PRDM16 restricts cellular senescence by upregulating GSTM1
Cellular senescence is a hallmark of aging, and the accumulation of senescent cells (SnCs) accelerates the aging process and contributes to aging-related organ disorders. The PRDMs exhibit robust transcriptional regulatory activity and govern a wide range of biological processes. However, the role of PRDMs in cellular senescence and aging remain unclear. Here, we have demonstrated that PRDM16, among PRDMs, is decreased significantly in multiple organs of aged mice compared to young mice. Global Prdm16 deletion contributes to cellular senescence in various organs, including the kidney, heart, lung, brain hippocampus, stomach, and gut; subsequently leading to accelerated aging-related organ injury. Furthermore, tubular specific Prdm16 deletion aggravates irradiation induced kidney aging, and aging-related kidney disease subjected to ischemia reperfusion surgery. Exogenous PRDM16 gene delivery by lentivirus effectively attenuates cellular senescence in vitro and in vivo. Mechanistically, PRDM16 improves glutathione metabolism and inhibits oxidative DNA damage, the driving force of senescence. Especially, PRDM16 increases glutathione-S-transferase activity by upregulating the transcription of GSTM1. Transfection of GSTM1 restored cellular senescence and kidney aging caused by PRDM16 deficiency. Taken together, we provide a potential target for investigating the anti-aging therapy. Overall design: PRDM16 overexpressing and control HK-2 cell lines were constructed by lentivirus transfection. HK-2 cells were exposed to a single dose of 8 Gy X-ray irradiation and harvested at the 7th day post-irradiation. We then performed gene expression profiling analysis using data obtained from RNA-seq of 6 different cells at two groups.