Science at this California institute focuses on healthspan—which is about living better, longer.
The leaders of the Buck Institute for Research on Aging want you to know that they’re not going to make you immortal. Even if they could, they wouldn’t necessarily want to. Because extending life just to spend a few more years on Earth is not the point.
But if their field has something deeper and better to deliver, they have reached the moment when they really have to prove it—which is what they are furiously working to do.
That’s what I found when I visited the institute, in Novato, California, earlier this year. The field of modern aging research is a millennial—only 34 years old. It officially began in 1988 when scientists at University of Colorado, Boulder identified a gene whose mutation extended the lifespan of a worm called C. elegans—the first evidence that aging could be deliberately changed through molecular means. Three-and-a-half decades later, aging research is a field still struggling with societal expectations even as it’s on the verge of delivering its true promise.
Longevity medicine has already generated several lifetimes’ worth of hype and hogwash. There have been opportunistic (or narcissistic) promises of 500-year lifespans that captured the popular press even as reasonable scientists labored for legitimate discoveries in the background. Bad-boy billionaires like Peter Thiel and Jeff Bezos reportedly poured millions into life-extension startups. Such cash influxes, plus popular culture portrayals, have spawned a new generation of longevity-obsessed fanboys. The HBO comedy Silicon Valley spoofed the unproven longevity practice of infusing older people with “young blood.” Entrepreneur Martine Rothblatt assured a set of Los Angeles VIPs that we will “make death optional.”
Now, leaders in the field are busy shaking off the shadow of immortality salesmen as they set up for a new stage of growth. Their science, they say, is almost mature enough to deliver real therapies. And the Buck Institute—a small, independent research center in a California suburb almost no one’s heard of—wants to lead the field into maturity.
Yet what experts there and elsewhere say the field will deliver may not be what you’d expect—especially if you’ve been listening to its fanboys.
The real promise of longevity science, they argue, is not a longer life—it’s a better one.
Eric Verdin, the Buck Institute’s president and CEO, decorates his office with photographs and models of vintage Formula 1 race cars, and races real ones recreationally on weekends. One wall is stacked with little lavender shot-bottles of Juvenescence Metabolic Switch, a supplement designed to put you in ketosis without the punishing diet, which Verdin helped develop and that he drinks for a boost of mental clarity on long work days. His email signature includes a quote from legendary race car driver Mario Andretti: “If everything seems under control, you’re just not going fast enough.”
It takes very little spark to start Verdin talking a streak about the possibilities of longevity research—but unlike those who promise imminent miracles, he tempers his predictions with scientific caution. And his predictions are not about finding eternal youth; they’re about fighting the diseases that shorten and darken the later years of our regular lifetimes.
“We’re only talking about how we are going to get the tech guys to live to 150, but that’s not where the real urgency is.”
“I don’t think it’s a stretch to think we could bring everyone to 95 healthy,” he says. “The field is not talking about this enough. We’re only talking about how we are going to get the tech guys to live to 150, but that’s not where the real urgency is.”
The real gold that Verdin and his fellow aging researchers are mining is insights about the common biology that underlies the diseases of aging—which include the vast majority of diseases. Heart disease, cancer, diabetes, arthritis, dementia, vision and hearing loss, neurodegenerative diseases, you name it—all are more likely to afflict us when we’re older. Ever since we could name these diseases we’ve seen and treated them as separate conditions. But aging scientists see them as connected, and they’re working to find the common threads. Seen through their eyes, the biology of aging is the biology of disease. Solving its mysteries is the key to being able to live in good health for almost our entire lives, then suffer only a brief, steep decline before our deaths. Longevity research, in other words, is designed to maximize our healthspans, not our lifespans. Sure, the discoveries could help us live a few years longer. But more importantly, they could help us live those years well.
“What excites me most is really this idea that the field of longevity research has the aim to change medicine,” says Verdin, a Belgian-born physician who holds an MD but has spent his career in research. “Medicine is right now a reactive process that only treats the end product of a long process, which is aging.”
Of the Buck Institute itself, he says, “We would love to be the impetus towards a reinvention of medicine to really prevent people from being sick in the first place.”
That’s a big ambition for a field that has yet to produce its first successful phase 3 clinical trial. But with the momentum the field has built, “We’re going to have the next clinical trial succeed in the next few years here,” says Matt Kaeberlein, a University of Washington professor and director of the UW Healthy Aging and Longevity Research Institute. “And it won’t be for aging,” he adds—but it will come from the biology of aging.
