Emerging uncertainty on the anti-aging potential of metformin

Metformin is the most commonly prescribed glucose-lowering agent worldwide for the treatment of type II diabetes. Due to evidence of improvements in healthspan(definition) and lifespan in model organisms, and mechanistic data relevant to the telomere(definition) attrition, cellular senescence(definition))." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">hallmarks of aging(definition), it has been considered a promising candidate in the search for pharmacological interventions that may attenuate the ageing process in humans. Various epidemiological studies have been influential in generating support for this hypothesis. These include pronounced anticancer and cardioprotective benefits compared to other antidiabetic treatments, and an observation of metformin use in type II diabetes being associated with better survival than that of the general population. Here we discuss recent developments in the evidence underlying the rationale for using metformin to target ageing. We describe the methodological limitations of some of the early and most influential findings and critically assess their scientific follow-up, including replication attempts of key experimental and observational findings, and a range of clinical trials of metformin in individuals without type II diabetes. These developments generally illustrate an emerging uncertainty in the anti-aging potential of metformin. • Metformin, an oral hypoglycemic agent, is widely considered to be a promising anti-aging drug and is scheduled to be tested in humans. • Early preclinical, experimental and epidemiological evidence helped to provide support for its purported benefits outside of type II diabetes. • Subsequent scientific follow-up has illustrated considerable uncertainties in the strength of the evidence provided by these early lines of research. • Metformin has generally not demonstrated its anticipated beneficial effects in most key clinical trials in nondiabetic populations. • A contemporary evaluation of this literature illustrates an emerging uncertainty in the anti-aging potential of metformin.