The promise of Metformin highlights the need for precision medicine

Metformin has been used successfully to treat type 2 diabetes for more than 60 years. In 2019 it was the fourth-most commonly prescribed medication in the US, with more than 85 million prescriptions written.

Metformin became a “darling” of research on aging when medical records revealed that people with diabetes taking the drug often lived longer, healthier lives not only those with diabetes who don’t take metformin but also among those without the disease as well. The drug has multiple reported health benefits, including lowering the risks of heart disease and cancer, and improving cognitive function as we age.  Given that metformin promotes youthful physiology and lifespan in several animal models, researchers hypothesize that the drug may influence fundamental factors in aging biology that drive multiple age-related conditions in humans.

Upcoming clinical trial

While there are other drugs that show promise in impeding aging in humans, metformin’s excellent safety profile and low cost made it a natural for testing in a large population of humans. A clinical trial dubbed TAME (Targeting Aging with Metformin) is expected to launch sometime in 2022. Researchers will be tracking the incidence and progression of age-related conditions including heart disease, cancer and dementia.  TAME will engage more than 3,000 individuals between the ages of 65 to 79 in a series of six-year trials at 14 leading research institutions across the country. If successful, TAME will provide proof-of-concept that aging can be treated in the same way we currently treat diseases.

But recent research from the Buck, the University of Oregon and Rutgers University shows that genetic variations among human trial participants will likely influence outcomes in TAME. Scientists came to that conclusion after treating diverse species of the tiny Caenorhabditis roundworm with metformin – with the set of three tested species representing genetic variability greater than that between mice and humans.  

What happened in worms

Publishing in Aging Cell, scientists found metformin increased median survival in three genetically distinct C. elegans strains, an exciting outcome because strains within the Caenorhabditis species themselves model considerable genetic diversity.  The increase in median survival was not shared by C. briggsae and C. tropicalis strains, however. In C. briggsae, metformin either had no impact on survival or actually decreased lifespan. In C. tropicalis metformin decreased median survival depending on the dose of the drug fed to the animals. Metformin prolonged the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, an exciting indicator of the ability to promote strong mobility even across species boundaries, but the drug had a negative impact on locomotion in C. tropicalis strains. 

“The data from the study shows that metformin can be a robust promoter of healthy aging across different genetic backgrounds,” says Buck professor Gordon Lithgow, one of the senior scientists on the paper. “But that genetic variation can determine whether metformin has a positive, neutral, or negative impact on lifespan and healthspan.” 

Lithgow says the results underscore the importance of utilizing precision medicine – tailoring treatments to individuals when testing for metformin’s health benefits in diverse populations of people. “Ideally it would be great to identify people as either likely or not likely to respond to metformin before the trial begins,” he says. “It’s not cheating. It’s a way of getting more useful results, especially if the trial is going to track conditions like heart disease, dementia and cancer.”

Moving to personalized medicine?

Steve Austad is a professor at the University of Alabama in Birmingham. He studies the biology of aging and is one of the scientists who successfully pitched the idea of doing the TAME trial to the FDA.  He wasn’t surprised by the results of the worm studies. “Of course, genetic background matters,” he says. “Response to virtually any known drug varies according to that background. Expecting that to be different with aging-retarding drugs is letting hope conquer experience.”

A potential add-on to TAME may help researchers navigate the conundrum of how best to deal with diverse genetic backgrounds in large populations.  The National Institute on Aging is reviewing an application for TAME BIO, which would involve a multi-faceted effort to research biomarkers of aging using biological samples (blood, plasma, urine, stool, RNA and DNA) taken from those enrolled in the TAME trial. Those samples would allow researchers to test and track how metformin impacts TAME participants during the course of the six-year trial.

Lithgow hopes that TAME BIO will come to pass; in the meantime he says the results from the recent worm experiments should provide a “heads up” for researchers in aging – many of whom talk about metformin all of the time.  “Our objective in writing this paper was to highlight the importance of taking genetic diversity into account as metformin grows in popularity as a possible anti-aging intervention,” he says. “The biology of aging is complex and so are humans. It’s essential that we take individual differences into account as metformin, and hopefully other drugs, move into the clinic. Personalized medicine is the wave of the future and we need to include that in our research plans.”

Lithgow also gave a shout-out to the fact that results from the recent worm experiments were reproduced in three separate labs involved in the Caenorhabditis Intervention Testing Program (CITP). The goal of the CITP, which involves the Buck, led by Lithgow, the University of Oregon, led by Patrick Phillip, and Rutgers University, led by Monica Driscoll, is to identify pro-longevity chemicals that are effective across diverse genetic distances which makes them excellent candidates for trials in more complex animals, including mammals. “Doing experiments in worms is an affordable way to hone in on the most promising interventions before moving them into more complex animals,” says Lithgow. CITP has fully tested 18 compounds to date (with multiple others exiting the pipeline early) and invites interested researchers to recommend interventions they believe are worth testing.