Cell intrinsic checkpoints and environmental alterations limit stem cell function in aging telomere dysfunctional mice

During ageing telomere shortening occurs in the vast majority of human tissues and organs including stem cells. The molecular mechanisms that limit stem cell function in response to telomere shortening are not well understood.

Here we studied stem cell function and ageing in telomere dysfunctional mice. Our studies show that telomere dysfunction induces cell intrinsic checkpoints in stem and progenitor cells of the intestine and the hematopoietic system. Deletion of p21 elongates lifespan and stem cell function of telomere dysfunctional mice without affecting upstream telomere dysfunction signalling. Exonuclease-1 (Exo-1) deletion prevented the induction of DNA damage signals at dysfunctional telomeres and also improved survival and stem cell function of ageing telomere dysfunctional mice indicating that the processing of dysfunctional telomeres in mammalian cells involves Exo-1. In addition to these cell intrinsic checkpoints, transplantation experiments revealed that telomere dysfunction induces defects in the hematopoietic environment that limit stem cell engraftment and hemato-lymphopoiesis in ageing telomere dysfunctional mice.