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


RESULTS
In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/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.


CONCLUSIONS
In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials. gov identifier: NCT01765946 - January 2013.
Department of Medicine - DIMED, University of Padova, Italy.
S Vigili
SV
de Kreutzenberg
Department of Medicine - DIMED, University of Padova, Italy.
G
G
Ceolotto
Department of Medicine - DIMED, University of Padova, Italy.
A
A
Cattelan
Department of Medicine - DIMED, University of Padova, Italy.
E
E
Pagnin
Department of Medicine - DIMED, University of Padova, Italy.
M
M
Mazzucato
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
P
P
Garagnani
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
V
V
Borelli
Interdepartmental Centre "L. Galvani" for Bioinformatics, Biophysics and Biocomplexity, University of Bologna, Italy.
M G
MG
Bacalini
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
C
C
Franceschi
Department of Medicine - DIMED, University of Padova, Italy; Venetian Institute of Molecular Medicine - VIMM, Padova, Italy.
G P
GP
Fadini
Department of Medicine - DIMED, University of Padova, Italy; Venetian Institute of Molecular Medicine - VIMM, Padova, Italy. Electronic address: angelo.avogaro@unipd.it.
A
A
Avogaro
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects*; D011134:Polysaccharides / Q000097:blood; D011236:Prediabetic State / Q000188:drug therapy*; D056564:Sirtuin 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059506:Telomere Shortening / Q000187:drug effects
D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011134:Polysaccharides; D008687:Metformin; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1
Aging; Dysmetabolism; Inflammation; Longevity genes; Metformin; Prediabetes