METFORMIN’S METABOLIC AND NON-METABOLIC EFFECTS LINKED TO AGING

Although metformin has been shown to increase health- and life-span in many models, the pleiotropic effects of metformin on the biology of human aging have not been studied. We obtained muscle and adipose tissue biopsies for ~70-year-old participants (n=14) in a randomized, double-blind, placebo-controlled, crossover trial in which they were treated with 6 weeks each of metformin and placebo. Over 600 genes were differentially expressed in muscle and ~150 genes were significantly and differentially expressed in adipose tissue. Each tissue had a signature reflecting its own function and in each tissue both metabolic and non- metabolic pathways were significantly influenced. We identified a cascade of predictive upstream transcriptional regulators, including mTORC1, MYC, TNF, TGFß1 and miRNA-29b, that may explain tissue- specific transcriptomic changes in response to metformin treatment. This study provides the first evidence that, in older adults, metformin has metabolic and non-metabolic effects linked to aging.