In this genotoxic stress model of ageing (Fig. 3), the core telomere–p53 axis integrates well with almost all genetic elements proven to be important in the ageing process. First, it accounts for the premature ageing phenotypes common to both telomere-dysfunctional mice and those with germline p53 hyperactivation28,29. Second, it explains why mice lacking SIRT1 or SIRT6 — proteins that attenuate p53 activity — develop premature ageing87. Third, it could account for the observed connections between mitochondria and key ageing factors such as PGC-1α, PGC-1β, FOXO proteins and BMI1; mice null for each of the genes encoding these proteins experience accelerated tissue degeneration and mitochondrial dysfunction.
