Aging of tissue specific stem and progenitor cells has been proposed to be the central cause of altered tissue function and diminished regenerative capacity in the elderly^1–3. Within the hematopoietic system, the consequences of aging are unbalanced within disparate lineages and their progenitors. In particular, the production of lymphocytes is markedly reduced in the elderly, while the myeloid compartment is thought to be relatively unperturbed⁴. In this dissertation, we identified the underlying molecular basis for the preferential effects of aging on lymphopoiesis. We determined that two genes, p16^Ink4a and Arf, are preferentially expressed in aged lymphoid progenitors and contribute significantly to their decline in proliferative potential and survival. In addition, we demonstrated that the increased expression of p16^Ink4a and Arf, both potent tumor suppressors^5,6, conferred upon aged lymphoid progenitors an increased resistance to malignant transformation. This provides a molecular basis for the clinical observation that lymphoid leukemias, although common in children, do not typically present in adults. These data provide a molecular explanation for the dichotomous effects of aging in the hematopoietic system, and demonstrate that aging and tumor suppression are mechanistically linked processes. These findings may have significant therapeutic implications, as our data suggest that inhibiting expression of p16^Ink4a and Arf can rejuvenate aged hematopoietic progenitors and depressed immune cell production in the elderly. In addition, our determination that tumor suppressors have concurrent pleiotropic effects in aging and cancer provide significant insight into the development and etiology of human malignancies.

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