The Scientific Search for Youth

Later this year, a handful of people with a rare eye condition will receive a novel injection that is designed to quite literally turn back time. 

Nonarteritic anterior ischemic optic neuropathy—known as NAION—can cause sudden blindness when blood flow to the optic nerve is blocked. It’s not clear what causes the condition, although diabetes, high blood pressure, and smoking are known to be risk factors. Some early evidence also suggests GLP-1-based weight-loss drugs such as Wegovy, Ozempic, Mounjaro, and Zepbound might also make patients twice as prone to the condition compared with those not taking the medications. Whatever its cause, there are no treatments for NAION. And if it strikes one eye, there is a good chance it will also affect the other, leading to complete blindness. 

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Scientists hope to change that with what is potentially much more than an eye treatment. The injection will test a new gene therapy that, instead of targeting specific genetic mutations that cause NAION, attempts to return certain optic-nerve cells to their pre-NAION state. It would be the equivalent of pressing a biological rewind button that takes the affected cells back to a younger condition—one in which they haven’t yet been struck by NAION or any other disease. 

To some scientists, this sounds wildly ambitious. To others, extremely unlikely. Either way, it is just the kind of big—and controversial—swing that is emblematic of the growing field of science devoted to untangling and reversing what is a central fact of life: aging.

The particular therapy behind the NAION treatment is based on the work of David Sinclair, a professor of genetics at Harvard Medical School and director of the Paul F. Glenn Center for Biology of Aging Research. He has spent decades trying to understand the wear-and-tear processes that age our cells and is convinced that many conditions that plague us—from joint issues to metabolic processes that break down as we get older—could be avoided and even reversed.

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“The real stroke of brilliance is the notion that you make the cell younger, and then it would be more resilient to injury,” says Dr. Joseph Rizzo, professor of ophthalmology at Harvard Medical School and Mass Eye and Ear, who is leading the study. “To me, that was the winning concept.”

Rizzo’s team will give the treatment to three volunteers, all of whom have NAION in one eye. Each will receive an injection of three genes designed to reprogram the targeted optic-nerve cells. 

If successful, the treatment could potentially be used for more common age-related eye conditions like glaucoma—and even other chronic diseases like dementia, arthritis, and heart disease. And it is only one of a growing suite of potential treatments designed to address aging, as scientists race to reverse time at a cellular level. 

Some, including Dr. Valter Longo at the University of Southern California, support the idea of periodic fasting regimens to stress cells into a more resilient, younger state, while others, like Dr. James Kirkland from Cedars-Sinai Medical Center, are developing drugs to remove older cells that refuse to die but damage healthy cells around them, contributing to age-related conditions.

Their ultimate goal? To uncover something that has long fascinated humanity: the key to defeating—or at least slowing—old age.

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Even if it works, the NAION study would only be a first step on the road to fulfilling that fantasy. The genetic and molecular science making the trial possible has advanced by leaps in recent decades—but it remains a good way off from delivering a pill or injections to erase the damage we inflict on our bodies by just living. Stress, exposure to pollution, drinking, and hours on the couch—there’s no easy way to undo it all. But that’s not hindering the search for a quick fix. Everywhere you look there is evidence of a voracious interest in clearing away the layers of daily life and somehow rediscovering the elusive fountain of youth—whether by popping anti-aging supplements touted on social media (even David Beckham sells one) or adopting some of the often extreme treatments depicted in billionaire Bryan Johnson’s Netflix documentary, Don’t Die.

This public frenzy has unlocked a flood of investment from venture capitalists—funding for longevity startups is up by 75% over the past year, according to CB Insights—and pharmaceutical companies. The opportunity for them, if they can create new drugs or pioneer techniques to slow or reverse aging, is potentially colossal. “Every single person on the planet is aging,” says Dr. Mehmood Khan, CEO of the aging philanthropy Hevolution, which is based in Saudi Arabia (one of the largest funders of aging research in the world). “This affects every organism. It’s personal.” 

But longevity scientists working today temper this enthusiasm with a sobering reality. Their focus is not on immortality, or even adding a few more years to people’s lives. It’s ensuring that they spend those final years in as healthy a condition as possible.

They are in the business of increasing health span, not lifespan. “We are not focused on trying to work on longevity,” says Kirkland, director of the Center for Advanced Gerotherapeutics at Cedars-Sinai. But it could be a welcome side effect. “Hopefully we live to 100 or something like that, completely functional, and just not wake up one morning.” The goal is to extend the number of years (however many they may end up being) during which people can live independently, actively, and without being encumbered by serious disease. 

That’s not just a matter of semantics; improving health span would have substantial economic and societal benefits. Researchers estimate that increasing health span by just one year in the U.S. would lead to a $38 trillion boost in the economy due to increased productivity from a larger, more vital workforce and savings in health care costs in treating age-related diseases. Reframing longevity in these terms is catalyzing a renewed interest in researching aging.

“Everybody recognizes that at this point of increasing prosperity and increasing life expectancy all around the world, the burden of caring for older adults suffering from chronic diseases has emerged as one of the most pressing global challenges of our times,” says Dr. Shalender Bhasin, professor of medicine at Harvard University and director of the Claude D. Pepper Older Americans Independence Center at Brigham and Women’s Hospital. 

