had popped by to listen to their science-fair presentation. At one station, I saw, rolling around in a petri dish, several organoids, tiny organic models the size of a grain of rice that contain the key elements of, say, a human heart. (It actually beats.) Altos is also using artificial intelligence to create a “virtual cell,” which would allow for exponentially more experiments than could be done in the lab.
Izpisua Belmonte published his most important work in 2016, when he stunned his colleagues by finding a way to rejuvenate genetically diseased mice, extending their lives by 30 percent. If it is news to you that a scientist you’ve never heard of found a way to reverse aging in mice, you might be wondering why. I have a theory, which is the impenetrable name of the procedure he invented: partial epigenetic reprogramming. It sounds like something that might require a call to tech support or mastery of a new remote control. But it describes a fascinating process that’s so easy to grasp that some of his colleagues eventually wondered why they didn’t think of it themselves.
Izpisua Belmonte figured out how to precisely manipulate the mice’s epigenetics — the term for the tiny clusters of molecules that sit on our DNA and give it instructions about which genes to turn on and off. They tell cells how to specialize — to decide whether they should become heart, lung or skin cells — and how to function well in their dedicated role. Although our DNA stays stable, these epigenetic molecules change with our exposure to the world — to sun, food, stress, even loneliness. Over time, some of them start to attach where they shouldn’t, and others lose their tight connection to the DNA, making it harder for our cells to read their instructions. When that happens, according to one theory, aging follows and our health suffers.
When Izpisua Belmonte had his breakthrough in mice, he was building on earlier research that had found a way to reset those epigenetic markers. In 2006, a scientist in Japan named Shinya Yamanaka identified four unusual genes that are active in early embryonic development. He introduced them into the skin cells of older mice in a petri dish and watched and waited. Over the course of two weeks, the skin cells transformed, becoming something close to embryonic stem cells — it was as if they were moving backward through time toward their infancy. “It’s a bit like learning how to turn lead into gold,” a competing scientist told The Associated Press.
The discovery of the power of these four genes, now known as the Yamanaka factors, won the Nobel Prize in 2012, but it wasn’t obvious at the time that they would be crucial for longevity research. As important as the work was, scientists recognized that applying those factors to humans could be risky. “Nobody wants to be a blob of stem cells,” says Eric Verdin, head of the Buck Institute for Research on Aging.
The first effort to treat mice with the Yamanaka factors resulted in biological disaster. In a 2012 experiment at a cancer research center in Spain, the mice’s organs failed as their cells started dividing uncontrollably and forming teratomas — tumors made of bits of tissues like hair, teeth and skin. “To me, the Yamanaka factors are not realistic for use in a clinic,” one of the lead authors of that study told MIT Technology Review in 2021; the cancer risks were too high.
Izpisua Belmonte disagreed. He had spent 30 years at the Salk Institute for Biological Studies, an esteemed research nonprofit in San Diego, exploring how tissues and organs form as the embryo develops. Now he wondered if his research team could find a way to fine-tune the rejuvenation process: to partially rewind the epigenetics so that cells could recapture their youthful resilience without losing their identity and ability to function. Rather than return the cell to infancy, figuratively speaking, maybe he could take it back to its glory days as a teenager.
Just as cancer treatments give patients time to recover from the toxicity of chemotherapy, Izpisua Belmonte’s approach entailed exposing the mice to the Yamanaka factors intermittently, cycling them on for two days, then off for five. By the end of the treatment, the mice looked so drastically different that some of the lab techs assumed that they had been replaced. Once feeble, they became energetic, their fur thicker and darker, their hearts stronger. “Our study shows that aging may not have to proceed in one single direction,” he told reporters after he published his work in Cell in 2016. “It has plasticity, and with careful modulation, aging might be reversed.”
That paper, now considered one of the most important of the decade, was initially rejected by several journals. “The objection was not, This is wrong, but, This cannot be true,” Izpisua Belmonte said. He understood the hesitation: He, too, felt incredulous when he first grasped that the mice had lost the human equivalent of 20 years of aging. He compared how he felt then to how he imagined NASA engineers must have felt after launching the first rocket into space. “That is often how science moves forward,” he said. “What first feels unbelievable can, with enough evidence, later seem almost self-evident.”
