It is well accepted that many aspects of aging are defined by tissue specific pathologies and that the increase in pathological burden is a contributing factor in determination of lifespan. Recent studies, for example, demonstrate that experimental manipulations that increase lifespan (e.g. moderate caloric restriction) alter specific pathological profiles and decrease total pathological burden. In this application, we propose that growth hormone and IGF- I have the potential to regulate age-related pathogenesis through their well-known actions on cell proliferation and apoptosis. Our general hypothesis is that the rise in growth hormone and IGF-I during development is adaptive for survival and the subsequent decline in these hormones is necessary to attenuate pathological burden and maximize lifespan. Thus, we propose that IGF-1 exhibits two opposing, but equally important actions; optimizing tissue function and increasing pathological burden. Despite the wealth of information on the beneficial effects of growth hormone and IGF-l that we, and others, have reported, only correlative information is available on the pathogenic nature of physiological concentrations of these hormones. The goal of this application is to determine the relationship between the growth hormone/IGF-l axis and the onset and progression of age-related pathologies. Three specific aims have been developed: 1) Investigate whether growth hormone deficiency and subsequent IGF- 1 deficiency delays the age-related increase in pathological burden and increases lifespan. Additional studies will investigate whether IGF-1 receptor antagonists alter pathological profiles and/or attenuate the age-related increase in pathological burden in animals with normal concentrations of growth hormone/IGF-I. 2) Assess whether the protective effects of moderate caloric restriction on age-related pathogenesis are mediated by decreased plasma IGF-l concentrations. 3) Determine a) whether growth hormone and IGF-l deficiency (using the model of adult-onset growth hormone/IGF-I deficiency) or specific IGF-1 antagonists protect against chemical-induced carcinogenesis are mediated by decreased levels of IGF-1 and c) whether caspase inhibitors (anti-apoptotic agents) attenuate the protective effects of moderate caloric restriction and growth hormone/IGF-l deficiency on chemical-induced carcinogenesis. Although published studies suggest that growth hormone is an effective agent for ameliorating functional deficits with age, a major health concern exists since there are no reliable data on the potential pathological effects of this hormone. Therefore, the results of these studies will provide critical information on the interrelationships between age-related changes in growth hormone and IGF- I, mechanisms regulating age-related pathologies and lifespan, and the actions of moderate caloric restriction. In addition, the results will provide important information on the potential risks of administration of growth hormone and IGF-l to the elderly.

R01AG019392

2001-05-01

2004-04-30