The question ‘Why do we age’ is not solved. Understanding the mechanisms driving aging may lead to innovative strategies to increase health span, an effort that would carry enormous human and economic benefit. The fact that many species (typically, though not exclusively, more slowly developing, longer-lived and larger species) possess somatic stem cells capable of self-renewal and tissue regeneration calls into question why these organisms and their somatic stem cells do age whereas the germline apparently does not.
We discovered that many quantitative traits affecting hematopoietic stem and progenitor cells show age-associated variation, and in fact correlate with life span. Furthermore, we observed that immunological aging, and more specific thymic involution, is also subject to quantifative genetic variation. We are currently examining how age-related changes in somatic stem cells in general, and in hematopoietic stem cells in particular, might affect organismal aging.
The function of somatic stem cells declines with age. While often viewed as a degenerative condition, aging of somatic stem cells may in fact be a reflection of the pervasive action of protective stem cell maintenance mechanisms that confer differential susceptibility to stress and injury compared to mature cells. Hematopoietic stem cells, which reside in the bone marrow, can self renew and generate all lineages of the hematopoietic system, expand with age, such that old bone marrow can even outcompete equal numbers of young bone marrow. The repopulation and differentiation capacity of individual hematopoietic stem cells is compromised however. The last two decades of work in this field by many investigators has shown that maintenance mechanisms in HSCs include quiescence (associated with the use of the error-prone non-homologous end joining DNA repair pathway), more active autophagy, and higher resistance to starvation and radiation-induced apoptosis compared to their progeny. Though not as thoroughly investigated, similar maintenance mechanisms are operative in stem cells in other tissues, such as skin and mammary gland. There is little or no evidence that stem cell-protective mechanisms fail with age. Radioresistance, starvation resistance, increased autophagy and the quiescence-associated use of the NHEJ DNA repair pathway suggest that somatic stem cells favor repair, even though incomplete, over disposal by damage-induced apoptosis. This preference would lead to stem cell compartments that expand with age, as has been shown for hematopoietic stem cells, and in doing so temporarily maintain their overall function. However, these mechanisms ultimately lead to accumulation of damaged stem cells, and likely also to the predominance of a limited number of stem cell clones, a possible prelude to malignancy. In contrast, whereas we posit that postnatal stem cells avoid selection and favor maintenance of the stem cells pool, the germline, immortal in a transgenerational sense, uses exactly the inverse mechanism, selection of the fittest gametes.1 Similarly, asexual reproduction may involve stringent selection of somatic cells. The lab is currently devising strategies to test this hypothesis, focusing on maintenance mechanisms involving ATP-independent roles of mitochondria.
Henckaerts E, Langer JC, Snoeck HW (2004) Quantitative genetic variation in the hematopoietic stem and progenitor cell compartment and in life span are closely linked at multiple loci. Blood, 104:379-384.
Kumar R, Langer JC, Snoeck HW. (2006) Transforming growth factor-beta2 is involved in quantitative genetic variation in thymic involution. Blood 2006 107:1974-1979.
Fossati V, Kumar R, Snoeck HW. (2010) Progenitor cell origin plays a role in fate choices of mature B cells. J Immunol. 184:1251-1260.
Snoeck HW (2015) Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline? Cell Stem Cell 16:528-584.