The Future of Aging

Neretti, who came to Brown from Italy to study physics, brought computational and genomics skills to his initial collaborations with Sedivy. Now an associate professor of molecular biology, cell biology, and biochemistry, he’s been studying senescence for much of his career. One thing he’s trying to unravel now, as part of SenNet, is the definition of senescence, because it has many different forms— which, in the context of drug development, complicates things.

“Most of the drugs that we used for senolytics [molecules that kill senescent cells]at the beginning were essentially chemotherapy drugs,” Neretti says. These early senolytics pushed senescent cells into apoptosis—but they impacted healthy cells as well, causing side effects. “The quest now is to find more and more specific drugs or targeted therapies that can identify and selectively clear only senescent cells. And to be very, very specific, you need to know a lot about how senescent cells are different from other cells.” Differences include cell type, how long they’ve been senescent, and what pushed them toward senescence in the first place.

Neretti’s lab is using spatial multiomics— technologies that map genes, RNAs, and proteins in cells—and artificial intelligence to image how chromosomes change and rearrange in senescence. “We want to identify the regions in tissues that have senescent cells, and then go in and look at them in more detail,” he says. Then there’s an even more basic problem: when they find a senescent cell, they don’t know how long it’s been there.

“So I’m very interested in trying to develop strategies to measure the age of a senescent cell in the body, which has been largely unexplored, just because the techniques are not easy,” Neretti says. “But I think we need to find out.” Right now, it isn’t clear if the accumulation of senescent cells is due to more of them being produced, or fewer being removed—knowledge that would inform drug development.

Jumping Genes

More than a decade ago, Neretti worked with Sedivy on a study of senescent cells that showed how snippets of DNA called retrotransposable elements wreak havoc on our aging genome. The findings led Sedivy down a new path toward trying to uncover the mechanisms of aging.

Retrotransposons, which Sedivy calls “molecular parasites,” work like HIV and other retroviruses: they insert themselves into the genome, via RNA, and can be passed down through the germline. The process can abet genetic diversity and evolution—nearly half of the human genome is made up of retrotransposons— but when unchecked, as in an aging cell, they can trigger senescence, inflammation, and disease. Sedivy calls retrotransposons a “classic example” of a target that could address many ills. He’s honed in on a class of retrotransposons, LINE-1, that’s particularly active in the human genome and in senescent cells, and has been linked to neurodegeneration and certain cancers.

Sedivy reasoned that reverse transcriptase inhibitors used to treat HIV could block LINE-1. But to get to the bottom of that, he needed structural biologist and RNA expert Gerwald Jogl, PhD, whose proficiency with x-ray crystallography would help them understand how the retrotransposon works at the molecular level. Jogl says when Sedivy proposed the collaboration seven years ago, he was all in.

“That was the most exciting thing I’ve seen in a long time,” says the associate professor of biology, not only because of the project’s translational potential but the opportunity to combine their expertise: First, his lab would delve into the molecular world to find and characterize inhibitors; then they’d go back to Sedivy’s lab, where they’d test how they worked in cell culture.

“We’re looking for something that is specific, stops retrotransposons, and has no further side effects,” Jogl says. “And this is where you can do this. You can afford to do this in academia because … this is really a long-shot experiment.”

Long shot that it was, they did find LINE-1 inhibitors; meanwhile, two other inhibitors have gone to clinical trials. A phase one at Butler Hospital, which is testing an HIV therapy in Alzheimer’s patients, is now underway; Sedivy says he expects “marginal” effects, but if it proves safe they will design trials with other drugs in the same class. Meanwhile Transposon Therapeutics, a biotech company in which Sedivy holds equity and serves as a consultant, ran a successful phase two trial of another HIV drug as a treatment for progressive supranuclear palsy, a rare neurodegenerative disorder. In May, the FDA granted the drug fast-track designation for PSP. Transposon plans to launch a phase three trial of the same therapy in people with a genetic type of ALS. “What the company is trying to do is build a case to launch Alzheimer’s trials,” Sedivy says.

If these drugs don’t work, Jogl will keep looking. The unknowns of aging—and that there’s so much to discover—is what makes the work so exciting. “There’s many other directions you could go” in terms of drug targets, he says. The main goal is to improve human health; if your hypothesis is wrong, you move on to a new one. “That’s the power of basic biology,” Jogl says. “The more we understand about that, the more you can see other angles that you might have a better choice.”

Gut Feelings

As with most complex conditions, aging has many drivers; senescence is just one of them. Another mechanism, hormone regulation, has been the research focus of Professor of Biology Marc Tatar, PhD, since a middle-of-the-night epiphany nearly three decades ago.

An insect ecologist who began studying aging in grad school (“I’ve been studying this longer than anybody in the whole group”), he connected diapause and dauer—types of dormancy that fruit flies and nematodes, respectively, enter to survive harsh conditions—with insulin signaling, which regulates not only those states but also aging in both flies and worms. “And then I found the hormones that are responsible for that, which I’m writing about, still, 27 years later,” he says.

