Abstract
The p16INK4a 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 p16INK4a knockout mice die prematurely from cancer, whether p16INK4a reduces longevity remains unclear. Here we show that, in mutant mice homozygous for a hypomorphic allele of the α-klotho ageing-suppressor gene (klkl/kl), accelerated ageing phenotypes are rescued by p16INK4a ablation. Surprisingly, this is due to the restoration of α-klotho expression in klkl/kl mice and does not occur when p16INK4a is ablated in α-klotho knockout mice (kl−/−), suggesting that p16INK4a is an upstream regulator of α-klotho expression. Indeed, p16INK4a represses α-klotho promoter activity by blocking the functions of E2Fs. These results, together with the observation that the expression levels of p16INK4a are inversely correlated with those of α-klotho throughout ageing, indicate that p16INK4a plays a previously unrecognized role in downregulating α-klotho expression during ageing.
Highlights
The p16INK4a tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing
The p16INK4a tumour-suppressor gene elicits irreversible cell-cycle arrest known as cellular senescence[5,6,7,8,9,10], and its expression increases with age in many tissues[11,12,13], along with the accumulation of dysfunctional senescent stem/progenitor cells[14,15,16]
The levels of a-klotho expression decline with age in both humans and mice[21], and overexpression of a-klotho extends the maximum lifespan in mice[22], suggesting that a-klotho acts as an ageing-suppressor gene in mammals[23]
Summary
The p16INK4a tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing. Recent studies using middle-aged mice lacking p16INK4a (p16 À / À mice) revealed that the ageingassociated induction of p16INK4a expression reduces the proliferative and regenerative capacities of certain stem/ progenitor cells during the ageing process[14,15,16]. P16INK4a has an established role in the implementation of cellular senescence in stem/progenitor cells[5,6,7,8,9,10], which are likely to reduce longevity[13], our results reveal that p16INK4a has an additional function in promoting ageing phenotypes by downregulating a-klotho expression in mice. Our findings advance our understanding of the molecular mechanisms underlying the development and progression of ageing in mammals
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