In fall 2014, about two dozen geroscientists — researchers who study the confluence of aging, biology and disease — gathered in a remote 15th-century Spanish castle-turned-luxury hotel in the province of Toledo to discuss turning a provocative idea into reality: a study in humans showing that a drug could put the brakes on aging.

In recent years, many experts in the aging field have come to believe that certain medications acting at the cellular and metabolic level can slow aging by staving off its most striking effects — frailty and ­age-related diseases, for example — and extend healthy life in doing so. Now they are setting out to prove it.

“We’re not about the fountain of youth,” says Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine, one of the meeting’s organizers. “That’s taking an old person and making him young. What we are saying is that we can delay aging.”

Drugs with the ability to postpone or prevent the onset of debilitating diseases could lead to additional healthier years, enhancing longevity and providing enormous societal benefits, experts say.

Leading the list of candidates is metformin, a longtime treatment for Type 2 diabetes, and rapamycin, a chemotherapy agent and immunosuppressant. Scientists also are studying a class of compounds known as senolytics, which attack “senescent” cells in the body that tend to proliferate with age. Senescent cells damage healthy cells around them, contributing to multiple age-related diseases.

“We’re all aging, but we don’t have to age poorly,” says Corinna Ross, an associate professor of population health at Southwest National Primate Research Center in Texas, who has been studying these drugs in animals. “Look at what is happening now — covid is exploding all around us, and the people at highest risk are in nursing homes. If we can keep people from needing long-term care by reducing the impacts of aging, we can reduce the impact on families, medical costs, the health-care system and the economy overall.”

But such drugs could face a daunting challenge, since aging is not considered a disease. This means the Food and Drug Administration is unlikely to approve a drug for its anti-aging effects, or as a new use for a licensed drug. Also, pharmaceutical companies probably wouldn’t be inclined to develop drugs for that purpose only.

Scientists who were at the meeting in Spain hope to circumvent that hurdle by conducting a study — in this case, with metformin — to test whether it can prevent or delay three age-related diseases — dementia, heart disease and cancer — and, in doing so, extend life.

At least one study had heightened their interest in the drug as possibly life-extending after researchers noticed that diabetics who took the drug outlived non-diabetics who did not. Moreover, metformin had shown an effect in separate studies against each of the three diseases, prompting the researchers to try to put all the pieces together in one large randomized controlled clinical trial.

The result is a proposed six-year clinical trial, known as Targeting Aging With Metformin (TAME), which will recruit 3,000 subjects ages 65 to 79 at 14 research sites. In testing whether metformin can prevent or delay the three diseases, researchers also hope to learn whether this results in those taking metformin outliving those not taking the drug, thus extending healthy life. (One reason for choosing metformin was because of its long track record, safety and inexpensive cost.)

“The goal is not to help people live forever, but help them stay healthy longer,” says Steven Austad, who chairs the biology department at the University of Alabama at Birmingham and is senior scientific director of the American Federation for Aging Research. “But the fringe benefit is that you live longer.”

Physicians are free to prescribe a licensed drug for any reason, a practice known as “off-label” use, but this isn’t the researchers’ goal. They want the study results to prompt the FDA and drug companies to start thinking about medications within an anti-aging framework.

“The FDA and the drug companies need to see a pathway to approval,” Austad says. “The reason Big Pharma has never been interested in anti-aging is because [such a study] would take 50 years. We came up with research that could provide some answers in five or six years.”

Barzilai has long championed the life-lengthening powers of metformin, and he has been taking it himself since 2015 after being diagnosed with prediabetes. He is adamant, however, that no one should use it to slow aging before there is scientific proof that it works.

“I wouldn’t recommend it to anyone until there is evidence from a clinical trial,” he says.

The drug works on several metabolic and cellular processes linked to aging, including inflammation, waning chromosome repair, metabolic and immune dysfunction, and it improves the efficiency of the mitochondria, the “powerhouses” within cells that drive respiration and energy.

Experts also think it might influence an enzyme that controls the body’s energy demands by mimicking the effects of a low calorie diet. Many scientists believe that drastically reducing caloric intake extends life.

“Aging occurs in multiple biochemical pathways — it’s not just one thing,” Austad says. “Metformin has multiple targets, which might make it the best thing in the world for aging.”

