Second are the DNA repair pathways. Specifically, mice that are defective in DNA repair capacity age prematurely and experience neuro-degeneration and loss of various stem-cell compartments, including HSCs, although the precise nature of the affected DNA repair pathway dictates the outcome. For example, nucleotide excision repair defects lead to progeroid syndromes, whereas mismatch repair defects increase the cancer risk but do not produce accelerated ageing. DNA damage in the form of telomere dysfunction has also been shown to precipitate premature ageing and diminish lifespan, causing widespread tissue atrophy with depletion of almost all tissue stem-cell reserves examined. This loss of stem cells is due largely to p53-mediated proliferative arrest, senescence and/or apoptotic elimination, as discussed in detail below26,27.The relevance of p53 activation in ageing is reinforced by florid premature ageing phenotypes and diminished stem-cell function in certain strains of mice engineered with germline alleles of hyperactive mutant p53 (the gene encoding p53, which is also known as Trp53)28,29.
