Metformin Remains a Poor Choice in the Treatment of Aging

Now that we find ourselves in an era in which there is growing support and funding for the treatment of aging as a medical condition, the battle ceases to be one of persuading people to take the idea seriously, and more a matter of convincing research and development concerns to focus on projects that are more likely rather than less likely to produce meaningful gains. Rejuvenation and many added years is the desired goal, not merely a gentle slowing of aging that is little better than the results of optimal exercise and diet. Unfortunately, most of the research and development community is indeed working on projects that will, at best, produce that gentle slowing of aging. A panoply of drugs and mechanisms relate to cellular stress responses, those triggered by calorie restriction and exercise, and which produce a gentle slowing of aging when triggered independently of those lifestyle choices. Far too much attention is directed towards ways to induce these stress responses, and far too little to more ambitious projects.

Metformin remains something of a poster child for these efforts. It is a very safe drug, with decades of widespread human use, and hence it was picked as the vehicle for the TAME trial, an effort to persuade the FDA to run a clinical trial with endpoints that represent aging, a blueprint for later trials. Metformin has terrible animal data, however: there is very little consistency to support a claim that it slows aging, and the most robust studies show no effect on life span. Where it does extend life in animal studies, the effect size is less than that of calorie restriction. There is a large human trial that produced a small extension of life in diabetic patients taking metformin, but there is no data for metformin to have any such effects in metabolically normal humans. Further, the effect is modest. One can do better with exercise. This is not the road to meaningful interventions in aging; it is a distraction from better paths forward.

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug.

Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan, and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin.

We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline, and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

Comments

There was a presentation on Tuesday at ARDD2021 indicating that in mouse studies metformin showed antiaging effects when given to young mice, but the effects were negative when given to old mice. This could be corrected by giving the old mice rapamycin as well.

On this basis, I am suspending taking metformin until I get my rapamycin supply straightened out.

Posted by: JOHN G CRAMER at September 2nd, 2021 3:21 PM

The head of the TAME trial is Nir Barzilai. He said in a video he will be in the board of directors in the new foundation with a 1 billion dollars a year budget. I'm afraid it will be a new Calico.

Posted by: Jonathan Weaver at September 2nd, 2021 5:21 PM

... 'beneficial effects of metformin ... result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress' ...

One really really needs this drug to have anti-hyperglycemic action. There's absolutely no other way to do that. Decreasing sugar intake or excercise would never ever do this. Just pop a pill!

Metformin's 'anti-aging effects' are mostly if not all observed in diabetics. Much like most of the mTOR inhibition equals longer health-/lifespan rapamycin quackery is based on 'observations' in cancer cell cultures and fake studies by David Sabatini and his friends.

Posted by: Jones at September 3rd, 2021 2:19 AM

TAME is the biggest waste of $$$

It's nothing more than an ego project that moves the field forward "0"

And Barzilai's "billion $$$ a year" foundation seems like pure vapor

Posted by: Tim Willis at September 3rd, 2021 12:36 PM

@Jones: but let that pill be: glucosamine! And wait for better alternatives...

Posted by: Peter at September 3rd, 2021 3:12 PM

it feels like we are fighting a losing battle. so little is being achieved and there is no therapy out there yet. im losing faith

Posted by: scott emptage at September 4th, 2021 12:05 PM

@scott The real meanigful therapies will be from SENS' spinouts : oisin, underdog, and so on... Those therapies are about to enter clinical trials (phase 1) in the next 2 years. This means they could be available by 2030.

Posted by: Jonathan Weaver at September 4th, 2021 12:16 PM

We tend to be quiet PR wise, but Methuselah Foundation were the Founding investor in Oisin, and then Oncosenx, Turn Bio. Leucadia, Volumetric, Organovo, Viscient, and if I am not mistaken, Repair Bio for Athero. We partnered with NASA and now the micro vascularity limit has been solved.We have much much more in the works. Don't lose heart. Keep on Keeping on!

Posted by: David Gobel at September 4th, 2021 1:11 PM

@David Gobel - Thank you for all your wonderful work with Methuselah Foundation, David! It means so much to the community.

Posted by: Jay at September 4th, 2021 1:34 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.