Are We on the Brink of Ending Aging?

This past April, in a nondescript examining room in Glendale, California, molecular biologist David Sinclair watched as an ophthalmologist injected a small amount of a substance Sinclair helped invent, called ER-100, into the left eye of a man with advanced glaucoma.

The treatment was part of an FDA trial, and the ophthalmologist had disinfected the eye beforehand with iodine and then anesthetized it with lidocaine. Glaucoma is a disease that damages the optic nerves. It primarily affects the elderly and can leave an individual functionally blind. The man, who was in his early 70s, had lived with the condition for decades and had undergone multiple surgeries to try to slow it down. But by now he could see only about 50 percent of what was in front of him. For instance, he could see the aide as she put the needle into his eye, but he had someone drive him to the appointment. This new treatment was unprecedented, involving a substance never before injected into a human, one that could reverse his glaucoma by essentially getting his genes to turn back the clock on the affected optic nerve bundle to a time decades before, when it was healthy.

If the patient had been waiting a long time for this moment, so had Sinclair. A professor of genetics at Harvard Medical School, Sinclair had spent more than a decade developing the formula for ER-100, in tandem with Yuancheng Ryan Lu, one of his former grad students. The process involved not just modifying the proteins but also attaching a piece of viral material that would guide them to the right cells. Sinclair said he would be happy if ER-100 eased the patient’s glaucoma, but that wasn’t his primary goal. Glaucoma was really a convenient target for the substance because it damages the eye, which boasts a special immune defense system to tamp down the body’s normal inflammatory response. “The FDA loves enclosed spaces for safety reasons,” Sinclair told me. “We just thought it was a great place to start.” If the injection succeeded, ER-100 would be one of the first medicines to reverse nerve damage in a human. This would be impressive on its own. But Sinclair developed the substance in the hope that it would be the first step toward reversing aging altogether.

ER-100 is a particle that contains the instructions for making transcription factors: proteins that switch genes on and off. The three transcription factors in ER-100 normally activate genes that the human embryo uses to keep its stem cells from differentiating into nerve, skin, heart, and other organs of the body. But the way ER-100 is designed, it actually sends the cells into reverse, essentially telling them to scrub away much of the instruction to grow into specific types of cells and the detritus—the years of exposure to things like radiation, chemicals in the air, smoking, and stress—that has settled on the cells’ DNA. ER-100 works to return the cells to a more youthful state. Sinclair compares it to removing the scratches on the surface of a CD, but to me—substituting one out-of-date image for a soon-to-be one—it was more like taking a corroded penny and dipping it in vinegar to slough off the oxide, revealing the shiny surface underneath.

Sinclair’s lab has reported success with this therapy in mice and primates, but the Glendale trial is the first time ER-100 has ever been used in a human. FDA drug approval is divided into separate steps, and the job of the first phase, which will eventually encompass giving a single injection to 12 patients with glaucoma and last up to five years, is to show only that ER-100 does no harm. But Sinclair—and Life Biosciences, the company that licensed the therapy and is running the trial—is hoping for much more. A substance that can undo damage in the optic nerve by reversing its history might be able to reverse damage in any cell by returning it to its earlier state. And assuming cells could be prevented from ever growing old, humans could—at least theoretically—live forever.

When someone pursues a goal as big as immortality, they tend to have company. And indeed, the injection in Glendale was the latest move in a fast-growing and lavishly funded race in antiaging biotechnology—an effort approaching the scale of AI aimed at rejuvenating human bodies rather than replacing human minds.

In 2013 Google co-founder Larry Page began the hunt for the new fountain of youth by funding a division called Calico Labs. (Calico stands for California Life Company.) The field was soon full of outsize enthusiasm. “Can Google Solve Death?” Time asked on its cover. Biomedical gerontologist Aubrey de Grey took to declaring that “the first person to live to 1,000 is probably already alive today.” A drove of new antiaging start-ups followed, many of them flush with money from some of the richest people in the world. Brian Armstrong, the head of the cryptocurrency company Coinbase, helped start a firm called NewLimit in 2022. “Diseases, then longevity,” its web page announces. The same year, Sam Altman, the CEO of OpenAI, invested in a company with a similar antiaging mission, named Retro Biosciences. Also in 2022 came the behemoth of the industry, Altos Labs, headquartered in the San Francisco Bay Area. It was started with three billion dollars in investor money, part of which reportedly came from Jeff Bezos. Altos is likely the largest bioscience start-up ever. The stampede made me think of an irony immunologist Élie Metchnikoff noted over a century ago: “Although the duration of the life of a man is one of the longest amongst mammals, men find it too short.”

