PRDM16 reduces cellular senescence by upregulating GSTM1

Cellular senescence is a hallmark of aging and the accumulation of senescent cells (SnCs) accelerates the aging process, contributing to aging-related organ disorders. The PRDF1 and RIZ1 homology domain (PRDM) protein exhibits robust transcriptional regulatory activities and governs a wide range of biological processes. However, its roles in cellular senescence remain unclear. Here, we demonstrated that PRDM16, a member of the PRDM protein family, decreased significantly in multiple organs of aged mice compared to young mice. Global Prdm16 deletion contributed to cellular senescence in various organs, including the kidneys, heart, lungs, hippocampus, stomach, and gut, leading to accelerated aging-related organ injury. Furthermore, tubular-specific Prdm16 deletion aggravated irradiation-induced kidney aging and aging-related kidney diseases in irradiated mice subjected to ischemia-reperfusion surgery. Exogenous PRDM16 gene delivery by lentivirus effectively attenuated cellular senescence in vitro and in vivo. Mechanistically, PRDM16 improved glutathione metabolism and inhibited oxidative DNA damage, which is a driving force of senescence. Specifically, PRDM16 upregulated the transcription of glutathione S-transferase mu 1 (GSTM1) by binding to its promoter region. Transfection with GSTM1 reversed PRDM16 deficiency-induced cellular senescence and kidney aging. Collectively, our results provide a potential target for the investigation of anti-aging therapies. The renal cortex of 9-month-old wild type (WT) and Prdm16 global knockout (Prdm16 ko) mice were isolated and analyzed using single-cell RNA sequencing.