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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 (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. 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. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: The G-protein regulator phosducin has been shown to be associated with stress-dependent blood pressure, but whether obesity is a modulator of the relationship between phosducin and risk of hypertension is unknown. We studied the effect of two phosducin polymorphisms on risk of hypertension in 273 overweight or obese (Ov-Ob) young-to-middle-age participants from the HARVEST and 287 normal weight (NW) participants. Methods and results: Genotyping of phosducin SNPs rs12402521 and rs6672836 was performed by real time PCR. For rs12402521, 64.6% of the participants were homozygous for the G allele, 27.9% heterozygous, and 7.5% homozygous for the A allele. During 7.7 years of follow-up, 339 subjects developed hypertension. In a Cox multivariable model, carriers of the A allele had a 1.28 (95% CI,1.00–1.63, p = 0.046) increased risk of hypertension. However, increased incidence of hypertension associated with A allele (AA + AG, 79% and GG, 59%, p = 0.001) was observed only among Ov-Ob individuals with a hazard ratio of 1.60 (95% CI, 1.13–2.21, p = 0.007) whereas in NW subjects the incidence of hypertension did not differ by genotype (56% in both groups). In the whole cohort, there was a significant interaction of phosducin genotype with body mass index on the risk of hypertension (p = 0.012). For SNP rs6672836 no association was found with incident hypertension. No haplotype effect was detected on the risk of hypertension. Conclusion: These data suggest that phosducin rs12402521 polymorphism is an important genetic predictor of obesity-related hypertension. In Ov-Ob carriers of the A allele aggressive nonpharmacological measures should be implemented. [Copyright &y& Elsevier]