Figure 2.

Study design schematic. To understand the translational potential of metformin to slow aging, this ongoing 12-week, double-blinded, randomized control trial aims to determine how antecedent metabolic health (insulin resistant vs insulin sensitive) and the relationship between skeletal muscle mitochondrial remodeling and function affect the potential healthspan-extending effects of metformin. After screening, eligible participants will be randomized to 12 weeks of placebo or metformin (1 500 mg/day) by the study statistician. Pre- and postintervention assessments include dual-energy x-ray absorptiometry (DEXA) to assess body composition, continuous glucose monitoring (CGM) to determine glucoregulation, proposed blood-based biomarkers of aging, hyperinsulinemic-euglycemic clamp to measure peripheral insulin sensitivity, and muscle biopsy samples to evaluate mitochondrial function by high-resolution fluorespirometry. We will also use deuterium oxide (D₂O) stable isotope labeling during the last 4 weeks of the intervention to determine individual and complex-specific mitochondrial remodeling from postmuscle biopsy samples. W = Week; con meds = concomitant medications.