TY - JOUR
T1 - Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults
AU - Kulkarni, Ameya S.
AU - Brutsaert, Erika F.
AU - Anghel, Valentin
AU - Zhang, Kehao
AU - Bloomgarden, Noah
AU - Pollak, Michael
AU - Mar, Jessica C.
AU - Hawkins, Meredith
AU - Crandall, Jill P.
AU - Barzilai, Nir
N1 - Funding Information:
Glenn Foundation for Medical Research; Nathan Shock Center of Excellence for the Biology of Aging, Grant/Award Number: P30AG038072; Einstein-Mount Sinai Diabetes Research Center; NIH, Grant/ Award Number: 5P60DK20541; New York State Department of Health; Burroughs Wellcome Fund
Funding Information:
This work was supported by the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation for Medical Research) (NB, JPC, & MH), the Nathan Shock Center of Excellence for the Biology of Aging (P30AG038072) (NB), the Einstein-Mount Sinai Diabetes Research Center, NIH-5P60DK20541, and New York State Department of Health (NYSTEM Program) shared facility grant (JCM) and PhD in Clinical Investigation: PCI—a training program funded by the Burroughs Wellcome Fund (ASK).
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - aging
KW - biguanides
KW - gene expression
KW - metabolism
KW - upstream regulators
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U2 - 10.1111/acel.12723
DO - 10.1111/acel.12723
M3 - Article
C2 - 29383869
AN - SCOPUS:85041180995
VL - 17
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 2
M1 - e12723
ER -