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. 2018 Apr;17(2):e12723.
doi: 10.1111/acel.12723. Epub 2018 Jan 31.

Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults

Ameya S Kulkarni  1   2   3 , Erika F Brutsaert  1   2 , Valentin Anghel  1 , Kehao Zhang  1 , Noah Bloomgarden  1 , Michael Pollak  4 , Jessica C Mar  2   5   6 , Meredith Hawkins  1   2   7 , Jill P Crandall  1   2   7 , Nir Barzilai  1   2   7
Affiliations

Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults

Ameya S Kulkarni et al. Aging Cell. 2018 Apr.

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 nonmetabolic pathways were significantly influenced, including pyruvate metabolism and DNA repair in muscle and PPAR and 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 nonmetabolic 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.

Keywords: aging; biguanides; gene expression; metabolism; upstream regulators.

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Figures

Figure 1
Figure 1
Metformin influences tissue‐specific metabolic and nonmetabolic genes and pathways in elderly humans: (a) volcano plots for 647 differentially expressed genes (DEG) in muscle and 146 DEG in adipose, with metformin treatment. (b) Pathways overrepresented in muscle and adipose‐specific DEG using ConsensusPathDB and ingenuity pathway analysis; (c) overrepresented pathways common to muscle and adipose; (d) predictive upstream regulators common to muscle and adipose, using IPA
See this image and copyright information in PMC

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