By 2030, the cost of chronic diseases like diabetes and heart disease, measured in lost productivity and health care expenditures, is expected to reach $47 trillion worldwide. “We have an historic opportunity and imperative for governments, companies, academic, and regulatory agencies to work together to modify the life trajectory,” he says. “Extending health span will be even more important than extending lifespan.” 

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For decades, antiaging strategies have largely been confined to the beauty and supplement industries, where the promises were grand but the evidence scarce. Science took longer to wade into the field, held back by the assumption that aging was inevitable. It wasn’t until the 1930s, when scientists first demonstrated that rats that ate drastically less tended to live longer, that scientific efforts to crack the aging conundrum attracted more scientists’ attention. But dramatically cutting calories isn’t practical for most people. So researchers shifted instead to restoring specific organs or tissues—but those efforts weren’t guided by a deep understanding of how cells and tissues age. 

Advances in genetics and molecular biology, including critical discoveries about stem cells and how they develop to become different cells in the body, began deconstructing the black box that had cloaked aging for so long. There are currently dozens of studies testing whether certain compounds can slow down the many cellular signs of aging, like the DNA damage and oxidative stress you collect from too much time in the sun or exposure to pollution or toxic chemicals in the environment. Damage is also caused by tobacco and poor diets, not exercising, and diseases like obesity and Type 2 diabetes. Some of the studies are exploring how the diabetes drug metformin, for example, might help slow down (and therefore preserve) the metabolic system. Researchers are also exploring ways in which the microbes that live in our guts and skin contribute to the balance between health and disease, and whether specific types of so-called microbiomes are more or less linked to health span. 

Kirkland focuses on yet another area: senescent cells, or cells that have stopped dividing and are on their way to dying, and the destructive signals they send as they expire. He’s developing drugs called senolytics that target these signals, which could minimize some of the damage that we all recognize as aging. Senescence is one of the fundamental processes of aging, Kirkland says, and each of these “can impact literally hundreds of conditions.”

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Positive results from such studies could potentially lead to medicines that may help chip away at the time people spend in poor health. No such products have emerged yet, but promising results from animal studies suggest that it may be possible for certain tissues and organs.

Sinclair, for one, believes that there is a more unified, efficient way to confront aging. The NAION trial is among the first to test his idea that aging is the end product of years of assaults on our genes brought on simply by living, as well as certain lifestyle habits. The net effect on our genes—which scientists call epigenetics, or the way genes are turned on or off within particular cells—is what is aging our cells, he thinks, so to address it, we should start treating aging like a disease. With that approach, he believes we can figure out how to erase the epigenetic changes that build up over time, and give our cells their youth back.

“Time does not go away,” says Sinclair. “We’ll still age.” But the challenge is to control the rate at which that happens as much as possible, so older age starts to look drastically different than it does today—without the extreme frailty, loss of muscle and bone strength, and deterioration of mental and metabolic processes that currently contribute to chronic conditions.

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Sinclair caused a stir in 2023 when he claimed to have reprogrammed old cells in mice that he had epigenetically aged, and found that their muscle and kidney cells were acting young again. (Not everyone in the scientific community agreed that he had effectively aged, then rejuvenated, the mice.) He used a technique for which the Japanese stem-cell scientist Shinya Yamanaka had won a Nobel Prize. Yamanaka discovered a set of four genes that could, when delivered by an inactivated virus using gene therapy, revert adult cells to their embryonic forms, so that they could theoretically develop into any of the body’s hundreds of different cells. Before being treated with three of these genes, the mice in which Sinclair accelerated aging were grayer, frailer, and suffering from a number of age-related diseases, compared with normal mice. Once the aged mice received the reprogramming therapy, however, the genes in their muscle and kidney cells began working like those in young mice.

“We saw reversal of gene-expression patterns back to a more youthful state,” Sinclair says. He used the same process to reverse age-related blindness in mice as well. Currently, his lab is testing a chemical cocktail that mimics the gene therapy but doesn’t require injections. It’s still early, but so far, older mice fed the cocktail for four weeks have less frailty and younger-looking coats.

The way he explains it, as mice age (and humans, he believes), the “information” that cells accumulate over time starts to become biological noise. It’s similar to being among the first to arrive at a cocktail party—it’s relatively quiet, you can see who’s there, and probably eavesdrop on a conversation or two. As more people join, the noise level rises, and the sum of everyone’s conversations becomes a cacophony. Similarly, as cells age, their epigenetic blueprint bears the legacy of what they’ve endured. Those effects don’t necessarily alter their genome, but they do change the way genes are activated and suppressed, and how well cells can repair themselves. Sinclair theorizes that cells accumulate these changes over time, and the burden of these alterations ultimately causes them to falter or function abnormally—a sign of aging.

Sinclair calls it the “information theory of aging” and is dedicating the remainder of his career to proving it. But he and his research have their critics, who question whether Sinclair truly rejuvenated the cells since he didn’t show the animals’ muscles or organs actually functioned like younger versions even if their gene activity was changed, without signs of aging. Not to mention the obvious question: What does any of this mean for people?

