This week, I’ve focused on the cyclin-dependent kinase inhibitor p16INK4a, a protein long known to play a role in cellular senescence and tumor suppression, and recently shown to limit the proliferative capacity of both hematopoietic stem cells and precursors of pancreatic ß-cells.
p16INK4a limits the proliferation of cells at risk for becoming cancerous, but this protective function stands in opposition to the ability of tissues to replenish themselves. This as an example of an evolutionary tradeoff in the genetic control of lifespan: infinite proliferative capacity would risk cancer, whereas infinite tumor protection would prevent recovery from cell loss and injury. The duration of a healthy lifespan is therefore determined in part by the balance between the two opposing forces.
Today, we finish the series with an article about the role of p16INK4a in the progenitor cells in the brain. From Molofksy et al.:
… 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 senescence. 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. … Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression.
As with articles discussed earlier in the week, the effect of p16INK4a knockout is manifest only in aging mice, suggesting that the protein acts late in life (perhaps in response to damage that takes a lifetime to accumulate above a particular threshold).
The story in brain is slightly different, however, from the one in bone marrow and pancreas. In the latter two tissues, cells from p16INK4a-/- exhibited increase proliferative capacity (and proliferation) relative to cells from their wildtype littermates. In the brain, in contrast, p16INK4a-/- suffers less age-dependent loss of neural progenitor cells, but the proliferation rate in knockout and wildtype cells is comparable. (Hematopoetic stem cells also exhibit decreased apoptosis in the knockout, but the increased proliferative capacity dominates, especially in a transplant paradigm where cells are demanded to regenerate an entire immune system from a small number of founder cells.)
These results are very likely to be general to mammals — we know from recent findings (some of which I addressed here last month) that even adult human brains contain active neural progenitors that can proliferate both in vitro and in a mouse model — but not entirely general to the whole brain: the authors point out that p16INK4a has an effect in the subventricular zone but not e.g. in the dentate gyrus, where other mechanisms of age-related decline may be operative.
Nonetheless, knowledge of the genetic control of cell loss in the aging brain (even part of the aging brain) holds the promise of someday intervening in the process in order to treat age-related neurodegenerative diseases, not to mention damage resulting from injury or stroke.
Now if we can just find a way around the pesky tendency of p16INK4a-/- cells to initiate tumors…