“The Buck,” as it’s called for short, is a neat jigsaw of triangles and cylinders perched high on a grassy hillside in Novato, California, with a sweeping view across marshes to the northern reaches of the San Francisco Bay. Inside its interconnected buildings, twenty faculty and some 300 staff study aspects of aging from genetics to immunology to cellular senescence to metabolism. The campus, specifically designed to foster interdisciplinary collaboration by internationally renowned architect I.M. Pei, features a sweeping sun-filled atrium lined with creamy Italian travertine and contains no right angles between walls—no corner where an idea could get stuck.
Since it opened in 1999, researchers at the institute have produced a variety of discoveries, perhaps the most significant of which is the role of cellular senescence in aging. In response to certain triggers, cells in our bodies shift into a senescent state, in which they keep living but stop reproducing themselves. Senescent cells play many crucial roles in our health: They prevent cancer in the young and promote tissue repair and regeneration as we mature, for instance. But as they accumulate in the old, senescent cells also release molecules that do almost the opposite, fueling tissue degeneration, chronic inflammation, and age-related diseases including cancer. Senescence is a pivotal finding of aging science and a likely basis for therapies to come, and one of the pioneers of research on this crucial biological process is Buck Professor Judith Campisi.
The odds that the Buck would even come to exist in its current form were incredibly long. When philanthropist Beryl Buck died in 1975, she left her $10 million estate in the care of the San Francisco Foundation with instructions to use it “in providing care for the needy” and “to extend help towards the problems of the aged” in Marin County, California. Four years later, Shell Oil bought a Southern California oil company in which the Buck estate owned a significant stake, and suddenly the trust was worth a whopping $260 million (roughly $1 billion in today’s dollars). Sitting on that staggering sum, the San Francisco Foundation and an association of Bay Area charities filed suit to break a central stipulation of the trust to distribute its funds beyond Marin—starting a legal slugfest with Marin County and several Marin nonprofits that would be dubbed the “Super Bowl of Probate.”
Today, the Buck stands as the country’s first independent research center focused exclusively on aging.
The optics of keeping that kind of cash locked up in one of the nation’s wealthiest counties weren’t good. But neither was the precedent of usurping a dead woman’s money for different purposes. In the end, a 1986 settlement kept the trust intact and turned the distribution authority over to a new entity, the Marin Community Foundation, with instructions that they use a portion of the funds for projects based in Marin with a benefit far beyond. That settlement was only the beginning of more turmoil.
Tom Peters, then the Marin County Health and Human Services Director and later the Marin Community Foundation executive director, remembers the ensuing “beauty contest” of ideas to fit that bill. When a center for aging research became a front-runner, the University of California fought to absorb the center while researchers elsewhere argued it should be independent. Then a land use battle sparked contentious community meetings. Approval ultimately went to the voters of Novato, who said yes. When grading of the hillside began, animal rights protestors formed a human chain and splashed red paint like blood on the construction equipment.
Today, the Buck stands as the country’s first independent research center focused exclusively on aging. This sets it apart from, say, a university pathology or genetics department that may study a wide range of health topics. People familiar with the institute say this narrow focus is a strength, allowing its critical mass of scientists to collaborate on a common subject across disciplines. The institute receives about 15 percent of the Buck trust’s annual grant distributions, or about $5 million to $7 million a year, and it raises the remaining $60 million in its operating budget through grants, donations, and corporate sponsorships. Currently, only three of the site’s five planned laboratory buildings are built—which means the Buck is positioned to grow, and that’s what Verdin intends for it to do.
The crucial next step for both the Buck and the broader field is to drive its decades of basic research into the clinic—a key mandate for Verdin when he took the helm at the Buck six years ago. Where in the past clinical translation was about 10 to 20 percent of the Buck’s work, Verdin wants to push it to 50 percent. “And I think that’s pretty much where the field is going, too,” he adds. Verdin intends to achieve this not by reducing the basic research that the Buck is known for, but by growing the institute through an expanded focus on translation.
To deliver on translation, researchers have to sift through the overwhelming array of biochemical signals and processes involved in aging—many of them still being discovered—and identify the ones they can target to produce a benefit. “If you think of aging as a process that’s malleable, that you can dial, you can dial all the diseases together,” Verdin says. What everyone’s after now, he adds, is to figure out which buttons control it.