In mammals and fruit flies, metabolic hormones called incretins increase the secretion of insulin when we eat. In a recent paper, Tatar and his colleagues showed that if you knock out incretin in flies, they live longer. “So the gut is regulating the aging,” he says. “I think we’re getting closer to saying, how do we translate this to humans?” For example, mammals, including humans, have the incretin GLP-1, the appetite-suppressing hormone in diabetes and weight-loss drugs like Ozempic and Wegovy; Tatar says some researchers are already testing whether it can extend lifespan in mice.

Tatar, meanwhile, is studying another diabetes drug that’s gotten attention for its potential to slow aging, metformin. Small studies in mice have shown some benefits, and a nationwide clinical trial is now underway. However, Tatar, who recently completed a genome-wide association study with more than 130,000 fruit flies, has doubts. At a low dose, metformin had no effect, his team found; at a higher dose, “it shortens lifespan,” he says.

Because metformin lowers blood sugar but doesn’t treat insulin resistance—the root cause of metabolic conditions linked to many diseases of aging—Tatar speculates that it won’t affect human longevity. However, he has found a mutation on the Drosophila insulin receptor that extends their lifespan by 25 to 30 percent. He and a colleague are now studying the mutation in mice, which they’ve been monitoring for several months. “Metabolically, they appear healthy,” he says. “There are some hormonal differences that have been shown in the past to be associated with slow aging in mice.” But they’ve not yet secured funding for this project, and it will take two years to draw any conclusions.

“It’s hard to convince people this is important, believe it or not,” Tatar says. Yet if he can figure out the precise mechanism of the mutation, “we should be able to make drugs that mimic what these special mutants do in flies and what we’re testing in mammals.”

Tatar’s newest colleague in the center, Karthikeyani Chellappa, PhD, is also using mice to manipulate metabolic genes that could affect lifespan and healthspan. For example, her team is scoring genetically identical mice of different ages on a frailty index similar to that used in humans, then measuring metabolites in biological samples like blood and stool, to identify a metabolic pathway that drives resilience.

“The key word for [my]lab is metabolism,” says Chellappa, the Basaviah- Ganesan Family Assistant Professor of Molecular Microbiology and Immunology. “Sometimes it’s just host metabolism that is driving everything; sometimes there could be a microbiome contributing to it too. So I’m interested in both.” While Tatar is studying hormones secreted in the gut, Chellappa is looking at the bacteria there. She notes that as we age, the metabolism of both host and microbiome change. But why? Her lab is using various groups of mice to study the interplay between host and microbes. They’re also manipulating the microbiome to understand how the coenzyme NAD affects metabolism and aging in mice.

“The thing that is very exciting about metabolism is there’s a lot still unknown,” Chellappa says. The gut microbiome has up to 100 times more genes than humans do, vastly expanding our metabolic capacity. “We are not by ourselves,” she says. “They bring in more diversity and more things to learn in terms of what can the microbiome produce, what are the molecules they can make, and how do these molecules impact host function. So there’s a lot to be done.”

Vital Signs

Chellappa says that while genes and the environment both play important roles in aging, “environment, I think, is always going to be the lead factor.” Her colleague Carlos Giovanni “Gio” Silva García, PhD, who also joined the center last year, agrees. He has focused his research on those external influences, and whether they can be passed to future generations via epigenetic modifications.

“What about what you do now could affect the health of your future children?” asks the assistant professor of molecular biology, cell biology, and biochemistry, who began his academic career as a developmental biologist. If he can figure out how epigenetic biomarkers regulate health across generations, that would open up the potential to “develop something that we can target and then improve the quality of life of people.”

Using the nematode C. elegans, which lives only about three weeks, Silva García’s lab has found that intermittent fasting can extend lifespan in the next four generations of offspring. He’s also studying how the nervous system regulates epigenetic modifications in other organ systems that promote longevity. “We cannot, of course, do [this research]in humans. And it will take ages to do it in mice,” he says. But in worms it takes just days to see results. For example, activation of an epigenetic modifier in neurons lengthened nematode lifespan by 40 percent, he says.

“How is the nervous system sending a [biomarker]to the rest of the body?” Silva García says. “I think it’s amazing. But we don’t have the answer. Yet.”

Biomarkers also travel from the nervous system into the saliva—a phenomenon Jill Kreiling, PhD, is investigating as an early indicator of Alzheimer’s and other neurodegenerative diseases. The associate professor of molecular biology, cell biology, and biochemistry and her colleagues at Rhode Island Hospital are analyzing RNAs in tiny particles called extracellular vesicles, which migrate along nerves from the brain to the salivary glands, ending up in our spit. They believe the vesicles’ contents change over time and could serve as an early warning system, and ultimately a diagnostic.

