SIRT6 Is a Key Regulator of Pancreatic β-Cell Survival and Function During Aging

Pancreatic β-cells undergo senescence and loss during aging; however, the underlying mechanisms remain incompletely understood. This study aimed to investigate what sirtuin 6 (SIRT6) does during β-cell aging. Pancreatic β-cell–specific Sirt6 transgenic (TgSIRT6) mice were generated for this study. DNA damage, cell death, and cell proliferation were analyzed in cell and mouse models. SIRT6 protein levels were decreased in pancreatic β-cells during aging. TgSIRT6 mice exhibited less DNA damage and cell death, including apoptosis, necroptosis, and pyroptosis, in β-cells than control mice. TgSIRT6 mice had increased total islet area and mass in pancreas compared with control mice. As a result, TgSIRT6 mice showed better glucose tolerance and glucose-stimulated insulin secretion than control mice. RRAD and GEM-like GTPase 2 (REM2), an endogenouse inhibitor of high-voltage–activated calcium channels, was negatively regulated by SIRT6. Knockdown of Rem2 in INS-1 cells partially rescued the SIRT6 deficiency– and palmitic acid–induced DNA damage, lipid peroxidation, and cell death. Rem2 β-cell–specific knockout mice had less DNA damage and cell death in β-cells than control mice. Our data suggest that SIRT6 is a critical antiaging factor in pancreatic β-cells and is a potential therapeutic target. ARTICLE HIGHLIGHTS Pancreatic β-cell function declines with age, but the underlying mechanism is poorly understood. In this study, we attempted to address how to reverse β-cell aging. Our data showed that sirtuin 6 (SIRT6) overexpression can reduce age-associated DNA damage, cell death, and functional decline in β-cells. Our findings suggest that improving Sirt6 gene expression and function may slow down β-cell decline in older patients.