The day we are born, the aging clock starts ticking. It may tick faster or slower depending on our genes, the good and bad habits we pick up in life, or just plain luck – but it always moves inexorably forward until the day we die.
The aging process is not fully outside of human control, however. And over the past few decades, researchers have uncovered some intriguing mechanisms that could one day be exploited to slow or potentially even reset the clock for key determinants of the aging process.
In 2014, for example, researchers led by Stanford University neuroscientist Tony Wyss-Coray performed experiments in which they infused old mice with blood from young animals—a technique known as parabiosis. The effects were striking, with the treated mice showing increased growth and connectivity among brain cells, and clear improvements in memory and cognition. Between 2017 and 2022, the Switzerland-based NOMIS Foundation would fund efforts by Wyss-Coray’s group to identify specific blood-borne molecules that can facilitate similar “rejuvenation” of the brain in humans.
This notion is still not universally embraced. “I think the general concept that age is malleable is something that has only recently sort of become acknowledged by most scientists,” says Wyss-Coray. “I think there’s still many who have not heard about it or are surprised about it.” But the implications could be tremendous and far-reaching.
Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York City, notes that the benefits of increasing the number of healthy years that humans can experience go well beyond public health and individual quality of life. “If they’re not in the hospital, where are they? They are traveling, they’re shopping, they have a contribution to the economy,” says Barzilai. As an example, he cites research from Andrew Scott at the London Business School suggesting that extending the healthy lifespan of humans could generate tens of trillions of dollars of economic activity.
But before humanity can achieve that potential, researchers must crack the many remaining mysteries underlying the aging process—and learn how to translate those into treatments. Fortunately, the field is rapidly making headway, thanks to innovative research powered by growing investment from government agencies, industry, and organizations like the NOMIS Foundation.
Hints of heterogeneity
Not so long ago, there was considerably less enthusiasm. Early in his career, Barzilai says that “nobody wanted to talk about aging.” Even studies into age-related diseases tended to underemphasize the physiological effects of aging.
For example, Wyss-Coray’s early research centered on Alzheimer’s disease, where he was especially interested in uncovering the influence of aging-related inflammation and immune dysfunction in disease pathology. “But in the Alzheimer’s field at the time, there were only neuroscientists, and neuroscientists 30 years ago only studied neurons,” he says. “Even glial cells were some fringe field.”
And for those relatively few who were studying aging as a broader physiological process, much of the effort revolved around trying to find specific biological pathways that transform “young” cells into “old” cells. Harvard University aging researcher Vadim Gladyshev recalls attending talks earlier in his career where presenters would focus on individual genes as “key drivers” of age-related decline. “This is complete nonsense, because there are no key drivers of aging,” he says. “It’s the whole system that transitions.” This is not to say that the genes identified in those studies were irrelevant, but rather that it is impossible to boil a complex and heterogeneous process like human aging down to a handful of genetic dials and toggle-switches.
Barzilai’s own interest in aging was fueled by his own encounters with this heterogeneity as a young medical resident, where he saw dramatically different outcomes for elderly patients depending on the extent to which they “looked their age.” “A person who’s 75 years old that looks like he’s 90, you know that you’re dealing with end of life,” says Barzilai, whereas one who looks 50 or 60 might have far greater resilience against injury or disease. These patients offered a clear object lesson: the rate and consequences of biological aging can vary widely between individuals, and differ considerably from what one might expect based purely on the passage of time.
Stanford University neuroscientist Tony Wyss-Coray received NOMIS funding to identify blood-borne molecules that can facilitate brain “rejuvenation.”
Rejuvenating the field
More recently, rapid advances in technology have given researchers the capacity to conduct extensive “omic” studies that deeply survey the DNA, RNA, proteins, and metabolic activity of both tissues and individual cells. “Before, we had to pick something that we said ‘represents aging,’ and then we measured that,” says Wyss-Coray. “Now we can measure thousands of [molecules] and show how the whole thing looks more like a younger organism.” These capabilities have advanced the field’s understanding of how and why biological systems break down over time.
