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

Ameya S. Kulkarni, Erika F. Brutsaert, Valentin Anghel, Kehao Zhang, Noah A. Bloomgarden, Michael Pollak, Jessica C. Mar, Meredith A. Hawkins, Jill P. Crandall, Nir Barzilai

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAging Cell
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Metformin
Subcutaneous Fat
Metabolic Networks and Pathways
Skeletal Muscle
Placebos
Insulin
Muscles
Peroxisome Proliferator-Activated Receptors
Pyruvic Acid
MicroRNAs
DNA Repair
Cross-Over Studies
Genes
Area Under Curve
Observational Studies
Meals
Adipose Tissue
Collagen
Fatty Acids
Therapeutics

Keywords

  • Aging
  • Biguanides
  • Gene expression
  • Metabolism
  • Upstream regulators

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

@article{ba5e4580fbf1424fb04e4feaf1507d1d,
title = "Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults",
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, TGF{\ss}1, 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",
author = "Kulkarni, {Ameya S.} and Brutsaert, {Erika F.} and Valentin Anghel and Kehao Zhang and Bloomgarden, {Noah A.} and Michael Pollak and Mar, {Jessica C.} and Hawkins, {Meredith A.} and Crandall, {Jill P.} and Nir Barzilai",
year = "2018",
month = "1",
day = "1",
doi = "10.1111/acel.12723",
language = "English (US)",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",

}

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 A.

AU - Pollak, Michael

AU - Mar, Jessica C.

AU - Hawkins, Meredith A.

AU - Crandall, Jill P.

AU - Barzilai, Nir

PY - 2018/1/1

Y1 - 2018/1/1

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

UR - http://www.scopus.com/inward/record.url?scp=85041180995&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041180995&partnerID=8YFLogxK

U2 - 10.1111/acel.12723

DO - 10.1111/acel.12723

M3 - Article

JO - Aging Cell

JF - Aging Cell

SN - 1474-9718

ER -