Advancing age is characterized by the functional decline of multiple organ systems. At first glance, the blood-forming system does not seem to reflect the effects of aging in that normal blood cell counts are maintained into old age. However, an age-related decline in function is apparent in the response to stresses requiring accelerated blood cell formation. The hematopoietic stem cell population lies at the heart of this response and, while able to maintain steady-state blood formation, its response to increased demand is blunted. Despite the key role of the stem cell population in blood formation, and increasing knowledge about its function in the young, there are large gaps in our knowledge of aging stem cells. We hypothesize that deleterious changes in the lympho-hematopoietic stem cell population, and perhaps in stem cells of other organs, limit organismal longevity. We have mapped a genetic locus in the mouse that regulates stem cell numbers in old animals, but not in young animals. It thus qualifies as an 'aging gene'. Allelic differences at this locus prescribe over a 3-fold increase in stem cells during aging of long-lived C57BL/6 (B6) mice and a 20 percent decline in stem cells during the same period in short-lived DBA/2 (DBA) mice. We hypothesize that this locus is an important determinant of the response of stem cells to hematopoietic demands in old animals and thus influences organismal longevity. The goal of this project is to genetically fine map the locus at a resolution that will permit positional cloning at the molecular level in the next phase. To this end, we have generated a B6 strain congenic for the DBA-derived telomeric segment of Chr. 2 harboring the locus. We propose to create a large number of recombinations within the congenic interval, and thus to create congenic sub-strains, enabling us to narrow the locus to less than 0.5 cM. Preliminary studies of the existing congenic strain have shown that the effect of the locus can be observed in stem cells of young animals under the rigorous demands of bone marrow transplantation. Thus, to aid in the future study of this locus, we propose developing a surrogate measure of the aging phenotype in young mice by using a transplantation assay.
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