Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial

S. Vigili de Kreutzenberg, G. Ceolotto, A. Cattelan, E. Pagnin, M. Mazzucato, P. Garagnani, V. Borelli, M. G. Bacalini, C. Franceschi, G. P. Fadini, A. Avogaro

Research output: Contribution to journalArticlepeer-review

Abstract

Background and aims: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. Methods and results: In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed.Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. Conclusion: In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials.gov Identifier: NCT01765946 - January 2013.

Original languageEnglish
Pages (from-to)686-693
Number of pages8
JournalNutrition, Metabolism and Cardiovascular Diseases
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 1 2015

Keywords

  • Aging
  • Dysmetabolism
  • Inflammation
  • Longevity genes
  • Metformin
  • Prediabetes

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics
  • Endocrinology, Diabetes and Metabolism
  • Cardiology and Cardiovascular Medicine

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