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. The function of somatic stem cells declines with age, and this decline is at least in part explained by cell-intrinsic mechanisms. 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. The `immortal' germline, however, undergoes extreme selection so that only the fittest gametes transmit their genome to the next generation. Evidence suggests that the quality of mitochondrial function is one mechanism based on which gametes are selected. In contrast to gametes somatic stem cells rely predominantly on glycolytic ATP production, while most mature cells use mitochondrial respiration. Likely because of their reliance on glycolysis, evidence suggests that hematopoietic stem cells, the best characterized adult stem cell type, are less susceptible to impaired mitochondrial function than progenitors. We therefore hypothesize that mitochondria play an important role in HSC maintenance that is not directly dependent on ATP production. We indeed observed that HSCs have high mitochondrial mass and do not perform mitophagy. Furthermore, impairment of mitochondrial dynamics decreases the number of HSCs with extensive lymphoid potential and induced cycling of the entire HSC compartment. These data show that mitochondria do play specific roles in HSC maintenance. In this proposal, we examine the mechanisms underlying mitochondrial maintenance of HSCs, and its implication for the aging of HSCs. We will test the hypothesis that impairment of mitochondrial maintenance of HSCs will negatively affect HSC function in young mice, but may lead to longer maintenance of HSC function in aged mice. Somatic stem cell maintenance as a mechanism underlying organismal aging would be remarkably consistent with an evolutionary theory of aging, the antagonistic pleiotropy theory, which proposes that mechanisms that provide reproductive or survival benefit early in life are detrimental late in life and contribute to aging.
Hematopoietic stem cells generate all cells of the blood and immune system, and are critical for the development of leukemia and its treatment by bone marrow transplantation. The mechanisms underlying the function of these cells their marked age-related changes are not well understood however. In this proposal, we examine the role of mitochondria, which fulfill diverse roles in cell biology, but whose role in the biology and aging of hematopoietic stem cells has never been analyzed in depth.
| Corrigan, David J; Luchsinger, Larry L; Justino de Almeida, Mariana et al. (2018) PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature. J Clin Invest 128:3250-3264 |
| de Almeida, Mariana Justino; Luchsinger, Larry L; Corrigan, David J et al. (2017) Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells. Cell Stem Cell 21:725-729.e4 |
| Snoeck, Hans-Willem (2017) Mitochondrial regulation of hematopoietic stem cells. Curr Opin Cell Biol 49:91-98 |
