Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage

Ageing of haematopoietic stem cells (HSC) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation, yet how aging impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage. The defective DDR of old HSCs was non-cell autonomous as ATM signalling, and clonal survival in response to DNA damage could be restored to levels observed in young HSCs post-transplantation into young recipients. These data suggest that defective DDR and diminished apoptotic priming provide a selective advantage to old HSCs that may contribute to mutation accrual and disease predisposition.