ABSTRACT: Administration of metformin increases healthspan and lifespan in model systems and evidence from clinical trials and observational studies suggests that metformin delays a variety of age-related morbidities. Although metformin has been shown to modulate multiple biological pathways at the cellular level, these pleiotropic effects of metformin on the biology of human aging have not been studied. We studied ~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. Following each treatment period, skeletal muscle and subcutaneous adipose tissue biopsies were obtained, and a mixed-meal challenge test was performed. As expected, metformin therapy lowered 2-hour glucose, insulin AUC, and insulin secretion compared to placebo. Using FDR<0.05, 647 genes were differentially expressed in muscle and 146 genes were differentially expressed in adipose tissue. Both metabolic and non-metabolic pathways were significantly influenced, including pyruvate metabolism and DNA repair in muscle and PPAR & SREBP signaling, mitochondrial fatty acid oxidation and collagen trimerization in adipose. While each tissue had, a signature reflecting its own function, 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. These data can inform the development of biomarkers for the effects of metformin, and potentially other drugs, on key aging pathways. Key words: Aging, biguanides, gene expression, metabolism, upstream regulators
