Metformin Regulates Metabolic and Non-Metabolic Pathways in Skeletal Muscle and Subcutaneous Adipose Tissues of Older Adults. Metformin Regulates Metabolic and Non-Metabolic Pathways in Skeletal Muscle and Subcutaneous Adipose Tissues of Older Adults

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 7 were processed for library preparation and sequenced in two/three technical replicates using multiplexed 100bp paired-end sequencing on Illumina HiSeq2500. Raw sequence reads were preprocessed using WASP 3.0, and FastQC was used for quality control. The raw FASTQ files were trimmed for adapter sequences using Trim Galore! RSEM algorithm (v1.2.25) in conjunction with STAR aligner (v2.4.2a) were used to quantify the raw reads to GRCh38 build of the reference human genome with transcript annotations from GENCODE. The raw counts matrix was exported from RSEM to edgeR, normalized using TMM normalization and used for differential expression analysis.