The implications for human health care were immediately galvanizing. Several biotech companies formed in the wake of the 2016 Cell paper, intent on harnessing rejuvenation. None were bigger or better funded than Altos, which successfully recruited Izpisua Belmonte and much of his team from Salk. Manuel Serrano, the lead author of the teratoma study, who was also recruited along with his team, told MIT Technology Review that Altos was paying him five to 10 times what he earned at the research institute in Spain where he previously worked.
At the lab in San Diego, Izpisua Belmonte took me to a microscope where Zeinab Chahine, a young bioengineer, showed me two slides that reflected, I came to understand, where much of the energy at Altos is going. The first slide showed an untreated skin cell taken from a 96-year-old. It had the look of an atomic-age textile design, with dashes in hot pink, askew at some distance apart from one another, against a paler pink background. “These cells are fairly well aged,” Chahine said. “And they’ve lost their capability to function as they should.”
Young, high-functioning cells shift easily between performing their intended roles throughout the body and repairing any damage that naturally occurs over time. In repair mode, they shore up the structures of the cell, as though adding layers of cement to a wall. Izpisua Belmonte’s research suggests that as they age, cells struggle to read their epigenetic instructions and get stuck in repair mode, unable to resume their normal duties. They add layer after layer of cement, causing the cell to become fibrous and stiff, which only leads to more — now harmful — efforts at repair. This process is what Izpisua Belmonte believes causes us to age and die. When he has managed to reverse it in the lab, by prompting cells stuck in repair mode to rejuvenate, he says that many of the other hallmarks of aging in the cell also disappear.
The second slide Chahine showed me displayed a skin cell that Altos had rejuvenated. Even I could see that the lines were spindlier, more parallel, closer together — a result achieved, they said, with a new formula that’s different from the Yamanaka factors, which are now considered just one of many potential ways that scientists could trigger rejuvenation. Altos and a handful of other start-up biotech companies are competing to find the safest version. Altos is conducting research on rejuvenation in the kidney, the heart and the liver, which are often the first organs to fail as we age. The hope is that in fixing whatever organ is aging first, scientists could give someone a longer, healthier life, with everything essentially winding down at the same time, making for a mercifully brief period of decline.
Hal Barron, the chief executive of Altos, told me that the brain is a key area of focus for the lab. No one wants to extend people’s lives only for them to suffer through those years with dementia. “I think everybody in the world agrees that if we make you live just long enough so that you get Alzheimer’s. … ” He shook his head. “That just is yet another challenge.”
For all Altos’s resources, the lab that has pushed rejuvenation the furthest so far is one at Harvard run by the most controversial scientist in the longevity field, David Sinclair. A professor of genetics, Sinclair has published dozens of breakthrough papers, but he has also developed a reputation for overhyping the state of longevity science. In 2019, Sinclair published a best-selling book, “Lifespan: Why We Age and Why We Don’t Have To,” and has theorized that the first person who will live to be 150 has already been born. “Aging doesn’t have to be acceptable,” he said at the World Government Summit held in the United Arab Emirates this year. “It’s increasingly treatable. Our bodies are more like computers that can be programmed and reprogrammed and rebooted to be young again.”
Other predictions that Sinclair has made in the past have not turned out as promised. In the early 2000s, he created a start-up based on his research finding that resveratrol, a compound found in red wine, could be harnessed to slow aging. In 2008, the business was sold to the pharmaceutical giant GlaxoSmithKline for $720 million. The deal started a biotech boom in longevity investment, but it is now also cited as a cautionary tale: Scientists at Pfizer who did their own research found that the compound did not show promise and suggested that Sinclair’s findings were a result of a recurring lab error; GSK then wound down its research on resveratrol in 2010, citing safety concerns. (Sinclair has said that subsequent research supports his claim.)
Sinclair has since founded several other companies, including a wellness business he runs with his girlfriend, the chef and energy healer Serena Poon, and a pet-longevity start-up. In the spring of 2024, Sinclair posted a news release on social media that quoted him saying that one of the pet company’s supplements had been “proven to reverse aging in dogs,” citing research that many scientists found woefully thin. Matt Kaeberlein, a researcher who once worked at an M.I.T. lab with Sinclair and now helps run a project on dog longevity, denounced Sinclair on Twitter as a “snake-oil salesman.” The former dean of Harvard Medical School suggested that Sinclair’s claims were damaging the school’s reputation. Sinclair was forced to step down as president of the Academy of Health and Lifespan Sciences, a group of top longevity scientists that he helped found. (Sinclair has said the news release misquoted him.)
