Balancing self-renewal and ageing

Mammalian ageing has been associated with reduced regenerative capacity. Three new studies now provide a potential link between the tumour suppressor p16^INK4a, the replicative capacity of stem cells and regenerative capacity in ageing tissues.

Expression of p16^INK4a increases with age, and increased p16^INK4a expression has been associated with cellular senescence and has been postulated to contribute to ageing. However, whether increased p16^INK4a expression functionally contributes to ageing by causing a decline in stem-cell function in vivo remained unclear.

Krishnamurthy et al. assessed the impact of p16^INK4a deficiency and overexpression in pancreatic-islet proliferation. The authors induced p16^INK4a expression (to a level similar to that observed in old mice) in young transgenic mice that harboured an extra copy of the p16^INK4a gene. These transgenic animals had reduced islet proliferation compared with controls, which prompted the authors to propose that increased levels of p16^INK4a in old animals inhibit islet proliferation. Further analysis showed that the loss of p16^INK4a did not alter islet proliferation in young mice, but did rescue the age-induced decrease in proliferation.

Because the tumour-prone nature of p16^INK4a-deficient animals limited the functional studies that could be carried out, Krishnamurthy et al. used a model of islet regeneration. Prolonged survival after a single, diabetes-causing treatment with a β-cell toxin requires the regeneration of significant numbers of functional β-cells. Animals that were deficient in p16^INK4a exhibited enhanced survival. The greatest differences in survival were observed in the oldest mice, which indicates that p16^INK4a mediates a decline in the replicative capacity of islets that is associated with ageing.

Molofsky et al. observed increased p16^INK4a expression with age in neural progenitors, which prompted them to examine the percentage of progenitors, proliferation and neurogenesis in the forebrain lateral ventricle subventricular zone (SVZ) in young and old p16^INK4a-deficient mice. The percentage of stem cells, their potential to self-renew and the overall proliferation rate all decline with age in the SVZ. Loss of p16^INK4a rescued the age-related decline in cells that can form stem-cell colonies in culture, and partially rescued the overall decline in SVZ proliferation and neurogenesis. The authors proposed that p16^INK4a expression could be developmentally programmed to increase with age in order to counter the increasing incidence of cancer in the ageing nervous system. Alternatively, increased p16^INK4a expression might reflect the induction of senescence in the ageing cells in response to damage that accumulates with age.

In a third report, Janzen et al. showed that p16^INK4a expression increased with age in haematopoietic stem cells (HSCs). Studies of differentiation and homing capacity in p16^INK4a-deficient mice indicated that the age-associated increase in p16^INK4a expression restricts the number of HSCs. Further analysis of cell proliferation in young and old wild-type and p16^INK4a-knockout mice showed no differences in young animals. However, old p16^INK4a-deficient mice had higher numbers of stem-cells and increased stem-cell function, which was associated with increased proliferation.

What is the mechanism of p16^INK4a function? Based on the analysis of markers that have been associated with stem-cell self-renewal, such as Bmi1 and Hes1, Janzen et al. proposed the following model: in aged animals, the increase in p16^INK4a expression is associated with a reduced repopulating capacity and decreased expression of Hes1, whereas p16^INK4a deletion is accompanied by an improved repopulating capacity of stem cells and increased expression of Hes1.

...p16^INK4a contributes to mammalian ageing by limiting the self-renewal of regenerative cells...

Taken together, these results from diverse tissues indicate that p16^INK4a contributes to mammalian ageing by limiting the self-renewal of regenerative cells — at least in the bone marrow, endocrine pancreas and brain. Whether the balance between self-renewal and ageing is also controlled by p16^INK4a in other tissues remains to be investigated.