Stem Cell Problems

An interesting snippet in Nature demonstrated that increasing the expression of the p53 tumour suppressor genes can lead to accelerated ageing in lab mice. This is an important result. The conventional answer as to why cancers tends to increase in frequency as we age relies on the fact that much of the increase happens after reproductive maturity, and the notion thus arises that late-stage cancers tend to arise because there is no strong selection pressure to remove them. They are thus seen as merely incidental.

This snippet instead suggests that at least some of the processes that lead to cancer are part of the body’s defences against premature ageing. Some cancers may be simply the price we pay for living so damn long compared to many animals. This also problematizes some of the putative treatments for organ replacment or repair that involve adding lots of new stem cells, many of which have a higher probability to become cancerous than other body cell types.

I think a good parallel is with gout, where an unusually high serum level of urate crystals (approaching the solubility limit) leads to inevitable deposition of condensed crystals in joints and kidneys, leading to gout and kidney stones. Why have levels so high? Primates that diverged dozens of millions of years ago from the human lineage have much lower urate serum levels, but they don’t live as long. It turns out that urate is a highly potent scavenger of reactive oxygen. Thus gout is an evolved price we pay for extending our life spans and reducing the probability of genetic mutations that would lead to tumour growth.

p53 mutant mice that display early ageing-associated phenotypes
For both p53+/m and pL53 transgenic models, we propose that the early ageing phenotypes are in part a result of enhanced activity of wild-type p53 in some tissues. The reduced cellularity and mass in organs of the older p53+/m mice suggests that organ cell numbers are not maintained. Moreover, some of the ageing phenotypes suggest a reduction in proliferation of stem cells. With the ageing process, this proliferative reserve may decline more rapidly in the p53+/m mice as their stem cells undergo replicative senescence sooner than their p53+/+ counterparts. The accumulation of genetic insults in the stem cells of p53+/m mice may provoke enhanced arrest responses that gradually result in fewer division-competent cells. The p53+/m mice eventually reach a point in which the proliferative capacity of stem cells is so reduced that sufficient numbers of mature cells cannot be provided to maintain organ homeostasis. The resulting phenotypes may include reductions in organ mass, function and tolerance for stress.

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