The task is made vastly more complex by the fact that all those buttons are interconnected. “In the past people would conclude that they’d identified the lever for aging: ‘Oh, it’s the proteins. Oh, it’s the senescent cells,’” says Buck professor Gordon Lithgow, who is credited with coining the term “geroscience” to describe the intersection of the biology of aging and the biology of disease.
“Now we’re at the point where we’re asking: Are these processes connected to each other?” Lithgow says, quickly adding, “Of course they are.” The immune system influences the nervous system, which influences metabolism, which influences epigenetics, and on and on.
Aging also makes a tricky target because it’s an accident of evolution that was never meant to occur. “Evolution did not select for aging,” says Campisi, the senescence pioneer. “There was no aging-related disease in our history. Everybody died by the time they were 40 or 45 or occasionally 50. So evolution put into place a series of pathways to protect young organisms against disease. And those pathways are now persisting way past the age of 50. So now they are what we would call maladaptive. They are now working against us to promote those phenotypes that we recognize as aging.”
The upsides of the mechanisms of aging present a puzzle when it comes to translating the science into therapies. Some senescent cells, for example, heal wounds, help develop eggs, and initiate labor. Others promote cancer. Some amount of inflammation is essential for healing, but too much drives disease. “There’s kind of a Goldilocks problem with so many of these potential aging-related therapies,” says Kevin Lee, senior scientific and programmatic advisor at the Glenn Foundation for Medical Research in Santa Barbara, California, a Buck funder which also focuses on aging. “The challenge is that so many of these processes are interwoven, and they have both a bad side and a good side, and you’ve got to inhibit the bad side without inhibiting the good side.”
Meanwhile, amid many promising discoveries, huge questions remain. Why do cells become senescent in the human body, and how does that compare to what happens in a Petri dish? Why does a mouse live for three years while a human might live over a hundred? We don’t know. Plus, no one can yet pinpoint the ultimate upstream cause of aging or even define exactly what the whole process is. “We’re doing all these experiments around aging, but no one is telling us: What’s aging?” says Lithgow.
“Think about a complex engine where you might take it apart and have all the pieces on the carpet. It still would not tell you how they all work together to create energy,” Verdin explains. “That’s the stage where we are. We’ve sort of disassembled the engine and identified a number of molecular problems, but what’s still lacking is an integrated understanding, especially identifying the key nodes, the places where we have to intervene to receive the maximum benefit.”
Verdin predicts that the first approved therapy from geroscience will come within five years.
The prospect of more humans living longer draws critics who contend that the planet cannot sustainably support so many bodies or that it’s fundamentally egocentric to seek to extend lifespan for its own sake. But Lee counters those arguments by reframing the question. “Do you ever really want to get Alzheimer’s disease?” he asks. “Do you ever really want to see your loved ones losing their independence or losing their ability to recognize their grandchildren or their ability to interact normally with society?” Those, he says, are the true callings of this science.
Verdin predicts that the first approved therapy from geroscience will come within five years, though he won’t forecast exactly when a full paradigm shift for healthspan will follow. “Some people have called me conservative or a dream killer, but let’s underpromise and overdeliver,” he says. “I can tell you this field will overdeliver, but I don’t know when.”
Even Campisi, who takes a cautious view of the clinical possibilities, sees promise. “I don’t think it’s the panacea that [Verdin] thinks it’s going to be,” she says. “We just don’t understand enough.” But to produce drugs to postpone or even reverse certain age-related diseases, and to stretch more of us toward the maximum species lifespan of humans, estimated around 120 years—that’s real talk, Campisi says. “This hope that we could extend healthspan, this is not beyond our dreams. This is, I think, within our grasp.”
What’s the most likely biochemical avenue for an aging-related drug? The University of Washington’s Kaeberlein (who does not work with the Buck) predicts the first one to market will be a senolytic (which selectively clears senescent cells) or rapamycin, an immunosuppressive compound given to people who have kidney transplants that inhibits the mTOR enzyme, involved in cell growth and survival. In fact, one of the early startups in geroscience, Unity Biotechnology, spun out of the Buck work on senescence, is developing senolytics to eliminate senescent cells involved in age-related vision loss and neurodegenerative diseases. A clinical trial for Unity’s first potential product, for knee osteoarthritis, failed in 2020, but that “doesn’t mean that there isn’t substance to the biology,” says Kaeberlein. “In fact, I think there is.”