Despite Sinclair’s controversies, many members of that academy told me they believe that Sinclair has done and will continue to do important work. Sinclair has championed the idea that aging happens when our epigenetics start to drift, making it hard for cells to access the information they need — what he calls the Information Theory of Aging. That theory has become influential in the field, though many of his peers believe it is just one of several drivers of decline. They have watched closely as Sinclair’s start-up, Life Biosciences, has made strides toward rejuvenation trials in humans after a major breakthrough in his Harvard lab in 2018.
That year, Yuancheng Ryan Lu, one of his graduate students, decided to try, after many failed attempts, a novel approach to cellular rejuvenation that he and Sinclair had already been testing in the lab: leaving out one of the four Yamanaka factors, specifically the one most closely linked to cancer. Lu’s idea was to try to apply the three remaining factors to the optical nerve cells of mice he’d blinded. He was surprised to find that the treatment worked — the mice regained sight.
Lu and Sinclair published the findings in Nature in 2020, and Life Biosciences eventually started moving toward F.D.A. approval for human trials, conducting follow-up studies on the mice and moving up the chain to primates. In a lab in St. Kitts, researchers contracted by Life Biosciences damaged monkeys’ optical nerves with a laser and then injected the monkeys’ eyes with the same three Yamanaka factors, which reset the epigenetic code and restored function.
The study was very small and its findings have yet to be published. But Michael Ringel, who has a Ph.D. in biology, was impressed enough by the results to leave his role as managing director at Boston Consulting Group and join Life Biosciences as chief operating officer. He knew he was signing up to work with a researcher who, he acknowledged, was “both famous and infamous.” But he maintains that Sinclair has done as much as any scientist to advance the field. In any case, he said, he found Sinclair’s data persuasive. “That was what convinced me,” Ringel said. In March, Life Biosciences began its first trials to treat glaucoma in an initial group of up to 18 people.
Daniel Ives, the chief executive of Shift Biosciences, a competitor in the field of cellular rejuvenation, felt that the F.D.A. had taken adequate safety precautions before approving the trial, but he remained anxious about the worst-case scenario. “This is an intervention with a cancer risk, and there’s a chance that it blows up,” he said. Should anything go wrong, it would most likely cast a pall over the entire field, which is just one reason the community was rooting for the experiment to succeed. “Maybe the person at the forefront isn’t your flavor of the month, but if they’re pushing forward with the medicine, that’s great. Let’s see if it can work,” Ives said. “If we can make someone or even a body part younger on demand, that could do a lot of good. That’s the excitement.”
Sinclair, clearly aware that he has been accused of overenthusiasm in the past, seemed to be making a point of demonstrating his sober approach to science in the only comment he provided for this article: “Scientific progress has always involved iteration, course correction, competition and criticism,” he wrote in an email. “My team and I are focused on advancing this work carefully and responsibly as it moves toward human studies.” Even one of Sinclair’s most outspoken critics, Matt Kaeberlein, said he had to give Sinclair credit for being the first scientist to test rejuvenation in humans. “It’s sort of ironic that after multiple things that he hyped, that turned out to be overhyped,” Kaeberlein said, “that this might be the one that breaks through.”
Early this year, I attended a longevity science conference in Miami hosted by the academy that Sinclair helped found. That weekend, about 65 scientists from around the world compared notes and waited in line for coffee and complained about the weather in the city, which was experiencing a freakish cold snap. Iguanas, stunned by the below-freezing temperatures, were falling from the sky, tumbling from their perches in trees and littering the sidewalks. Scientists wearing Oura rings and Apple watches skirted the tropical reptiles as they tried to get their 10,000 steps or maximize their high-intensity interval training. Others snapped photos to send to friends who were zoologists: Were the iguanas done for? Or might they be revived?
