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

## TL;DR

Frequent blood withdrawals in mice reduce DNA damage in hematopoietic stem cells as they age, without harming their function.

## Contribution

Repeated proliferative events in HSPCs ameliorate age-related DNA damage without affecting function.

## Key findings

- Serial blood withdrawals reduce age-associated DNA damage in HSPCs.
- Increased proliferation activates DNA damage response pathways in HSPCs.
- Proliferation in aged mice decreases double-strand breaks in HSPCs.

## Abstract

Repeated proliferative events during the lifetime reduce DNA damage accumulation in HSPCs over aging without impacting their function.

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.