Teacher: Bart, what other paradoxes affect our lives?
Bart: Well, you’re damned if you do, and you’re damned if you don’t.

— The Simpsons

Healthy life requires a balance between cell division (to replenish damaged tissues) and regulation of the cell cycle (to prevent unchecked cell proliferation, i.e., cancer). Both of these bear on lifespan: self-replenishment lengthens lifespan; cancer shortens it. To the extent that these opposing forces are regulated by the same genetic mechanisms, evolution will produce tradeoffs: we will get the highest replenishment potential that allows for a cancer-free life, at least up until the point that we’ve successfully reproduced.

This is one take-home message of Janzen et al., who demonstrate that the aging of hematopoietic stem cells — and in particular, their ability to replenish the blood — is regulated by the tumor suppressor gene p16INK4a:

Stem-cell ageing is thought to contribute to altered tissue maintenance and repair. Older humans experience increased bone marrow failure and poorer haematologic tolerance of cytotoxic injury. Haematopoietic stem cells (HSCs) in older mice have decreased per-cell repopulating activity, self-renewal and homing abilities, myeloid skewing of differentiation, and increased apoptosis with stress. Here we report that the cyclin-dependent kinase inhibitor p16INK4a, the level of which was previously noted to increase in other cell types with age, accumulates and modulates specific age-associated HSC functions. Notably, in the absence of p16INK4a, HSC repopulating defects and apoptosis were mitigated, improving the stress tolerance of cells and the survival of animals in successive transplants, a stem-cell-autonomous tissue regeneration model. Inhibition of p16INK4a may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue.

The authors start with a simple observation: In old mice, p16INK4a levels are higher in hematopoietic stem cells (HSCs) but not in other types of bone marrow cells; hence, p16INK4a is a biomarker of aging in the bone marrow. They then demonstrate that p16INK4a regulates self-replenishment potential: p16INK4a+/+ cells from old donors have less capacity to regenerate the immune system in competitive-transplant experiment than do p16INK4a-/- cells; this difference is specific to older donors, and is not observed in cells from young animals.

p16INK4a seems to govern the replenishment potential of HSCs by simultaneously limiting cell cycle progression in HSCs and increasing the rate of apoptosis. Knockout cells (p16INK4a-/-) have both a greater proportion of cycling cells and a lower rate of cell death. Once again, this difference is manifest only in cells from older animals.

So it would seem that p16INK4a promotes aging in this tissue, and indeed it does, in the sense that it limits replenishment. Why not get rid of the gene altogether, then? Because without it, the mice (and by extension, the humans that we hope to be learning about by studying the mice) would never live to a hematopoietically ripe old age: p16INK4a-/- animals start dying of cancer at around 18 months, around the same time that the differences in rejuvenation potential become statistically significant.

Dammit.