Many of us can remember when we were little and learned the stunning fact that one day we would die. Memento mori. Even worse, before we die, most of us will experience years of debilitation. Physical weakness, dementia, failing sight and hearing, incontinence, sexual dysfunction—the list goes on. There will be three times as many 80-year-olds on the planet by 2050, close to a half billion, and for many of us, our end will not be pleasant. But is this last act necessary? What if aging isn’t inevitable? What if even death isn’t?

For as long as mortality has existed, people have tried to outsmart it. The Epic of Gilgamesh, from around 2000 B.C., describes a plant called the-old-man-will-be-made-young (a serpent steals it before the protagonist can test it out), and Herodotus, the Greek historian from 500 B.C., wrote of a legendary spring that slowed aging, a vision that helped send the Spaniards chasing the fountain of youth fruitlessly to the New World.

In modern times, researchers have learned to ask less fanciful, more focused questions about aging. Does it progress only on the level of the organism? The tissue? The cell? Is its essence to be found in the nerves? The blood? The brain? Or is it glandular? Scientists tried out several theories over the years. One contemporary of Metchnikoff, Serge Voronoff, posited that youth lay in the reproductive organs. What could be more youthful, after all, than creating life? He grafted thin slices of tissue from the testicles of executed criminals onto the testes of rich men. Soon his procedure was in such high demand that he had to turn to monkeys for tissue. Voronoff noted overall improvement on the part of his subjects (more energy, better stamina, sharper minds, and keener eyesight), though modern historians of medicine have concluded that any perceived gain was a placebo effect—the subjects just felt younger. But in the end, how different is that from being younger?

An important clue in the hunt for the essence of aging came from a series of experiments that began in the mid-19th century, when researchers grafted two rats together, one young and one old. Sharing a blood supply with a juvenile, the older rat over time began to behave younger. His movements were faster, his senses more acute. The blood of the younger rat rejuvenated the older one. The younger rat, in turn, grew ill but soon recovered. The realization that aging was something palpable contained within an organism was strengthened in the 1960s by the discovery that cells themselves are mortal. Before then, scientists had assumed that though the body as a system may fail, a cell on its own could live forever. The new knowledge that normal cells can divide only roughly 50 times before they enter a senescent phase suggested that cells have a limited lifespan too.

It was not until the past 30 years—well into the age of genetics—that the possibility this limit might not be absolute began to receive serious research confirmation. An important early experiment to show that aging could be slowed down was undertaken at the University of California, San Francisco in 1993, when molecular biologist Cynthia Kenyon demonstrated that altering just one gene in the worm Caenorhabditis elegans could increase the organism’s lifespan by half. A worm that had lived only two weeks could now live three. Because the genes of C. elegans often have counterparts in humans, the implications for human aging were hard to ignore.

Still, worms are one thing, mammals another. The first key discovery about human aging wouldn’t come for another decade. In 2005 Shinya Yamanaka, then a medical researcher at Kyoto University, was trying to solve a supply problem. Scientists needed immature stem cells—cells that exist in humans before they begin to differentiate into our organs, nerves, and blood—for much of their research work. But the naturally occurring sources, discarded embryos from assisted reproductive efforts, were tricky to obtain. The U.S. government, for instance, had all but prohibited their use since 2001. Yamanaka found that by using the transcription factors produced by four genes that were known to maintain stem cells in their immature state, he could take a mature cell and return it nearly to its pre-differentiated state. The transcription factors instructed the cell to reverse the instructions its genes had executed over the years. The proteins didn’t change the genetics of the cell. They removed molecules around the genes, the so-called epigenome, including small molecules that bond to DNA, called methyl groups, that instruct other genes when to turn on or off. It is the methyl groups that help guide a fertilized egg along the process of human development.

The four proteins soon became known as Yamanaka factors in the scientist’s honor, and in 2012 Yamanaka was awarded the Nobel Prize. By then, the fledgling longevity community had already begun to suspect that he had also provided a road map for how to reverse time at the cellular level.

Juan Carlos Izpisua Belmonte stands atop the pyramid of antiaging researchers from his perch as the founding scientist of Altos Labs. Rejuvenation science is largely funded by private partnerships, which means there’s little obligation for the scientists involved to give other researchers—or the press—a peek at what they are working on, but this past May I received an invitation from Belmonte to visit his lab in San Diego. As I drove to the facility, part of the city’s new biotech hub, I passed the renowned Salk Institute, where Belmonte had worked for some 30 years before Altos hired him away. At the lab, I was met by rows of gleaming, spotless shelves, bright red biohazard containers, and researchers in immaculate white coats, as if someone had doused a conventional university lab with Yamanaka factors and returned it to a state of dewy newness.