In 2013, for example, University of California–Los Angeles geneticist Steven Horvath published a highly influential article in which he described the identification of a “molecular clock” for the aging process. His approach focused specifically on how patterns of genomic methylation—chemical modifications to chromosomal DNA-have a profound impact on the expression of nearby genes. “It was really, really impressive,” says Gladyshev, noting that the clock offered remarkable accuracy and predictive power in terms of tracking chronological age in mammals.
Subsequent studies have built on Horvath’s foundational work to assemble a more detailed dossier of age-related biomarkers. In December 2023, for example, a multi-national team led by Wyss-Coray published an extensive survey of blood-borne proteins secreted by 11 different organs in the human body. Remarkably, this analysis revealed that different organs age at different rates in different people, where the existence of an “age gap” between an organ and its owner can be a red flag for future disease risk. “If we measure that your kidney is 2 years older than you actually are, a person with that profile is more likely to have kidney failure in the future,” says Wyss-Coray.
Finding such genomic, proteomic, and metabolomic signatures is extremely useful, but not the end-all-be-all of aging research. “Biomarkers are just a tool-our focus is actually to understand aging,” says Gladyshev. Accordingly, his group has put considerable effort into deciphering the biological role of those biomarkers. He notes that some signatures of aging are purely chronological-marks on the biological calendar, rather than products of ongoing physiological decline. By separating out the biomarkers that specifically herald or arise from such decline, Gladyshev aims to develop even better clocks that distinguish “bad” aging from healthy aging.
Sorting this out makes it possible to get a better handle on the different ways biology fails with aging. “To me, aging is the accumulation of negative consequences of life,” says Gladyshev. The human genome naturally acquires mutations over a lifetime that can gradually increase the risk of developing cancer, and there are numerous other mechanisms by which the mere act of living can contribute to the accumulation of toxic biological byproducts. For example, cellular metabolism naturally produces chemical compounds that inflict damage on DNA, proteins, and other biomolecules. If the body cannot clear these cellular pollutants in a timely fashion, they have the potential to accelerate the aging process.
From mice to medicines
Turning these insights into interventions has not been easy, however. And to date, there are no supplements or clinically approved drugs with a proven capacity to mitigate or reverse aging-related damage in humans.
Much of the field’s work to date has been built on a foundation of experiments in animal models. This typically means mice and rats, but other studies have employed more specialized species such as the African killifish, which undergoes the aging process in a matter of months, or the long-lived naked mole rat. “I think all of the major findings that we have in the field come from animal models,” says Gladyshev. In 2023, his team published a study in which they systematically evaluated signatures of longevity in 41 different mammalian species to identify mechanisms that might offer good targets for anti-aging interventions.
This makes basic research with cell and animal models an essential component of contemporary aging research (see Sidebar: Growing opportunities) – but that does not make it sufficient. “If you’re a mouse, I can take care of you – I can make you live longer by 24 percent,” says Barzilai. “But it hasn’t been translated.” Accordingly, much of his group’s work focuses on discovery in humans—for example, generating genetic and molecular profiles of centenarians and their families to understand the processes that contribute to their remarkably healthy aging. “They’re sick for a very little time at the end of their lives,” says Barzilai. “Thirty percent of our centenarians don’t take drugs and don’t have any disease.” The pathways uncovered here can then be tested more systematically in animal models.
This combination of basic and clinical research is finally beginning to bear fruit, and the experts are finding cause for enthusiasm about a few particular drug candidates. Importantly, some of these already have an established clinical track record. Wyss-Coray highlights the various GLP-1 agonists like semaglutide—the diabetes drug that is now upending the weight loss world. “Approaches like that, which we know have clear effects on the molecular processes of aging, I think will probably be the first to be applied,” he says.
This drug family was also among the most promising anti-aging candidates identified in a recent publication from Barzilai, in which he evaluated a wide range of U.S. Food and Drug Administration (FDA)-approved drugs for their impact on various physiological “hallmarks of aging.” Barzilai’s list was topped by another category of drugs known as SGLT-2 inhibitors, such as empagliflozin. These drugs already have an excellent track record as approved diabetes therapies, with extensive testing data from both mice and people, but these and other studies also suggest more far-reaching health benefits as well. “In humans, when you look over 32 months versus placebo, they decrease incidence of diseases-renal-specific, cardiac-specific, and deaths from all causes,” says Barzilai. He and his colleagues are also in the process of trying to launch the Targeting Aging with Metformin (TAME) program, a series of clinical trials designed to evaluate yet another FDA-approved diabetes drug with putative anti-aging benefits.
