A drug taken by millions of people to control diabetes may do more than lower blood sugar.
Research suggests metformin has anti-inflammatory effects that could help protect against common age-related diseases including heart disease, cancer, and cognitive decline.
Scientists who study the biology of aging have designed a clinical study, known as The TAME Trial, to test whether metformin can help prevent these diseases and promote a longer healthspan in healthy, older adults.
Michael Cantor, an attorney, and his wife Shari Cantor, the mayor of West Hartford, Connecticut both take metformin. "I tell all my friends about it," Michael Cantor says. "We all want to live a little longer, high-quality life if we can," he says.
Michael Cantor started on metformin about a decade ago when his weight and blood sugar were creeping up. Shari Cantor began taking metformin during the pandemic after she read that it may help protect against serious infections.
The Cantors are in their mid-60s and both say they feel healthy and have lots of energy. Both noticed improvements in their digestive systems – feeling more "regular" after they started on the drug,
Metformin costs less than a dollar a day, and depending on insurance, many people pay no out-of-pocket costs for the drug.
"I don't know if metformin increases lifespan in people, but the evidence that exists suggests that it very well might," says Steven Austad, a senior scientific advisor at the American Federation for Aging Research who studies the biology of aging.
An old drug with surprising benefits
Metformin was first used to treat diabetes in the 1950s in France. The drug is a derivative of guanidine, a compound found in Goat's Rue, an herbal medicine long used in Europe.
The FDA approved metformin for the treatment of type 2 diabetes in the U.S. in the 1990s. Since then, researchers have documented several surprises, including a reduced risk of cancer. "That was a bit of a shock," Austad says. A meta-analysis that included data from dozens of studies, found people who took metformin had a lower risk of several types of cancers, including gastrointestinal, urologic and blood cancers.
Austad also points to a British study that found a lower risk of dementia and mild cognitive decline among people with type 2 diabetes taking metformin. In addition, there's research pointing to improved cardiovascular outcomes in people who take metformin including a reduced risk of cardiovascular death.
As promising as this sounds, Austad says most of the evidence is observational, pointing only to an association between metformin and the reduced risk. The evidence stops short of proving cause and effect. Also, it's unknown if the benefits documented in people with diabetes will also reduce the risk of age-related diseases in healthy, older adults.
"That's what we need to figure out," says Steve Kritchevsky, a professor of gerontology at Wake Forest School of Medicine, who is a lead investigator for the Tame Trial.
The goal is to better understand the mechanisms and pathways by which metformin works in the body. For instance, researchers are looking at how the drug may help improve energy in the cells by stimulating autophagy, which is the process of clearing out or recycling damaged bits inside cells.
Researchers also want to know more about how metformin can help reduce inflammation and oxidative stress, which may slow biological aging.
"When there's an excess of oxidative stress, it will damage the cell. And that accumulation of damage is essentially what aging is," Kritchevsky explains.
When the forces that are damaging cells are running faster than the forces that are repairing or replacing cells, that's aging, Kritchevsky says. And it's possible that drugs like metformin could slow this process down.
By targeting the biology of aging, the hope is to prevent or delay multiple diseases, says Dr. Nir Barzilai of Albert Einstein College of Medicine, who leads the effort to get the trial started.
The ultimate in preventative medicine
Back in 2015, Austad and a bunch of aging researchers began pushing for a clinical trial.
"A bunch of us went to the FDA to ask them to approve a trial for metformin,' Austad recalls, and the agency was receptive. "If you could help prevent multiple problems at the same time, like we think metformin may do, then that's almost the ultimate in preventative medicine," Austad says.
The aim is to enroll 3,000 people between the ages of 65 and 79 for a six-year trial. But Dr. Barzilai says it's been slow going to get it funded. "The main obstacle with funding this study is that metformin is a generic drug, so no pharmaceutical company is standing to make money," he says.
Barzilai has turned to philanthropists and foundations, and has some pledges. The National Institute on Aging, part of the National Institutes of Health, set aside about $5 million for the research, but that's not enough to pay for the study which is estimated to cost between $45 and $70 million.
The frustration over the lack of funding is that if the trial points to protective effects, millions of people could benefit. "It's something that everybody will be able to afford," Barzilai says.
Currently the FDA doesn't recognize aging as a disease to treat, but the researchers hope this would usher in a paradigm shift — from treating each age-related medical condition separately, to treating these conditions together, by targeting aging itself.
For now, metformin is only approved to treat type 2 diabetes in the U.S., but doctors can prescribe it off-label for conditions other than its approved use.
Michael and Shari Cantor's doctors were comfortable prescribing it to them, given the drug's long history of safety and the possible benefits in delaying age-related disease.
"I walk a lot, I hike, and at 65 I have a lot of energy," Michael Cantor says. I feel like the metformin helps," he says. He and Shari say they have not experienced any negative side effects.
Research shows a small percentage of people who take metformin experience GI distress that makes the drug intolerable. And, some people develop a b12 vitamin deficiency. One study found people over the age of 65 who take metformin may have a harder time building new muscle.
"There's some evidence that people who exercise who are on metformin have less gain in muscle mass, says Dr. Eric Verdin, President of the Buck Institute for Research on Aging. That could be a concern for people who are under-muscled.
But Verdin says it may be possible to repurpose metformin in other ways "There are a number of companies that are exploring metformin in combination with other drugs," he says. He points to research underway to combine metformin with a drug called galantamine for the treatment of sarcopenia, which is the medical term for age-related muscle loss. Sarcopenia affects millions of older people, especially women.
The science of testing drugs to target aging is rapidly advancing, and metformin isn't the only medicine that may treat the underlying biology.
"Nobody thinks this is the be all and end all of drugs that target aging," Austad says. He says data from the clinical trial could stimulate investment by the big pharmaceutical companies in this area. "They may come up with much better drugs," he says.
Michael Cantor knows there's no guarantee with metformin. "Maybe it doesn't do what we think it does in terms of longevity, but it's certainly not going to do me any harm," he says.
Cantor's father had his first heart attack at 51. He says he wants to do all he can to prevent disease and live a healthy life, and he thinks Metformin is one tool that may help.
For now, Dr. Barzilai says the metformin clinical trial can get underway when the money comes in.
This story was edited by Jane Greenhalgh
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