At least one other aging study is using metformin in humans, this one to determine whether it can prevent the onset of frailty, a cluster of symptoms that typically afflict the elderly. Frail people suffer from three or more of five symptoms, including unintentional weight loss, muscle loss, fatigue, slow walking speed and low levels of physical activity. Frailty often leads to serious consequences, such as a disabling fall, even death.

Frail people have a difficult time recovering if they become ill or enter the hospital.

“There is no widely accepted intervention to prevent or improve frailty,” says Sara E. Espinoza, associate professor of medicine at the Sam and Ann Barshop Institute for Longevity and Aging Studies in San Antonio, who is conducting the study. “Although some studies have shown that exercise is beneficial, not all older adults are able to exercise at the recommended amounts due to chronic diseases or chronic pain. Further, some people lack motivation for exercise, which is another barrier.”

The trial will enroll 120 people 65 and older from the San Antonio area with diabetes or prediabetes — which increase the risk of frailty — but who aren’t yet frail, and who are otherwise healthy. They will receive metformin or a placebo, and be followed for two years.

“Metformin is known to have anti-inflammatory properties, improving the body’s sensitivity to insulin, the hormone that lowers blood sugar,” Espinoza says. “We suspect that metformin will improve frailty, because inflammation and poor insulin sensitivity are also important mechanisms for frailty development.”

Rapamycin, another promising drug, also has shown strong anti-aging and other benefits in mice, but it hasn’t yet been tested for that purpose in humans.

“It extends life even when you give it to mice that are 75 in mouse years, and eliminates or delays several types of cancer,” Austad says. “It delays the development of mouse Alzheimer’s and enhances the immune system. It even delays periodontal disease. It’s a miracle drug for mice.”

It works by inhibiting a gene turned on after meals and turned off — or down — with fasting. “It responds to nutrients, in other words,” Austad says. “This is what led researchers to hypothesize it might target aging, because fasting makes laboratory rodents live longer. I’d like to see scientists set up a [human] study in rapamycin pretty much like the metformin study.”

Researchers also are optimistic about a group of drugs called senolytics. These attack senescence, a condition that results when certain cells in the body become damaged over time, and stop dividing, which impairs the body’s ability to replace old and injured tissue.

Senescent cells secrete inflammatory proteins that destroy or harm the function of healthy cells around them, resulting in such age-related disorders as cancer, cardiovascular disease, stroke, dementia, mobility disorders, arthritis, osteoporosis and metabolic diseases.

“They do very bad things, and are hard to get rid of,” says James L. Kirkland, director of the Mayo Clinic’s Robert and Arlene Kogod Center on Aging. “Senescence also spreads from cell to cell. They take off and start spreading.”

In 2013, Kirkland and his colleagues discovered “survival pathways” within senescent cells that keep them alive. They further found that senolytics disrupt those pathways, causing the cells to program their own death. “Senescent cells die, but the good ones don’t,” Kirkland says.

Studies in mice have demonstrated that senolytics reverse cell damage wrought by senescent cells, and extend life. Recently, they also have shown promise in humans. More than a dozen clinical trials are underway testing different combinations of these drugs.

“It takes 10 days to six weeks for a cell to become senescent, but only a brief exposure to these drugs to get the cells to kill themselves,” Kirkland says. “It’s a hit and run approach. We give these drugs intermittently, not continuously.”

Because senolytics are approved for other medical uses, Kirkland urges people not to take them to slow aging. “We don’t know yet if they are going to work or whether there are side effects,” Kirkland says.

Once the research is complete and the drugs clear regulatory and other obstacles, experts will have to figure out how best to use them. “At what age do we start?” Ross says. “Do I give them to my 90-year-old grandfather to prevent dementia? Or at age 60 to decrease the risk of heart disease?”

Mindful of the work ahead, researchers are nevertheless upbeat about the prospects.

“Death is inevitable, but aging is not,” Barzilai says. “It’s actually quite flexible. We want to make the elderly more resilient, especially against severe disease, and we can do it. This will change society.”

Austad agrees. “If we could give you an extra 10 to 20 years of healthy life, it could change everything,” he says. “It would change the way we think about our careers. When we have children. How we educate ourselves. Everything.”