Towards tailor-made treatments
Success with a repurposed drug could give clinical aging research some much-needed momentum, but Wyss-Coray cautions that we are unlikely to see a single blockbuster drug that delivers broad benefits to the aging population. For example, the anti-aging effects produced by certain blood-borne factors in his team’s parabiosis experiments were not evenly distributed across cell and tissue types. Furthermore, the parabiosis effect works both ways—donor serum from older animals can accelerate aging in young recipients, revealing the presence of other bloodborne molecules that promote decline and degeneration.
“You may need dozens of different factors that have beneficial effects, and you may at the same time have to block detrimental factors in an old organism to really mimic what we see with parabiosis,” says Wyss-Coray. This scenario is further complicated by his team’s recent findings on organ aging, which highlight how different organ systems in the same individual can decline at radically different rates relative to each other.
These findings suggest that effective aging therapy will require the same level of personalization currently applied in domains like cancer care. In some cases, this might involve simple lifestyle changes-for example, dietary interventions tailored to stall accelerated aging in the digestive tract or cardiovascular system. The evidence also suggests that many of the FDA-approved drugs now under consideration for repurposing may only benefit a subset of patients and organ systems. “We have clinical studies that have endpoints related to obesity, pre-diabetes, renal, cardiovascular, frailty, flu,” says Barzilai, “and we’re trying to basically help clinicians to know when do you choose one drug over the other.”
There is also considerable evidence for a firm upper bound to the human lifespan. To date, only one person—Jeanne Calment, who survived to 122 years-has been verified as living beyond the age of 120. Gladyshev says that scientists currently estimate a biological limit in the range of 138 years, after which the body will inevitably fail even with access to treatments and lifestyle adjustments that slow the aging process. “We expect a relatively small effect, maybe 5 or 10 percent,” he says.
To get a bigger benefit, more radical technological solutions may be needed. For example, Wyss-Coray is particularly excited about ongoing research into so-called reprogramming methods that can literally roll back the clock. This concept is well-validated in cell culture, where certain cocktails of chemicals or proteins can cause fully mature cells to transform into “young” stem cells with many, if not all, of the properties of embryonic tissue. If that process could be tightly controlled—to avoid, for example, the risk of creating unwanted reservoirs of tumorigenic stem cells—a similar “partial reprogramming” strategy could significantly extend the range of human longevity or delay the onset of age-related disease.
Wyss-Coray sees real opportunities to help ensure that people can stay healthy and active at the upper limits of human aging, but believes that greater leaps in rejuvenation are unlikely to occur in the near future. And this may not be a bad thing, he adds. “What would we do with our lives if we live twice as long?” he asks. “It has so many implications in terms of the resources on this planet – everything becomes philosophical very quickly.”
Growing opportunities
What a difference a few decades make. In the early days of Barzilai’s career in aging research – some 30 years ago – there was limited funding to support the development of anti-aging interventions. “The problem is the concept was not accepted widely, and therefore the funding was rate limiting,” says Barzilai.
The money problem has not disappeared, but investment has been steadily growing in recent years. For example, in 2023, the U.S. National Institutes of Health (NIH) spent 6.4 billion USD on aging-related research – more than doubling its budget from 2016. Numerous other funding opportunities have emerged as well. “There’s large foundations that just give money to people that studied basic mechanisms of aging,” says Wyss-Coray, who has received support for multiple such projects through the NOMIS Foundation.
Barzilai says the funding situation is “still rate-limiting,” but things are moving in the right direction. He and Gladyshev both point to the proliferation of startups dedicated to advancing aging research and turning their findings into anti-aging therapies, such as Altos Labs-a Jeff Bezos-backed venture that launched in 2022 with 3 billion USD in funding. This excitement is also drawing talent from other fields, and Gladyshev is optimistic about the future. “I feel things are improving,” he says. “Smart people who used to go to study cancer or some other field-now they go to aging.”
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