Elderly mice on the popular weight-loss drug semaglutide aged slower and lived longer, mimicking the longevity effects of caloric restriction.
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Fitsum Admasu on Unsplash
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It’s a hot GLP-1 drug summer. Semaglutide—better known as Ozempic and Wegovy—seems to be everywhere. The blockbuster weight loss aid mimics a natural hormone that tells the brain “you’re full,” making it easier to shed pounds without the constant hunger and cravings that make traditional dieting miserable.
The drug may also have longer effects. A new study in mice suggests that starting semaglutide in old age extends lifespan roughly 12 percent. The mice regained their curiosity and memory and improved on myriad age-related hallmarks. Chronic inflammation cooled. Senescent “zombie cells” dwindled. Their genomes and proteins became more stable, and the hippocampus—a brain region crucial for learning and memory—sprouted new neurons.
The findings are reminiscent of calorie restriction, a way to boost longevity and stave off age-related health problems, at least in lab animals. But sticking to a diet for years, let alone decades, is tough. Scientists have long searched for a drug that could deliver some of the benefits without hunger pangs. Semaglutide seems to fit the bill, with surprising perks beyond dieting.
“If these results from mice hold true in people, this is a promising hint that people taking GLP-1R agonists [GLP-1 drugs] may have an age-slowing benefit as well as benefits to reducing diabetes and obesity,” said Tara Spires-Jones at the University of Edinburgh, who was not involved in the study.
But don’t go ordering GLP-1 drugs online just yet. The study used inbred female mice, whose physiology differs from that of women aging through or beyond menopause. Rapid weight loss in people taking these drugs can also reduce lean muscle, potentially increasing fragility in older people. And while GLP-1 drugs are already being tested in the battle against neurodegenerative disorders, whether they sharpen the aging brain remains an open question.
Still, longevity researchers are cautiously optimistic.
“The findings reframe a key question that has often been asked back to front,” wrote Maria Fernandez and Rafael de Cabo at the National Institute of Aging, who were not involved in the study. “Rather than considering the broad health benefits of GLP-1 drugs as something to be explained one disease at a time, these results suggest that the positive effects have a common cause: slowed aging.”
Fountain of Youth
One way to live healthier and longer is seemingly mundane: adopt a healthy lifestyle.
Diet and exercise have repeatedly been linked to better health in our twilight years. As we age, our bodies slowly break down. Damage and mutations accumulate in DNA. Telomeres, the protective caps at the ends of chromosomes, grow shorter, contributing to genomic instability. The molecular switches that turn genes on or off go haywire, and our cells become less able to make working proteins and clean up damaged ones.
There’s more. Mitochondria, the cell’s power plants, struggle to produce energy and leak toxic molecules. Damaged cells stop dividing, lose their function, but stubbornly refuse to die. Instead, they leak a toxic chemical soup that damages tissues. Chronic inflammation flares, and stem cells run out of steam, making it harder for the body to regenerate or repair itself.
Together called the hallmarks of aging, this laundry list has long challenged scientists looking for a silver bullet against the march of time. They have discovered some exotic options. Transferring components of young mice’s blood to older recipients has rejuvenated faltering hearts, kidneys, and brains. And clearing senescent “zombie” cells with drug cocktails or genetic engineering has attracted billions of dollars in investment.
But perhaps the most studied, and most robust, intervention is caloric restriction. In flies, rodents, and other lab animals, slashing energy intake without causing malnutrition has repeatedly extended lifespan and delayed multiple age-related diseases. Restriction triggers broad changes, including improved metabolism and insulin sensitivity. It also helps prevent damage to cells. In humans, moderately reducing calories seems to improve heart health and slow the speed of biological aging.
Sticking to a diet for years on end, however, is hardly sustainable.
Cheat Code
GLP-1 drugs may make it easier.
Originally designed to control blood sugar and appetite, the drugs have also shown promise for reducing rates of cardiovascular, kidney, liver, and neurodegenerative diseases, at least in people with obesity or Type 2 diabetes. Clinical trials are now exploring their effects in people with metabolic liver disease, which becomes more common and consequential with age.
Not all these effects can be explained solely by weight loss, raising a bigger question: How can a single class of drugs influence so many seemingly unrelated conditions that often crop up with age?
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“If GLP-1 medications slow down the aging process itself, a wide range of clinical benefits is
exactly what would be expected, because aging is the root of most chronic diseases,” wrote Fernandez and de Cabo.
To test that theory, the team gave daily semaglutide injections to 20-month-old female mice—roughly comparable to women in their early-to-mid 60s—for as long as they lived.
Compared to a group of mice given saline, the treated mice lived an average of 834 days, versus 724 days for a control group. Both groups could feast on standard chow to their hearts’ content. After just three months of treatment, the mice taking semaglutide were more lively and curious than their peers. They readily explored new environments, balanced better on a skinny rotating rod, ran faster on a tiny treadmill, and solved mazes more quickly.
Under the hood, semaglutide blunted the hallmarks of aging across the board. Stem cells in the bone marrow and hippocampus sprouted, suggesting renewed regenerative capability. DNA damage and protein and energy dysfunction declined. Zombie cells partially disappeared.
The results weren’t simply a consequence of eating less. In another three-month experiment, the team compared the drug with a calorie-restricted diet that cut energy intake by 24 percent—the same reduction seen in the semaglutide-treated mice.
The drug seemed to have a leg up. Compared with caloric restriction, it produced more improvement in cognition and blood sugar control, without the metabolic adaptations normally driven by hunger, such as lowered energy expenditure. The mice also showed fewer signs of hunger. They ate on a normal schedule rather than prowling for food before feeding time and gobbling rations once available.
Genetic sequencing of the liver found semaglutide triggered similar molecular signaling pathways as caloric restriction, like for example, those that sense nutrient availability, cell stress, and proteins involved in longevity. Both interventions tamped down inflammation and boosted genes involved in handling fats, but they didn’t follow the exact same biological playbook.
The findings raise the “intriguing question of whether GLP-1 drugs target an alternative biological route into aging that has its own side effects and therapeutic ceiling,” wrote Fernandez and de Cabo. Exactly how that route works remains unclear, but the team is eager to find out.
The findings are promising, but the study also has major limitations. It didn’t directly compare dieting and semaglutide for lifespan extension. And because gender affects the aging process, the team will need to see if the results hold in males. Then there’s the potential loss of lean muscle, a serious concern for people who are already frail or saddled with age-related health conditions.
Even so, “semaglutide is probably the best caloric-restriction mimetic I have seen,” Tim Rhoads at the University of Wisconsin–Madison , who was not involved in the study, told Chemical and Engineering News.
Untangling semaglutide’s bonus effects could ultimately reveal new ways to slow—or even rewind—aging’s ticking clock.
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