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. p16^INK4a is an effector of senescence and a potent inhibitor of the proliferative kinase Cdk4 (ref. 6), which is essential for pancreatic β-cell proliferation in adult mammals. 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 β-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 β-cells, which requires islet proliferation, declined with advancing age; however, mice lacking p16^INK4a demonstrated enhanced islet proliferation and survival after β-cell ablation. These genetic data support the view that an age-induced increase of p16^INK4a expression limits the regenerative capacity of β-cells with ageing.