Interventions that could prevent or delay age related loss of T lymphocyte function might diminish the morbidity caused in elderly populations by neoplastic and infectious disease, and thus extend the number of years of independent life. The steroid hormone dehydroepiandrosterone sulfate (DHEA-S) has been shown to prevent or reverse important aspects of immunosenescence in mice. DHEA-S has also been reported to affect a wide range of non-immunologic aspects of aging and disease. The central goal of this study is to see if long-term administration of DHEA-S can delay the development of serious illness or disability in mice. The study will use genetically heterogeneous mice bred in the Pepper Center's Core Facility for Aged Rodents, since the range of pathophysiologic variation in this animal population may mimic human aging more closely than the traditional inbred animal models. Groups of mice will be treated with oral DHEA-S, and then followed until the development of serious morbidity (or death), to determine if the agent extends disease-free lifespan. Half of the treated mice will be treated from the 6th month of life, and half from the 15th month, to see if a therapeutic effect can be obtained when treatment is initiated only at mid-life. Necropsies will be carried out on each mouse found moribund or dead, to determine if the interventions alter the age-adjusted incidence of specific major illnesses. Each treated and control mouse will also be tested at 6 and 12 months after initiation of the intervention using several measures of age-sensitive immunological and virologic status, including (a) the proportion of memory T cells in the CD4 and CD8 subsets; (b) the proportion of T cells expressing high levels of P-glycoprotein function; (c) serum IL-6 levels; (d) production of IL-2 and IL-4 and IL-2 responsive cells; and (e) the presence of potentially tumorigenic retrovirus. The immunoassay data will be used to assess the hypothesis that the effects of DHEA-S on disease are attributable to preservation of vigorous immune function into old age, and may also allow the development of prognostic indices that can identify in youth or middle age individuals that are particularly prone to specific forms of late-life disease. The use of genetically heterogeneous animal models to test immunopharmacologic approaches to the prevention of disease is extremely cost effective compared to correspondingly powerful tests in aging humans, and could provide both a rationale for human intervention trials and insights into the pathophysiology of age-dependent disease.
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