PRDM16 Controls Cellular Senescence and Organ Aging by Promoting Oxidative DNA Damage

Background: With the increasing lifespan, the burden of aging and age-related diseases has emerged as a global public health concern. The accumulation of senescent cells contributes to accelerated body aging through the secretion of senescence-associated phenotypes. Epigenetic modifications, including DNA methylation, histone methylation, and histone acetylation, play crucial roles in promoting cellular senescence. PRDM proteins interact with various epigenetic-modifying enzymes along with transcription factors, to collectively regulate gene expression. However, the precise involvement of PRDM family members in cellular senescence and aging remains elusive. Methods: We screened PRDM family in multiple organs from mice at young (2 months) and old (24 months) age by qRT-PCR. Bioinformatics analysis and qRT-PCR were utilized to verify the correlation between PRDM16 and age in humans and mice. Natural aging global and renal tubular specific PRDM16 knockout mice were obtained to observe multiple organ aging, and kidney aging associated diseases with single-cell RNA sequencing. PRDM16 overexpression lentivirus was applied in old mice. RNA-sequencing, ChIP-seq, ChIP, were used to clarify the mechanism of PRDM16 in senescence. Results: By detecting the expression of PRDM family members, particular attention was given to PRDM16 due to its significantly altered expression between young and old lung and kidney tissues. The levels of PRDM16 in brain hippocampus, kidney, and lung tissues exhibited a negative correlation with age and p21 expression. Notably, global deletion of PRDM16 in mice at only 3 weeks of age resulted in the accumulation of senescent cells in multiple organs. Renal tubular specific PRDM16 knockout aggravated ischemia reperfusion injury in aging kidney induced by irradiation. Conversely, overexpression of PRDM16 using lentivirus successfully rescued kidney aging in aged mice as well as senescent tubular cells. Mechanistically, deficiency of PRDM16 promoted oxidative DNA damage through disruption of glutathione metabolism. Specifically, downregulation of PRDM16 led to reduced production of reduced glutathione via transcriptional downregulation GSTM1. Conclusion: PRDM16 deficiency accelerates cellular senescence and multiple organ aging by promoting oxidative DNA damage in a GSTM1-dependent manner. Funding: Government Support – Non-U.S.