The TAME Trial: Targeting Aging with Metformin

Given the evidence that diabetics taking the drug metformin may live longer than people who don’t even have diabetes suggests metformin has an anti-aging effect, slowing the diseases of aging and, in doing so, extending both health and lifespans, but you don’t know until you put it to the test. There are a few small, brief trials of metformin on healthy volunteers, for example, randomizing a dozen or so individuals to metformin or placebo for a few weeks, comparing the effects on muscle and fat biopsies. Beneficial changes in gene expression in various aging pathways were noted, along with objective improvements in risk factors, such as LDL cholesterol and triglycerides, but what we’d really like are hard endpoints, like disease outcomes and death. Enter the TAME trial, Targeting Aging with Metformin.

Spearheaded by the nonprofit American Federation for Aging Research, TAME has the ambitious goal of randomizing 3,000 nondiabetic individuals aged 65-79 to metformin or placebo over a period of six years to assess the effect on age-related conditions, such as heart attacks, stroke, cancer, dementia, and death. Current treatments “just exchange one disease for another,” railed the principal investigator. Someone cured of cancer may just drop dead the next year from a heart attack. “What we want to show is that if we delay aging, that’s the best way to delay disease.”

Sadly, though the TAME trial received FDA approval in 2015, it has yet to get off the ground. You can guess why. As the editor-in-chief of an anti-aging journal put it, “There is no way in hell to make money out of it.” Metformin’s patent expired decades ago, and generics retail at pennies a pill. It’s considered a “genuinely good use of 75 million dollars,” but the researchers have only evidently been able to raise $11 million from private donors.

Some in Silicon Valley tech circles aren’t waiting for the results. Apparently, some techies have started taking metformin in a bid to live longer, though it’s only officially available by prescription for diabetes. Metformin is cheap, relatively safe, and one of the most promising drugs to combat age-related diseases, but there are reasons to temper our expectations. Though it’s been referred to as a “magic drug,” the longevity benefits in mice were small and dose dependent. At best, it may increase the average lifespan of certain mice by 5 percent but at a higher dose actually shortens lifespan. Much of the enthusiasm for the TAME trial rests on it acting as a test case to successfully get regulatory authorities, like the FDA, to formally recognize any treatment for the aging process itself, in hopes this will arouse Big Pharma to invest large-scale R&D to advance the field.

Further reservations about the panacean prospects placed on metformin arise from the landmark Diabetes Prevention Program study published in the New England Journal of Medicine. Thousands of prediabetic individuals were randomized to metformin or placebo for years to see if the drug could prevent their prediabetes from turning into full-blown diabetes. It worked, reducing overall diabetes incidence by 31 percent compared to placebo, but it didn’t for everyone. For example, it didn’t appear to significantly benefit those 60 years or older and only seemed to help those most at risk—those with class II obesity and the highest blood sugars. Those with lower (but still elevated) blood sugars and those under a BMI of 35 did not have their diabetes risk significantly dampened by the drug. One small study even found that, while metformin alleviated the insulin resistance of diabetics and those with a family history of diabetes, metformin actually worsened the insulin resistance (the cause of prediabetes and type 2 diabetes) of nondiabetic obese individuals that didn’t have a genetic predisposition. If you have diabetes, it can make things better; if you don’t, it may make things worse. So, healthier individuals may not reap the benefits of metformin that some try to extrapolate from those longevity studies on diabetics. In fact, even those researchers are explicit that they don’t think metformin is ready for prime time as an anti-aging intervention by the general population.

What’s safer and works even better? There was a third arm of the Diabetes Prevention Program study. Thousands of prediabetics were randomized to metformin or placebo or lifestyle changes—a cholesterol-lowering low-fat diet and exercise, at least about 20 minutes a day of moderate intensity exercise, such as brisk walking. Compared to the placebo group, those taking metformin were 31 percent less likely to develop diabetes. The lifestyle group was 58 percent less likely. Making simple lifestyle changes was nearly twice as effective as metformin (and with fewer side effects—for example, six times fewer cases of gastrointestinal distress).

Other randomized controlled trials have found the same thing—lifestyle approaches superior to drug-based approaches for diabetes prevention. And, that 60 or so percent drop in risk was not among those that actually made the lifestyle changes, just those instructed to do so. Another diabetes prevention trial published in the New England Journal of Medicine that found the same 58 percent reduction in diabetes risk among those asked to make lifestyle changes drilled down to see what the benefit was for those who fully complied. Only a fraction of the lifestyle intervention group met the modest goals. Only about a third increased their exercise, for example. Only about a quarter met the minimum recommended intake of fiber (found concentrated in whole plant foods) or cut down on enough saturated fat (mostly dairy, dessert, chicken, and pork). But, they did better than the control group, and fewer of them developed diabetes because of it. But, what if you looked just at the folks that actually made all (or even just 4 out of 5) of the recommended lifestyle changes? They had zero diabetes—none of them got diabetes over the course of the study, meaning effectively a 100 percent drop in risk.