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

• Published in: Aging cell Vol. 17; no. 4; pp. e12765 - n/a
• Main Authors: Fang, Jingqi, Yang, Jiping, Wu, Xun, Zhang, Gangming, Li, Tao, Wang, Xi'e, Zhang, Hong, Wang, Chih‐chen, Liu, Guang‐Hui, Wang, Lei
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2018; John Wiley and Sons Inc
• Subjects: Aging; Animal models; Antioxidants; Cells, Cultured; Cellular Senescence - drug effects; Diabetes mellitus; Dose-Response Relationship, Drug; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - enzymology; Fibroblasts; Glutathione peroxidase; Glutathione Peroxidase - metabolism; glutathione peroxidase 7; Humans; Life span; Longevity - drug effects; Mesenchyme; Metformin; Metformin - pharmacology; nuclear factor erythroid 2‐related factor 2; Original; oxidative stress; Regulatory sequences; Senescence; Stem cell transplantation; Stem cells; Up-Regulation - drug effects; senescence; metformin; glutathione peroxidase 7; aging; nuclear factor erythroid 2-related factor 2; oxidative stress
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.12765

Summary 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.