Metformin improves healthspan and lifespan in mice

Abstract

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

“…Previously, metformin was found to increase the healthspan and longevity of mice (Martin‐Montalvo et al ., 2013). Given that metformin elevates DICER1 in cultured cancer cells (Blandino et al ., 2012), we wanted to examine whether changes in DICER1 expression occur in mice chronically treated with metformin and to compare these findings with those of mice on dietary caloric restriction, an intervention that extends lifespan in mice.…”

“…Previously, we reported that chronic metformin treatment increases both healthspan and lifespan in mice (Martin‐Montalvo et al ., 2013). Here, we have found that DICER1 levels are upregulated by metformin treatment in both mice and humans in part through a post‐transcriptional mechanism involving the RBP AUF1.…”

“…The fact that modulating DICER1 and miRNAs may be important for regulating lower organismal aging and our recent findings that metformin significantly increases the longevity of mice (Martin‐Montalvo et al ., 2013) led us to examine mechanisms by which DICER1 expression is altered by metformin and the possible role of DICER1 in aging. As gene expression is affected post‐transcriptionally by noncoding RNAs and RNA‐binding proteins (RBPs), we hypothesized that post‐transcriptional mechanisms may play a role in modulating levels of DICER1 in response to metformin.…”

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

“…Metformin (Met) has been reported to increase longevity in male mice of the C57BL/6 inbred stock (Martin‐Montalvo et al ., 2013) at a dose of 1000 ppm, started at 54 weeks of age, leading to an increase in mean lifespan of 5.8%. This increase was deemed to be significant using the Gehan–Breslow statistic, which gives greater emphasis to deaths at earlier ages than the log‐rank test used in our own work.…”

“…In the ITP dataset, the age at 90th percentile mortality declined by 2% in the Met group. In C57BL/6 mice, Met was toxic at a higher concentration of 10 000 ppm (1%) (Martin‐Montalvo et al ., 2013), and it is possible that evaluation of doses higher or lower than the 1000 ppm dose we used might have produced stronger evidence of benefit. Observational data suggest that patients with diabetes who take metformin have lower mortality risks than age‐matched non‐diabetic patients (Bannister et al ., 2014).…”