p16INK4a induces an age-dependent decline in islet regenerative potential

The p16(INK4a) tumour suppressor accumulates in many tissues as a function of advancing age(1-3). p16(INK4a) is an effector of senescence(4,5) and a potent inhibitor of the proliferative kinase Cdk4 (ref. 6), which is essential for pancreatic beta-cell proliferation in adult mammals(7,8). Here we show that p16(INK4a) constrains islet proliferation and regeneration in an age-dependent manner. Expression of the p16(INK4a) transcript is enriched in purified islets compared with the exocrine pancreas, and islet-specific expression of p16(INK4a), but not other cyclin-dependent kinase inhibitors, increases markedly with ageing. To determine the physiological significance of p16(INK4a) accumulation on islet function, we assessed the impact of p16(INK4a) deficiency and overexpression with increasing age and in the regenerative response after exposure to a specific beta-cell toxin. Transgenic mice that overexpress p16(INK4a) to a degree seen with ageing demonstrated decreased islet proliferation. Similarly, islet proliferation was unaffected by p16(INK4a) deficiency in young mice, but was relatively increased in p16(INK4a)-deficient old mice. Survival after toxin-mediated ablation of beta-cells, which requires islet proliferation, declined with advancing age; however, mice lacking p16(INK4a) demonstrated enhanced islet proliferation and survival after beta-cell ablation. These genetic data support the view that an age-induced increase of p16(INK4a) expression limits the regenerative capacity of beta-cells with ageing.