Fight Aging!

The SENS Research Foundation staff here continue their series of posts on the problems with studies of metformin as a potential means to modestly slow aging. Taken as a whole, the animal data for metformin is dismal, and the human data often touted as a rationale for use of metformin is problematic. If one feels motivated to make use a small molecule drug that may act to modestly slow aging, and which has extensive existing safety data for human use in other contexts, then look to rapamycin instead, where the animal data is robust.

Serious scientists have championed the diabetes drug metformin as a potential longevity therapeutic for more than two decades, but more careful scientific testing of the hypothesis over the last ten years has soured many critical thinkers on this use of the drug. Notable evidence against the idea include that metformin failed to extend lifespan in rodents in the National Institute on Aging (NIA)'s Interventions Testing Program and other well-done lifespan studies, and the debunking of the human epidemiological study that appeared to show that people with diabetes who took metformin lived longer than nondiabetics who didn't.

But interest was rekindled by a new study of metformin in aging cynomolgus monkeys. The authors claim to have shown that metformin preserved brain structure, "enhanced" cognitive function, and slowed biological aging by more than six years after less than three and a half years of treatment, as measured on a new species-specific aging clock. So like gamblers who have lost their shirt but can't stop themselves from playing, the conviction that this time it's different has set into the longevity community.

The monkeys in the metformin trial began the study at a body mass index (BMI) of 28, which is in the "overweight" category, and remarkably, the control animals ballooned to BMI 32 (obese) just three months later. By contrast, the monkeys on metformin remained 3 to 5 BMI points lighter than the controls through most of the experiment, up until the control animals began their late-life decline. That's a quite profound weight-protective effect, comparable to the new GLP-1 receptor agonist drugs.

So the first two interrelated problems with the study are that the control animals were obese throughout almost the entire study and that metformin had such a profound protective effect against weight gain in these animals. Why would metformin have made these monkeys so much lighter than their untreated labmates? Metformin is known to cause modest weight loss in humans, especially when it is "enhanced" by common side effects like indigestion or diarrhea. But the weight-buffering effect in these monkeys is much greater than you'll typically see in humans on the drug. Whatever the mechanism, the protective effect against the substantial weight gain seen in the control animals seems highly likely to be responsible for much or all of the benefits in the metformin-treated monkeys, for reasons that have nothing to do with a direct effect on aging processes.

Link: https://www.sens.org/monkeying-with-clocks-metformin/