Verdin, for his part, sees exciting prospects in several areas:
- Yamanaka factors
Japanese Nobel Prize winner Shinya Yamanaka, a professor at the Gladstone Institutes and Kyoto University, found these proteins can transform a mature cell into an embryonic state—a so-called induced pluripotent stem cell. As Verdin explains it, cell function gets “wobbly” with age, so the Yamanaka factors open the possibility of a cellular reset. Other researchers have since found that if you revert a cell to a stem cell and then allow it to resettle, it resettles in a youthful state. Verdin wants to know: Could we do this in the immune system? Or could we use it to regenerate an organ, like by rejuvenating heart cells after a heart attack? But he cautions that human applications are still far away.
This is the focus of Verdin’s own lab at the Buck. We know that food is not just energy. It has signaling properties that affect the epigenome (the set of chemical signals that dictate which of our genes is activated, and when and where). Verdin studies how diet affects the levels of key metabolites in the body, and how these in turn influence the immune response—especially the chronic inflammation associated with aging. Several startups have spun out of this work, including Buck-based Napa Therapeutics and BHB Therapeutics and the virtual Selah Therapeutics, which studies the role of ketones (produced in response to a low-carb diet) in heart disease.
- Environmental influences and the exposome
This realm of inquiry grapples with the fact that, in many respects, we are the places we inhabit. The exposome is the sum total of every environmental thing we are exposed to starting in utero, from lead paint to phthalates in plastic packaging to air pollution. “The incredibly complex chemical environment in which we live interacts with all of our molecules. How does that influence our aging?” asks Verdin.
You could argue that affordable housing and education are anti-aging interventions.
Amid all this acceleration, one of the biggest causes of early illness and death is barely on the field’s radar: inequity. Social forces in our lives can influence our health even more than genetics or health care—factors such as income inequality, lack of access to safe and affordable housing, inadequate health care, food insecurity, and education. The unequal distribution of these essential conditions for health, which largely tracks with race and poverty, helps explain why the poorest people in the U.S. can expect to live 10 years less than those of middle-to-higher income. Globally, the life expectancy gap between the richest and poorest countries is 18 years. In this sense, you could argue that affordable housing and education are anti-aging interventions. “The real reason why there are big, big differences in the age of death in the U.S. has nothing to do with medicine, nothing,” says Campisi. “It has everything to do with wealth disparity, and there are many people who don’t want to talk about that, especially in Marin and Silicon Valley.”
Verdin wants to change that, and he sees this as fertile territory for the Buck. He’s fundraising now to build the fourth of the Buck’s five laboratory buildings and make it home to a new entity called the Healthspan Center, which will conduct research not on worms or mice but humans. (The Buck for years was known for its research on C. elegans, the microscopic worm that has informed much of our basic understanding of the biology of aging, so this move up the species ladder reflects the readiness of the science for the next stage.) Along with social conditions, Verdin wants the center to examine biomarkers of aging, the exposome, and the biology of stress—which also tends to reflect disparities of race and poverty—and how stress shortens lifespan. “That’s probably the quickest way that we can increase lifespan, is by looking at the whole field that people call social determinants of health,” he says. “All of this influences your healthspan profoundly… People say, ‘Well, it’s the business of the politicians,’ but I think there’s a lot that we’re leaving on the table.”
The fifth building, as Verdin envisions it, will be a hub for clinical translation, including clinical trials. Equity matters there, too, especially in the cost of any therapies the science produces. The Glenn Foundation’s Lee, who oversaw some of the field’s seminal grants as executive director of the Larry Ellison Foundation (formerly called the Ellison Medical Foundation), says, “We have to be really careful that the kinds of interventions and things that come from aging research don’t just make these disparities even worse, where only the poor or those people who are under-resourced are the ones who suffer the ill effects of aging.”
To usher the Buck into geroscience’s next stage, Verdin is encouraging veteran faculty to do more clinical translation and recruiting younger faculty who are already doing it. Malene Hansen, who recently moved from Sanford Burnham Prebys Medical Discovery Institute in San Diego to become the Buck’s chief scientific officer, hopes to make the Buck a center for training and education, hosting workshops and sabbaticals, akin to the Cold Spring Harbor Laboratory in New York. The Glenn Foundation’s Kevin Lee would like to see it become “a convening point” on the big unanswered questions of geroscience—especially the root cause of aging-related disease and aging itself.
