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.
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.