p16, senescence, and kidney transplantation

Last week we discussed at length the role of tumor suppressor and senescence activator p16INK4a in limiting the regenerative potential of bone marrow, pancreas, and brain. The take-home concept was the balance between tumor protection (senescence prevents old and stress-damaged cells from dividing) and self-renewal, and the implications of this balance for lifespan.

This week, two abstracts from the 2006 World Transplant Congress expand on this theme, though here the balance is between division potential and successful kidney transplants. Stevenson et al. (pdf) describe data showing that “cold ischemic time” (i.e., the time spent by an organ in a cooler awaiting transport and surgery) is positively correlated with senescence-associated gene expression and that this pattern of gene expression is negatively correlated with successful transplant.

Senescence is p16INK4a-dependent in many cell types. Hence, consistent with the ischemia result are the data of Melk et al. (pdf), which demonstrate that kidney transplants from p16INK4a-/- mice show better survival than organs from wildtype animals.

These findings are significant in their own right, but also as a counterexample to a point I made last week in the “damned if you do, damned if you don’t” discussion of the p16INK4a tumor suppression/self-renewal tradeoff: One certainly wouldn’t want to treat aging cells with a p16INK4a inhibitor in order to boost regeneration, since it’s the very cells at risk of becoming cancerous that are the targets of p16INK4a senescence. If one knew, however, that senescence was going to be acutely induced by an exogenous stress (e.g., ischemia following explantation of a donated organ), then perfusion of the organ with a short-lived p16INK4a inhibitor might be just the thing to increase the chances of successful transplantation.

My personal tastes in life-extension therapy per se don’t extend to a scenario in which we patch people’s failing bodies with donated organs (it strikes me as necessarily zero-sum, in any case). However, inasmuch as transplants are an important component of existing treatments for a range of conditions, it seems to me that these findings represent a potentially important contribution of aging-related research to mainstream medicine.