Belmonte, a fit man of 66 with a shaved head and a deeply ridged brow, is responsible for the experiment that launched the cellular reprogramming gold rush, one he conducted when he was a professor at the Salk Institute 10 years ago. At that point, it had been several years since Yamanaka had taken mature cells and returned them to stem cells using the transcription factors he had found. But since then, the four Yamanaka factors had shown themselves to be less like a mild cleanser and more like bleach—no one could control the process, so their use killed cells or led to uncontrolled cell growth and cancer. To use the coin metaphor, the process was so powerful it stripped the face right off the penny. Belmonte’s innovation was to calibrate just the right amount and frequency of Yamanaka factors to return cells to their state after they had differentiated but not so far back that the organism grew disorganized and collapsed. To control this process, he added an injection with doxycycline, the common antibiotic, which in genetically modified genes can be made to function as an on-off switch.

Belmonte’s key experiment involved mice with a rare condition called progeria, a premature aging syndrome that also affects humans. After Belmonte’s modified Yamanaka factor treatment, they on average lived 30 percent longer than untreated mice. He next tested his formula on injured but otherwise healthy mice, and he was able to show their deficits healed faster with Yamanaka factors—fast recovery is a signature of youthful cells. The experiment drew worldwide attention. Unlike some of his contemporaries, Belmonte is not the type to overstate things. “With careful modulation,” he said at the time, his study showed that “aging might be reversed.” He cautioned that it would take 10 years before there was a human trial.

Belmonte has done a lot of thinking about aging in the years since, and while he’s eager to go to trial, he recognizes this is a long-term effort. “The goal here,” he told me at his lab, “is setting the basis for that future medicine, not going after one particular problem.” He led me down a hall and past a bench that held a microscope and several skin samples in clear, sealed containers. Under the magnification, a sample from a 21-year-old woman looked like rows of half-curly grains of rice arranged by a very orderly chef. By comparison, in a sample from the skin of a 75-year-old woman, the strands looked like they were in disarray. Then he showed me a third sample, this one from the 75-year-old but corrected with the therapy containing Yamanaka factors. It didn’t quite boast the 21-year-old’s cell tidiness, but it looked at least like someone had neatly combed its hair.

Down the hall, a computational scientist and a microscopist were evaluating stressed skin cells and comparing which interventions reversed the damage most effectively. The microscopist wasn’t looking into the microscope near his arm. He didn’t have to. His partner had encoded an AI program to evaluate and select tissue that showed the best response to the treatments; they were just there to train it and watch. “It’s actually running right now,” he said. “This is a great way to basically eliminate all of the subjectivity.”

Aging, Belmonte stressed to me when we returned to his tidy office, was not the result of a single process. He showed me an image of the hallmarks of aging, a wheel displaying the various factors that contribute to senescence. They range from chronic inflammation to something called telomere attrition, a process in which the protective caps on the spindles on the ends of our chromosomes shrink with time, causing our DNA to replicate wrongly or to stop copying itself entirely.

Belmonte explained that the hallmarks of aging give a hint as to why the rejuvenation field is so challenging: It is really multiple fields. Yamanaka factors are clearly remarkable, but nearly 20 years after their discovery, there is little understanding of how they can reverse age in such varied cell types. The human body contains over 27 trillion cells divided into 200 kinds. Yamanaka factors appear to work well almost everywhere, but why? It seems too good to be true. Some skeptical scientists warn that it might be, citing among other possibilities that in some experiments the cells are responding to other changes in their environment and not Yamanaka factors.

To have such a huge question at the center of antiaging research has in turn promoted great diversity in the approaches competing labs take to solve the problem, from genetically altering Yamanaka factors to finding chemicals that can mimic their function. (No one has yet been able to safely give a human gene therapy orally, so Sinclair believes a truly universal solution would likely be a pill with a chemical cocktail that executes the same tasks as Yamanaka factors.) The entire rejuvenation research effort feels like a race where the basic learning is taking place at the same time early therapies are being concocted. NewLimit, the start-up backed by Coinbase’s Armstrong, plans to begin human trials next year for its own medicine that restores youthful function in liver cells. It is possible that nothing will come of these initial efforts, at least not in their current form or not for a long time—think of how many times researchers have declared they are on the verge of curing cancer. But that won’t likely calm things down in the near term with so much at stake.

