Aging Cell. 2018 Apr 16:e12765. doi: 10.1111/acel.12765. [Epub ahead of print]

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7.

Fang J^1,2, Yang J^1,2, Wu X^1,2, Zhang G^1,2, Li T^1,2, Wang X¹, Zhang H^1,2, Wang CC^1,2, Liu GH^1,2,3, Wang L^1,2.

Abstract

Metformin, an FDA-approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low-dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum-localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin-Nrf2-GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2-GPx7 pathway in pro-longevity signaling.