Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing

Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells(1,2). It has been proposed that this is at least partially caused by the senescence of progenitors with age(3,4); 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 p16(INK4a), which encodes a cyclin-dependent kinase inhibitor linked to senescence(5). Ageing p16(INK4a)-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16(INK4a) 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 p16(INK4a) expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16(INK4a) expression.