However, the independence that makes the Buck so appealing in some ways could also prove a challenge to its growth. Its almost monastic environment among the oak trees of northern Marin allows faculty to immerse in their work together. In its open-design labs, one professor’s staff works literally just a bench away from the next—Lithgow’s lab adjoins Campisi’s; Julie Andersen’s lab, which studies neurodegenerative diseases, adjoins Pankaj Kapahi’s lab, which studies metabolism and nutrition—fostering cross-pollination. That appeals to some researchers. “I wanted to work here because it would be like coming to an aging conference every day,” says CSO Hansen. But for others, the isolated setting could be an obstacle to recruitment.
“I think there’s going to be a real supply and demand problem in the next 10 years for people who are trained in the biology of aging,” says Kaeberlein. With more resources flowing into the field and Silicon Valley taking an interest, while the number of people trained in aging biology remains relatively small, top talent will command high salaries from industry and prestigious universities. Biotech company Altos Labs, for example, launched in January 2022 in California and the U.K. with a lineup of all-star longevity scientists and $3 billion in funding. How do you continue to recruit in that ecosystem? “The real answer is it’s going to take money,” Kaeberlein says, “and that’s a hard thing for an institute to ensure unless they’ve got a huge endowment.”
With the Buck name and the I.M. Pei design, “a lot of people think the Buck is loaded,” Verdin says, but in reality it mostly relies on its own fundraising. Independence is “a curse and blessing,” he adds. “A curse because sometimes it’d be great to have all the infrastructure of a university. The blessing is we don’t have to ask for permission to do anything. … We are small and nimble and as long as what we are contemplating doing is ethical and aligned with our mission, we can do it. There are no rules.” With that freedom, for example, the Buck in 2019 launched the Center for Reproductive Longevity and Equality to study the neglected question of why women age out of fertility so early in life—and how to delay that.
For the geroscience field to graduate from its youth, many researchers feel it needs to change not only its orientation to clinical translation but also its narrative. When most people think of aging research, says Lee, “You see this elderly couple walking along the beach, like Viagra ads. You think the obvious target audience are people in their 60s, 70s, 80s. But ultimately it seems like everyone should be thinking about this more, and there’s more to it than those later-in-life interventions.”
The key, he says, is to push the car right to the edge of its capability, with each control perfectly dialed.
Equally important is casting off the cloud of pseudoscience that has always shrouded the field. “The field has turned a corner and is going to grow and expand regardless of what happens,” Kaeberlein says. “But the misrepresentation of the field, particularly among the general public, can still do harm, so we need to be thoughtful and honest and rigorous in the way we present the science, because there are always going to be people who don’t and aren’t.” It doesn’t help, for example, when a scientist with the stature of Harvard Medical School’s David Sinclair calls the resveratrol compound that he studies “as close to a miraculous molecule as you can find,” or touts the NAD+ coenzyme as “the closest we’ve gotten to a fountain of youth.”
Meanwhile, even as longevity fever rises, those working on clinical applications need to convince funders to stay patient, because however exciting the prospects, research unfolds especially slowly when it’s about a process as gradual as aging. Ask Campisi how long it will likely take to produce drugs to relieve or reverse certain age-related diseases, and she says, “Ask me what the stock market will do tomorrow. If I give you an answer and you believe me, you’re not competent. We don’t know.”
For his faculty and staff at the Buck, Verdin says he tries to keep the pressure for a big clinical breakthrough tamped down, because “pressure is not consistent with the truth.” He admits, however, that the pressure is there and he feels it. Ratcheting expectations drive him to work harder, to focus on what’s important—and, when he needs a release, to speed his race cars around the track. The key, he says, is to push the car right to the edge of its capability, with each control perfectly dialed.
“It’s the same working in this field in some way,” he says. “I push my team to be on that edge where it might not be very comfortable, but we’ve got to drive on the edge to go as fast as we can to do the best we can,” to not get complacent—especially when, as Verdin acknowledges, there is a degree of social pressure for the Buck to demonstrate the validity of its work.
“We’ve built a huge enterprise, $65 million a year, 300 employees,” Verdin says. But, he pauses, “Where’s the beef? Are we just a group of dreamers up on the hill or are we actually going to deliver something of significance to humanity?”
His answer is the latter. And even as he steps on the accelerator, he says, “I think we’ve still got a little bit of time, and we have to do it right.”