As we age, our organs gradually lose their ability to maintain constant levels of function, either in the context of regeneration from injury or in the broader sense of replacing cells that get worn out over the course of “normal use.”

Why? One possibility is that stem cells are dying off over the lifespan; another is that stem cells persist but lose their efficacy.

A collaboration between two labs — one led by stem cell giant Irving Weissman, the other by preeminent DNA repair scholar Jan Hoeijmakers — comes down in favor of the latter hypothesis. At least for the hematopoietic stem cells (HSCs) of the bone marrow, stem cell numbers remain constant even at very late ages, but their ability to regenerate drops drastically. Genetic studies using the many DNA repair-deficient mouse mutants currently available suggest that the mechanism for this decline in efficacy involves the accumulation of DNA damage. From Rossi et al.:

Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age

A diminished capacity to maintain tissue homeostasis is a central physiological characteristic of ageing. As stem cells regulate tissue homeostasis, depletion of stem cell reserves and/or diminished stem cell function have been postulated to contribute to ageing. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline. We have tested these hypotheses by examining haematopoietic stem cell reserves and function with age in mice deficient in several genomic maintenance pathways including nucleotide excision repair, telomere maintenance and non-homologous end-joining. Here we show that although deficiencies in these pathways did not deplete stem cell reserves with age, stem cell functional capacity was severely affected under conditions of stress, leading to loss of reconstitution and proliferative potential, diminished self-renewal, increased apoptosis and, ultimately, functional exhaustion. Moreover, we provide evidence that endogenous DNA damage accumulates with age in wild-type stem cells. These data are consistent with DNA damage accrual being a physiological mechanism of stem cell ageing that may contribute to the diminished capacity of aged tissues to return to homeostasis after exposure to acute stress or injury.

So as DNA damage (from any one of a variety of sources) builds up in HSCs, they become less capable of doing their job: differentiating into blood cell progenitors and proliferating to renew their own numbers. Especially when the system is stressed (say, by the need to repopulate the marrow in a transplant model), this decrease in proliferative capacity makes old HSCs fall short.

I’m a little fuzzy on why diminished self-renewal capacity wouldn’t result in a lower steady-state level of HSCs (since presumably some HSCs are lost stochastically over time, and slower self-renewal should drive down the absolute numbers of cells). Still, the authors show by a number of different methods that the long-term reconstituting HSCs of interest seem to persist over the lifespan at relatively constant levels, so I’m convinced by the result even if I feel like I need more explanation on that particular question.

One of the mechanisms by which self-renewal might be hindered is cellular senescence, a permanent growth arrest that can result from DNA damage and telomere shortening (both of which are covered in the mutant studies here). We’ve seen senescence bearing negatively on self-renewal before, in the context of the p16 tumor suppressor (see our earlier article, Devil’s bargain: Tradeoffs between stem cell maintenance and tumor suppression, and especially the articles linked at the end of that post). These new findings, while clearly operating through different signaling pathways (DNA damage doesn’t induce p16 directly), are entirely consistent with the p16 story.

This paper is complementary to one discussed here earlier this week, which demonstrated that embryonic stem cells can lose regenerative potential in an aged tissue microenvironment (see Babes in the woods). That is the non-cell-autonomous side of the story. Here, the competitive transplantation experiments of Rossi et al. — which show the DNA-damaged stem cells from aged or repair-deficient animals faring poorly — remind us that there are still critical cell-autonomous determinants of aged phenotypes.

For the trifecta, someone now needs to figure out whether the hostile microenvironment of the aged niche is cell-autonomous (i.e., the niche cells change as a result of something going on inside themselves) or non-cell-autonomous…perhaps the consequence of long-term exposure to aged, damage stem cells nearby.