Most, if not all, of the body's organ systems show the effects of aging. It is now increasingly apparent that homeostatic maintenance of organ function owes to cellular renewal derived ultimately from stem cells. Therefore, aging stem cells may critically impact maintenance of normal organ function. Adult stem cells, in all organs studied, rely on micro environmental cues from supporting stroma to modulate, if not direct, stem cell replication, differentiation and quiescence. This proposal investigates the effect of aging on both stem cells and the microenvironment. Using hematopoietic stem cells as a model, we test the hypothesis that the number of stem cells available in bone marrow affects that organ's capacity to supply blood and immune cells during aging. Quantitative trait loci (QTL) affecting natural variation in stem cell numbers in mice have been mapped and congenic strains have been generated in which independent effects of the loci can be studied. Efforts underway to identify the genes responsible for the QTL will identify molecular pathways important in regulating stem cell numbers and the effect of aging on them. Effects of age on the stem cell microenvironment will focus on two essential functions. The first is to capture stem cells from the circulating blood. Stem cells are in a natural state of flux between the marrow and blood with evidence that this pathway is bidirectional. Homing of stem cells to the marrow is the first critical step in stem cell transplantation in the treatment of hematologic and non-hematologic malignancies. As more and older patient's become candidates for transplant, the effects of age on homing are largely unexplored. Lastly, clinical science has found ways to dramatically alter the flux of stem cells from the marrow microenvironment into the blood in a process called mobilization. Despite its widespread use in harvesting stem cells for transplantation, the basic mechanisms are not only incompletely understood, the effects of aging are uncharted. We will use mouse models to test the hypothesis and the flux of stem cells both to and from the marrow is altered in aging.
