Syndromes with defective genome maintenance are often associated with accelerated ageing in humans. Mice engineered with analogous mutations demonstrate an essential role for intact DNA repair machinery in stem-cell maintenance and ageing processes. In young mice deficient in KU80 (also known as XRCC5) or XPD (also known as ERCC2), HSCs do not show significant DNA damage or functional decline; however, HSCs from the corresponding aged mice show an accumulation of DNA damage foci and are significantly compromised in their repopulation capacity in the transplantation setting64. The relevance of these experimental findings to normal ageing is not clear, although it is notable that greater numbers of DNA damage foci and increased functional impairment are observed in HSCs of aged wild-type mice64. Several other engineered mouse lines with defects in the DNA repair machinery, including mice with a hypomorphic ligase IV allele and mice in which Msh2 and Fancd1 (also known as Brca2) have been knocked out, also experience increased DNA damage and stem-cell decline8. Hyperactivation of the DNA damage response pathway, apparently in the absence of excess DNA damage, can also
