p16^INK4a induces an age-dependent decline in islet regenerative potential

The p16^INK4atumour suppressor accumulates in many tissues as a function of advancing age1-3. p16^INK4ais an effector of senescence4,5and a potent inhibitor of the proliferative kinase Cdk4 (ref.6), which is essential for pancreatic β-cell proliferation in adult mammals7,8. Here we show that p16^INK4aconstrains islet proliferation and regeneration in an age-dependent manner. Expression of thep16^INK4atranscript is enriched in purified islets compared with the exocrine pancreas, and islet-specific expression ofp16^INK4a, but not other cyclin-dependent kinase inhibitors, increases markedly with ageing. To determine the physiological significance of p16^INK4aaccumulation on islet function, we assessed the impact ofp16^INK4adeficiency and overexpression with increasing age and in the regenerative response after exposure to a specific β-cell toxin. Transgenic mice that overexpress p16^INK4ato a degree seen with ageing demonstrated decreased islet proliferation. Similarly, islet proliferation was unaffected byp16^INK4adeficiency in young mice, but was relatively increased inp16^INK4a-deficient old mice. Survival after toxin-mediated ablation of β-cells, which requires islet proliferation, declined with advancing age; however, mice lackingp16^INK4ademonstrated enhanced islet proliferation and survival after β-cell ablation. These genetic data support the view that an age-induced increase of p16^INK4aexpression limits the regenerative capacity of β-cells with ageing.