Becoming a member of the academy is an honor for longevity scientists, and protecting the group’s reputation was on the agenda for the first day of discussion. Its leaders had come to believe that they had a P.R. problem, as groundbreaking research like cellular rejuvenation gets mixed up, in the public’s mind, with businesses selling unproven supplements and billionaires like Bryan Johnson grabbing headlines by infusing himself with his son’s blood. “There are too many terms, too little clarity, mixed messaging, public confusion and so on,” Nir Barzilai, a professor at the Albert Einstein School of Medicine and the academy’s president, told the crowd.
Barzilai, who is known for his work exploring longevity genes in centenarians, went on to introduce a branding consultant he hired, who warned the group that there was a misalignment between the work they were doing and “the fringe anti-aging approaches” and the “snake oil” that did the field harm. After some debate, the group voted to rebrand itself the Academy of Geroscience — the name the consultant recommended. (“Geroscience” literally means “the science of aging.”) Ringel, the Life Biosciences executive, seemed undecided about the name — he wasn’t sure it captured the great potential of the field to transform the human life span.
The conference showcased the debate that longevity researchers — or geroscientists — are having about how to set expectations for the public. Until he joined Altos, Juan Carlos Izpisua Belmonte, like Sinclair, had been known to make grand proclamations about just how much life extension we could anticipate and how soon: In 2019, Izpisua Belmonte told MIT Technology Review that he believed there was probably already an individual born who would live to be 130; humans, he said, might eventually live 50 years beyond our current life span.
By contrast, Barron, the Altos chief executive, shies away from that sort of prediction. He fears that others in the field are raising expectations so high that the public might not recognize a miracle of progress when it occurs. Even if we cured all cancer tomorrow, Barron said, we’d add maybe only two or three years to the average American’s life span. “So if we extend health span by three years,” he said, “you’re doing the equivalent of something which will not happen anytime soon, which is curing cancer.” Should Altos manage to add five years to life expectancy — more than Barron even could hope for, he said — he feared that the public would still be disappointed. “Even delaying ovarian aging by three years or Alzheimer’s by three years — that would be transformative,” he said.
Scientists even disagree about the language they should use to describe what they do. Sinclair often talks about his work as “age reversal” research. In a recent exchange on X with Elon Musk, he promised that “age reversal is coming.” Altos, by contrast, declares on its website that its mission is to use rejuvenation to reverse “disease, injury and the disabilities that occur throughout life.” It sounds like medicine, rather than a bending of the time-space continuum in our biology.
Eric Verdin of the Buck Institute, who also attended the conference, expressed frustration with public statements implying that full-body rejuvenation might be right around the corner — that someday soon, cellular rejuvenation might lead to a pill or an infusion that would melt away our wrinkles, perk up the cells of our bodies so we can heal as quickly as children or run as fast as we did in our prime. “It’s a very different thing to regress a localized disease and to actually revert aging,” Verdin said. Even if Sinclair’s study of the eye is successful, what worked in the eye — which is a contained system — might never prove safe in organs more interconnected with the rest of the body.
On the last night of the conference, Barzilai, addressing the group, said he wanted to see more people at the gym the next morning. It was a reminder that for all their efforts, and for all the money poured into high-tech rejuvenation experiments, they could agree on only one scientifically certified approach to extending human life: vigorous exercise, along with a healthy, ideally low-calorie diet.
Sinclair is one of the scientists who have conducted and popularized research explaining why the body ages more slowly when food is scarce. Caloric restriction encourages the body to hunker down into cell-healing mode, so that it can live long enough to reproduce in better times. The same phenomenon, some research suggests, applies to other difficult conditions like intense heat and cold.
In the cold weather, the grand pool outside the Miami hotel where we gathered went largely untouched. Even inside, the hotel’s heating system wasn’t equipped to address the unexpected chill. Some of us started taking shawls and sweaters to the presentations, many of which promised we were close — very close — to a breakthrough that might change the paradigm of aging forever. As we shivered our way through the weekend, waiting for the future, we could at least console ourselves that we might be adding precious minutes to our lives.
Susan Dominus is a staff writer for the magazine and the author of “The Family Dynamic,” a book about high-achieving siblings.
The post Longevity Science Is Overhyped. But This Research Really Could Change Humanity. appeared first on New York Times.