“Right now, it’s really hard to diagnose somebody early enough to have the treatments be really effective. By the time you show symptoms, it’s so far gone that you can’t reverse it,” says Kreiling, an associate director of the Center on the Biology of Aging. Existing tests for Alzheimer’s, like cerebrospinal fluid testing and brain imaging, are invasive and expensive, she notes.

To test their hypothesis, Kreiling and her team are following 150 cognitively normal people, age 65 and up, who are spitting into a tube once a year, to look for signs of Alzheimer’s, Parkinson’s, and other diseases. (The researchers are also collecting saliva from people who have been diagnosed.) They hope they’ll be able to renew their five-year, National Institute on Aging grant for at least another five years. “If we can follow [the participants]long enough, we may be able to pick out individuals that started out cognitively normal now, but down the line develop a neurodegenerative condition,” Kreiling says.

For many people, Alzheimer’s is one of the scariest diseases of aging—the loss of self, the lack of a cure. The possibility of a noninvasive, early diagnostic made it relatively easy to recruit study participants, all of whom care for Alzheimer’s patients. “I guess they see it as they’re … hopefully contributing to finding a cure or at least a way to diagnose people early enough that things can be slowed down,” Kreiling says.

The Fountain of Youth

There’s an old joke in the aging field, Jogl says: “Aging research gets more and more interesting the older you get.” Yet the young scientists training in Sedivy’s lab seem as fascinated by the topic as any of their mentors.

“I’ve known that this is what I wanted to dedicate my career to” since sophomore year of college, says Maxfield Kelsey PhD’26, MS. “It’s just a problem that you can wake up every day thinking, yeah, this is important. And the clock is ticking.”

Ethan Grant PhD’29 says the mystery of aging drew him to the field, and that its fundamental importance is looking at disease in a different way. “There’s also the more science fiction aspect of it, of extending lifespan—but that’s science fiction. Well, it’s still science fiction as of 2024,” he says.

While they and their peers are intrigued by efforts of some scientists to rejuvenate tissue or the purported anti-aging properties of metformin and rapamycin, none expect to enjoy significantly longer lifespans or healthspans than people do today (except for Grant, who assumes he’ll live past 120). But they believe their work will help address many of the diseases of aging.

“The aging research we do now is essentially looking at dysfunctional systems in their worst state to address issues that are affecting people who are much younger than the state that we’re looking at,” Jon Anthony Marthone PhD’28 says. “So if you’re able to solve diabetes in someone who’s 80 years old, you’ll help someone who’s 20.”

“There’s a lot of precision medicine happening right now,” adds Radha Kalkar PhD’26, MS. “Now you can sequence someone’s DNA and understand what’s their particular biology, and then maybe target it that way, instead of having one drug” per disease.

By aiming to extend healthspan, postdoc Dovydas Širvinskas, PhD, points out, scientists almost surely will lengthen lifespan. But that may “generate new challenges,” he says. “We will probably find a specific disease that is only for people who have lived, let’s say, to 110.” The aim, he adds, should be to minimize suffering at the end of life. “Why do we have to live until, I don’t know, 80 and still decline, decline, decline? Why couldn’t we just be healthy, healthy, healthy and then drop off?”

While superagers do, of course, die, they often avoid the slow deterioration brought on by the diseases of aging— because for the most part, they don’t get them. Some are lucky enough to have genetic advantages, like the well-studied Ashkenazi Jews, who routinely live into their 90s and 100s. But most centenarians around the world tend to share lifestyle factors, not genes.

“It’s all the things we already know make us healthy,” Kreiling says. “Don’t drink too much. Don’t smoke. Don’t eat too much. Exercise.”

All of the faculty in the center say much the same thing—and most practice what they preach. Jogl even runs marathons, while Tatar races road and cyclocross bikes. But Neretti points out that people in the “blue zones”—regions of the world with higher concentrations of centenarians, such as Sardinia and Okinawa—don’t “do a lot of running and jumping and pushing iron.” Instead, they’re tending their gardens and walking everywhere. “So I don’t call it exercise, I call it physical activity,” he says.

“Every time I go to a dinner and [other guests]find out I work in aging, everybody asks me, what should I do?” Neretti adds. They don’t want to hear his standard answer about diet and activity; “everybody wants a pill.” He used to be skeptical that a longevity drug could ever be as effective as eating better and moving more; since the success of the new weight-loss medications— which cause people to eat less— he’s had second thoughts. “So maybe what we need in aging is a drug that changes your behavior towards these things that we already know,” he says.

Jogl, for one, is philosophical about the purpose of his research. “What are we actually after? Is it about living forever? Is this what we should be doing? … What do you die from if you’re not sick?” he says. He recalls an acquaintance who, while in hospice care, sent an email that read, in part, “I’ve done everything I wanted to do. I’m ready to go.”

Leaning back in his chair, Jogl says, “That’s a great way to go, I would say, if you can honestly say that to yourself.” He pauses. “Now, that takes a lot of work.”