Even Yamanaka, who until recently served as an unpaid senior scientific adviser to the Altos board, is surprised by the possibilities of the field he birthed. I had earlier written him to discuss what he thought its future might be. He did not think the use of the factors named after him was “the only possible approach to anti-aging,” he replied to me by email. “Aging is influenced by multiple factors, including not only epigenetic changes but also genomic damage, mitochondrial function, and the tissue environment. Therefore, it is likely that future strategies will involve a combination of different approaches.” At Kyoto University, he was looking at a gene called NAT1 that affects embryonic development. When deleted, it also returns cells to a less mature state.

Belmonte told me he has been working on a way to unify the field. He thinks he has found an overarching machinery behind aging. The common mechanism is called mesenchymal drift. (“Sorry for the term,” he warned me.) Mesenchymal drift is a normal cellular process by which genes turn specialized cells into fibroblasts, which heal wounds but also decrease tissue function and contribute to many diseases. He showed me the hallmarks-of-aging wheel again and described how each aspect could be explained by mesenchymal drift. “We have looked by now [at] more than 40 diseases in humans,” he emphasized. “This is not mice now. This is humans.” One way he saw to treat this meta-condition would be to use the basic cocktail of Yamanaka factors but introduce genetic modifications to make them more effective, he hoped, than Sinclair’s ER-100. AI was speeding that process enormously. Even so, I asked him if he thought any of the hallmarks of aging would be reversible in his lifetime, and he was doubtful. He guessed maybe in 30 years, adding that he didn’t expect to live to see it. “We’re next,” he said with a light laugh.

If Belmonte is the cautious superego of cellular reprogramming, David Sinclair is its instinctual id. Throughout the industry, I found that the early days of massive start-ups touting grand plans had been replaced by more careful talk, and companies now primarily highlight the practical, near-term benefits of their work. The CEO of Altos Labs, Hal Barron, told me that Altos wanted medicine to move “from a disease-care model to a true health-care model.” And Jerry McLaughlin, the CEO of Life Biosciences, which licensed Sinclair’s ER-100 treatment, emphasized the focus of their work was “really on the quality of a life,” not its length.

But Sinclair remained unafraid to make the claims others danced around. Belmonte had spoken generally of reversing the diseases of old age, like cardiac fibrosis. Sinclair’s agenda was more specific: After glaucoma, he thought he might tackle hearing loss and then liver illness. “Would the liver be an easier subject because it would be sort of primed to fix itself?” he asked rhetorically. “It’s super easy.” (Sinclair’s history of big claims has led to a considerable amount of critical press and his own chief operating officer calling him “both famous and infamous” in the New York Times earlier this year.)

After that would come the big trophy, aging itself—not just the diseases that come with it but the underlying cellular mechanism. Sinclair said he hoped to see widely available medicines reversing “aspects of aging” within 20 years. “And if we’re lucky, we might even see something that does whole-body aging restoration.” It frustrated him the way other scientists tiptoed around the implications of the work he and they were doing. “It’s just a euphemism,” he said. “Obviously, if you don’t get sick,” he pointed out, “you don’t die.”

Sinclair, who is 57, met me in his office in his Harvard Medical School lab. The entryway was lined with framed copies of his articles from Cell and Nature. I was the only journalist allowed to visit his lab since the glaucoma trial had been announced.

He explained that his motivation to work on aging dated from childhood. He had been close to his grandmother, who had fled both the Nazis and the Communists in Hungary. When Sinclair was four, he asked her if she would always be there. “She said, ‘No, I won’t be. Everybody dies. And I’m going to be gone. Then your parents are going to be gone. The first thing that’s going to be gone is your cat.’” Sinclair fell to the ground crying. He told me he still does not want his grandmother to have been right. To that end, he takes several over-the-counter supplements—among them NAD+, a cellular coenzyme that may have antiaging properties and that he first brought to public recognition. He added that the soup he’d just eaten was his first meal in six days, the result of his research on the health benefits of calorie restriction. “I nibble on nuts,” he clarified. “When I went to the doctor the other day,” he said, “the receptionist asked for my ID because she didn’t believe my age.”

After touring his lab, I sat in on a meeting of his two dozen researchers, a mix of graduate students and postdocs. The presenter, a woman in her 20s, was researching whether Yamanaka factors could slow cancer. She referred to the current way the factors are used to reverse aging as “partial reprogramming,” because Yamanaka factors are stopped before they take the cell all the way back to the time before it differentiated. Sinclair, seated at the head of the table, jumped in: “I want to ban those words from the lab,” he said. “I don’t want to spend the rest of my life being called ‘partial.’” He suggested instead the team adopt the terms “in vivo reprogramming” or “rejuvenation,” then settled on “iPSC programming” (short for induced pluripotent stem cells).

