Repeated proliferative events ameliorate age-associated accumulation of DNA damage in HSPCs

Upon aging, hematopoietic stem cells show accumulation of DNA damage that has been causally linked with their functional decline, with debatable role of proliferative events. In this study, we sought to enquire the effect of increased proliferation rate in hematopoietic stem and progenitor cells (HSPCs) on hematopoietic aging. Multiple rounds of blood withdrawals were performed during adult life to maintain a higher proliferation rate in HSPC population in mice. Our experiments showed little effect of increased proliferation on age-associated functional decline in the hematopoietic system. However, we noted a decrease in the double-strand breaks accumulated with age after the serial bleeding regimen. Analysis of scRNA-Seq data from mouse and human HSPCs showed enrichment of DNA damage response pathways. Importantly, we demonstrate that the induction of HSPC proliferation in aged mice was sufficient to activate the DNA damage response in vivo and decrease the load of double-strand breaks. Hence, these results show that repeated blood withdrawals equivalent to clinical blood donation clear DNA damages without impacting the functioning of HSPCs.