Nat Commun. 6:7035 2015/04/29

The p16^INK4a tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing. However, since p16^INK4a knockout mice die prematurely from cancer, whether p16^INK4a truly reduces longevity remains unclear. Here we show that, in mutant mice homozygous for a hypomorphic allele of the α-klotho ageing-suppressor gene (kl^kl/kl), accelerated ageing phenotypes are rescued by p16^INK4a ablation. Surprisingly, this is due to the restoration of α-klotho expression in kl^kl/kl mice and does not occur when p16^INK4a is ablated in α-klotho knockout mice (kl^-/-), suggesting that p16^INK4a is an upstream regulator of α-klotho expression. Indeed, p16^INK4a represses α-klotho promoter activity by blocking the functions of E2Fs. These results, together with the observation that the expression levels of p16^INK4a are inversely correlated with those of α-klotho throughout ageing, indicate that p16^INK4a plays a previously unrecognised role in down-regulating α-klotho expression during ageing. These results advance our understanding of the molecular mechanisms underlying the development and progression of ageing in mammals.