Sinclair’s crucial innovation with Yamanaka factors was to find a way to make them safer. His team showed that of the four transcription factors, one was primarily concerned with cell growth—this was the cause of the risk of cancers that was associated with the treatment. His group began trying the other three alone and found that they were far less harmful. The scientists first tried the new concoction in organoids—lab-derived mini-organs—then tested it on the eyes of living mice and then primates. They published an article in Cell in 2020, with the headline “Turning Back Time,” that demonstrated they had successfully repaired the vision of the mice they had treated. Sinclair told me that though they have not yet published the data, they got similarly good results in primates.

Sinclair said the solution that worked in mouse eyes should work in other parts of the body. But he added that the technology of ER-100 had already been superseded. He had developed a new treatment called SL-100 (for Sinclair Lab), which was a chemical cocktail, not a gene therapy, so it could be taken as a pill. It didn’t just target individual organs either. “This is whole-body rejuvenation,” he said. “And we’ve been doing this for a while now. It’s insane. We’ve been doing it for over a year.” He was waiting on the pathology report on mice to see if it could move forward to human trials. If the pill were to succeed in trials, it might make antiaging medications something you could buy with a prescription at any drugstore.

Sinclair put on his white lab coat, and we walked through his lab. It was a sliver of the size of Belmonte’s, and he says it costs just five million dollars a year to run. Life Biosciences has raised a mere fraction of the money Altos has. This has not made Sinclair’s goals any less ambitious. First we walked by a postdoc working on nerve diseases, then another regenerating liver cells, both using SL-100.

“So now we’ve gone brain, kidney, muscle, motor neurons,” Sinclair said. “We’ve rejuvenated brain tissue.” Most researchers doubt that one treatment could be so versatile. As Johnny Kim, a researcher in regeneration at TRON, the biopharmaceutical institute in Germany, told Nature earlier this year, the spillover effect from an attempt to reprogram a large organ like the heart could easily overwhelm neighboring cells and kill them. “It would be enough to transform them into cancer,” he commented.

We came to a bench where a graduate student was working on one of the key mysteries behind antiaging: How does a cell remember its former state? Borrowing from information theory, Sinclair believes in the existence of something he calls the observer, a molecule in the cell that retains all the data about the cell’s history. Thus, when Yamanaka factors send the cell back to an early stage, the cell has a memory of what that stage once was. If you imagine the cell as a smartphone, Sinclair is trying to find the location you would go to if you wiped the data from your phone and wanted to reload it again. Sinclair pointed out that there is an existing parallel in nature. Soon after an egg is fertilized, processes within the embryo delete all the epigenetic information that has come with the parents’ DNA. “There’s a switch that says we’re going to erase that and go back to being young,” he explained. “Otherwise, all babies would be born old and wrinkled and diseased.” And somewhere, he believes, the embryo stores the information about what that state looks like.

The researcher was testing the properties of various nucleic acids to see if they could be the observer molecule. “Well, we’re looking for instructions,” Sinclair said. “How does the cell encode youth? Is it a protein? Is it DNA? Is it something else?” He told me he and his team had already used AI to go through some eight billion compounds before getting to this point. He wouldn’t say which nucleic acid he was now zeroing in on—it was proprietary information. Whoever controlled the backup would effectively control cell reprogramming (and, Sinclair has noted, likely win a Nobel Prize).

Antiaging is science for the age of entrepreneurial inequality, conducted by private companies that keep close what they learn rather than air any doubts they may have for broader academic consideration. As a result, it moves fast but also leaves huge ethical questions that no one seems to have the job of publicly debating. What if only some people could afford immortality? What would happen to new generations if the old didn’t die? Yamanaka brought up the idea that the field lacks ethical guidelines. I suggested it was comparable to the current debate over AI. “Significantly extending lifespan itself,” Yamanaka responded, “may involve questions that are even more deeply connected to human existence and values than AI. This is because such research directly touches on fundamental issues for humanity, including societal balance, life, and death.” He called for a “broad societal dialogue” before we move forward much further.

Back in his lab, Sinclair watched as a researcher loaded a droplet of clear goop containing a nucleic acid into a nanopore, a tiny sequencer that can quickly determine the nature of a molecule.

“You’ve got the nanopore going?” he asked.

“It’s primed and ready to go.”

“Doing this used to cost a billion dollars and take up a whole building,” Sinclair marveled. “If I’m right, this is the first time anyone has ever done this experiment.”

Sometimes in medicine you make history and sometimes you don’t, but you can’t know—at least not right away. The researcher hovered as the nanopore sequenced the nucleic acid, waiting for the answer.