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Part of the controversy centers on the fact that the aging field is still trying to establish the standards by which it defines and ultimately measures success. “Where we are right now is that we’ve got three or four leading classes of interventions that people think may be worth exploring in larger human studies,” says Bhasin. They include senolytics, as well as metabolic drugs like metformin and compounds that boost nicotinamide adenine dinucleotide (NAD), a molecule critical to how cells use energy. But “there is very vigorous debate over what will be the primary end point for the clinical trials of these candidate drugs, and how we define the success or efficacy of the drug.”

Ideally, Bhasin says, what researchers should measure aren’t changes in a specific health metric, such as blood sugar or blood pressure, but a broader range of chronic disease incidence that better captures the overall ability of older people to thrive. “If we can show that the onset of these age-related diseases, which is a quantifiable indicator, or their incidence, is reduced, then that would be very strong evidence of health-span extension,” he says. But such studies would be expensive and require long periods of follow-up, which have hindered the field.

Sinclair, however, remains convinced that his approach does slow aging, and stands by the metrics he used. “Two hundred thousand people die each day from age-related diseases, and I’m not going to wait 15 years,” he says.

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Sinclair has long been a lightning rod of controversy in the field because of that defiance—among other things. Depending on whom you ask in the scientific community, he is either a pioneering scientist pushing the limits of our understanding of aging, or a snake-oil salesman. He has a tendency to make grandiose claims about what science can do to slow aging. (The title of his best-selling 2019 book is Lifespan: Why We Age—and Why We Don’t Have To.) He recently resigned from a professional group of aging researchers that he had helped to create after tension arose when he was quoted in a press release claiming that a company he had created had reversed aging in dogs. (Sinclair blames the sloppily written press release and has reworded the statement.) “I probably agree with 80% of what David says about the importance of the field and what it could be, and with the excitement and enthusiasm about the future and discoveries being made,” says Matt Kaeberlein, co-director of the University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging. “But in my personal opinion, he often gets ahead of his skis and sometimes says things that are not true.”

It doesn’t help that Sinclair is also a serial entrepreneur, which some believe creates a conflict of interest between pursuing commercial interests and objective scientific principles. None of the companies he has helped to create, based largely on work from his lab, has led to a commercial product to slow aging, and some have shuttered before conducting critical studies. That includes his first venture, which GSK bought in 2008, to develop his finding that the red-wine compound resveratrol helped yeast and worms live longer. GSK dropped the project, but Sinclair stands by his findings. What others see as failures, he describes as perhaps before their time.

He and others are now focused on studying the effects of NAD, a jack-of-all-metabolic-trades enzyme involved in determining how well the cell functions.

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“You could call them the crown jewels of metabolism,” says Charles Brenner, professor of diabetes and cancer metabolism at City of Hope, of the NAD co-enzymes. “But while the crown jewels of any country in Europe are inside a safe inside of a vault inside of a castle patrolled by armed guards, the crown jewels of our metabolism are exposed to the elements of metabolic stress. When we go outside, get a sunburn, or live life in an oxygenated environment, we generate DNA damage and reactive oxygen species that attack the NAD system.”

The more the NAD system is perturbed, the less able it is to perform its critical functions in regulating a cell’s energy, among other things. Some scientists, including Sinclair, believe that boosting the body’s stores with a NAD supplement is a promising way to slow aging. And Sinclair has created a company, Metro International Biotech, that is manufacturing a precursor molecule that the body turns into NAD; human testing began in March. “Every-one who’s been dosed is doing fine so far,” he says. 

Brenner—one of Sinclair’s critics—takes NR (nicotinamide riboside), a precursor that the body turns into NAD, that he discovered in 2004. But he says it’s not because he thinks it will help him live longer or age more slowly. “I don’t make any extravagant claim that NR is a longevity drug,” he says. “The idea of NAD boosting, in my opinion, is to essentially equip people to have higher resiliency in the face of conditions like metabolic stress.”

Brenner believes it’s nearly impossible to truly do a trial that tests NAD boosting’s role in extending life, since too many factors contribute to aging, lifespan, and health span. “There is no way to do that trial, and people who think they can, using biomarkers, are probably fooling themselves,” he says.

That’s not stopping researchers from trying. Bhasin is currently recruiting healthy, fit people to test NMN, another precursor that the body converts to NAD, with a version made by Metro International Biotech. Everyone will be put under physical stress with an intensive exercise regimen and randomly assigned to take the pills or a placebo. They’ll then undergo physical and psychological tests: running on a treadmill, having their respiratory function and muscle tone checked, and having their cognitive skills evaluated. The study will shed light on how boosting NAD affects people under physical stress, which is one of the factors that can indirectly contribute to cell aging. 

More research—and replication of results—is needed before any of this will help us all live to 100. But “we are now living in an era where we have the tools to accelerate [the] pace of research,” says Khan. “There is a recognition that with early intervention, we can change the trajectory of health span.”

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