Metformin has been used successfully to treat type 2 diabetes for more than 60 years. In 2019, it was the fourth most prescribed drug in the USA, with more than 85 million prescriptions issued.

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Metformin became a “darling” of aging research after medical records showed that people with diabetes who took the drug often lived longer and healthier. The drug has several proven health benefits, including reducing the risk of heart disease and cancer and improving cognitive function in old age. Since metformin promotes adolescent physiology and lifespan in several animal models, the researchers believe that the drug could influence fundamental factors in the biology of aging that are responsible for several age-related diseases in humans.

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Upcoming clinical trial

While there are other promising drugs to prevent aging in humans, metformin's excellent safety profile and low cost make it a natural tool for testing on a large group of people.

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A clinical trial called TAME (Targeting Aging with Metformin) began this year. The researchers are monitoring the onset and progression of age-related diseases such as heart disease, cancer and dementia. More than 3,000 people aged 65 to 79 participate in TAME in a series of six-year studies at 14 leading research institutions across the country. If successful, TAME will prove that aging can be treated in the same way we currently treat diseases.

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However, recent research from Buck University, the University of Oregon, and Rutgers University shows that genetic variation among human study participants is likely to influence the results of TAME. Scientists came to this conclusion after treating various types of the tiny roundworm Caenorhabditis with metformin — with the three species tested showing greater genetic variability than mice and humans.

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“The data from the study show that metformin can significantly promote health across various genetic backgrounds,” says Buck Professor Dr. Gordon Lithgow, one of the study's lead scientists. “But genetic variation can determine whether metformin has a positive, neutral, or negative impact on life span and health.”

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Dr. Lithgow stresses that the findings underscore the importance of precision medicine, i.e. tailoring treatments to individuals when studying the health benefits of metformin in different populations. “Ideally, it would be great to be able to determine whether people are likely to respond to metformin or not before the study starts,” he says. “It's not fraud. It is a way to get more meaningful results, especially if the study is intended to look at diseases such as heart disease, dementia and cancer.”

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On the road to personalized medicine?

Steve Austad, a professor at the University of Alabama in Birmingham, studies the biology of aging and is one of the scientists who have successfully submitted the idea of the TAME study to the FDA. He was not surprised by the results of the worm studies. “Of course, the genetic background plays a role,” he says. “The response to virtually every known drug varies depending on the background. The expectation that this might be different with age-inhibiting drugs means that hope conquers experience. ”

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A possible addition to TAME could help researchers solve the puzzle of how best to deal with different genetic backgrounds in large populations. The National Institute on Aging is currently reviewing an application for TAME BIO, which involves researching biomarkers of aging using biological samples (blood, plasma, urine, stool, RNA, and DNA) taken from TAME study participants. These samples would enable researchers to test and track the effects of metformin on TAME participants over the course of the six-year study.

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Dr. Lithgow hopes that TAME BIO will be implemented; in the meantime, he believes the results of recent worm experiments should be a “warning” for aging researchers, many of whom talk about metformin all the time. “It is important to stress how important it is to take genetic diversity into account, as metformin is gaining popularity as a potential anti-aging measure,” he says. “The biology of aging is complex, and this is also true for humans. It is imperative that we take individual differences into account when metformin and hopefully other medications come into the clinic. Personalized medicine is the wave of the future, and we must incorporate this into our research plans. ”