Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing

In this issue, three separate labs report the discovery of a protein that regulates ageing specifically in stem cells. This helps answer a fundamental question: why do mammalian progenitor cells gradually lose their ability to divide and generate new cells as they grow old? Norman Sharpless and colleagues generated a knockout mouse lacking tumour suppressor p16INK4a, a protein involved in cell cycle control and known to be expressed in an age-dependent manner. Studying its role in regeneration of the blood, pancreas and brain, the three groups separately found that p16INK4a is not only a biomarker, but an effector of ageing. By comparing the effect of elevated or reduced p16INK4a expression in mice, they found that p16INK4a halts proliferation of stem cells, but only in older mice. Taken together, the work suggests that p16INK4a reduces cancer incidence via its tumour suppressor action, at the same time contributing to ageing by reducing stem cell function. The work also suggests that type 2 diabetes might be linked to the failure of the pancreatic islets to renew, and that blocking this protein in certain tissues might combat some effects of ageing. Three separate labs report that p16INK4a, a protein known to be expressed in an age-dependent manner regulates ageing specifically in stem cells. Studying its role in regeneration of three different tissues, the blood, pancreas, and brain, the three groups separately found that p16INK4a is not only a biomarker, but an effector of ageing. Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells1,2. It has been proposed that this is at least partially caused by the senescence of progenitors with age3,4; however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16INK4a, which encodes a cyclin-dependent kinase inhibitor linked to senescence5. Ageing p16INK4a-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16INK4a deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression.