Further evidence of a role for activated p53 in organismal ageing comes from two genetically engineered mouse alleles of hyperactive mutant p53: such mice experience premature ageing and are significantly cancer resistant28,29. As they age, different tissues derived from these hyper- p53 mice develop increased numbers of senescent cells; furthermore, their HSCs exhibit decreased activity in competitive transplants, as well as decreased engraftment capacity78. These observations are in line with the capacity of p53 deficiency to rescue many accelerated ageing phenotypes in various models engineered with deletion of Terc (as above), Brca1, Zmpste24 (a mouse model for Hutchinson–Gilford progeria syndrome, which is a human progeroid syndrome) or Ku80 (refs 79, 80); see Box 4 for other progeroid syndromes. However, transgenic mice carrying one extra copy of the intact (wild-type) p53 locus, the Ink4a/Arf locus or both are found to have a normal or extended lifespan (up to 16% longer), with delayed onset of the ageing phenotype, a result that has been attributed to lower ROS concentrations and ROS-related damage to proteins and lipids81. Further highlighting the complexity of p53 signalling,
