[O5.IMMUNOLOGY] Aging typically involves progressive decline in the body's ability to maintain homeostatic cell replacementand to regenerate tissues and organs after injury. Age-associated defects in the hematopoietic (blood-forming)system cause characteristic deficiencies in lymphocyte production, over-proliferation of hematopoietic stemcells (HSCs), and excessive myeloid cell production, which together lead to reduced immune function andfrequent hematopoietic malignancies in elderly populations. How aging causes deterioration of hematopoieticfunction is still unclear, but our data strongly suggest that loss or functional impairment of HSCs is a criticalcomponent of this process. Our work further suggests that the effects of aging on HSCs arise largely fromalterations in the aged environment that act to suppress HSC activity in older animals and can be reversed byfactors that circulate naturally in the bloodstream. Thus, a primary focus of my laboratory, and central goal of this proposal, is to identify age-regulatedpathways that can be manipulated to restore appropriate HSC number and function in aged individuals. Myapproach will exploit my laboratory's unique capacity to identify and isolate both HSC and HSC-supportivebone-lineage 'niche' cells, in conjunction with our novel in vivo and in vitro models for assaying the influence ofsystemic factors on stem cell and niche cell function. Together, our studies will: (1) identify mechanisms ofhematopoietic stem cell aging and rejuvenation, (2) determine the relationship between stem cell rejuvenatingactivity and longevity, and (3) reveal signaling pathways that may be useful for halting or reversing acquiredHSC dysfunction during aging. Our findings ultimately may uncover conserved mechanisms of stem cellmaintenance that are perturbed in old age and contribute globally to acquired deficits in tissue function.Application of these findings ultimately may help to delay or reverse the detrimental effects of aging, therebyextending the healthful life of aging individuals.
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