TRANSGENIC PROBES OF GLUCOCORTICOID INVOLVEMENT IN AGING

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DESCRIPTION: (adapted from the application): Dietary restriction (DR) increases the diurnal elevation of plasma free corticosterone (CORT) two- to-four fold and maintains this elevation throughout life. Many biological endpoints are changed by DR in a direction consistent with elevated plasma CORT. These include: reduced cell proliferation and attenuated inflammation; two processes that may contribute to the reduced malignancy and pathophysiology of DR. Hyperadrenocorticism may thus be an important hormonal trigger of the altered gene expression that ultimately retards aging in DR animals. The object of this proposal is to test more directly the hypothesis that the hyperadrenocorticism of DR plays a role in its anti-aging actions. This objective will be accomplished using a transgenic intervention (Corticotrophin Releasing Hormone knockout [CRH-\-] mouse) that eliminates the elevated CORT in DR mice. These investigators will also restore CORT to DR levels in CRH-/- mice and raise CORT to DR levels in CRH-/- mice as two independent means to ensure that any effects of CRH deficiency are specific to elimination of CORT and not to other effects of CRH deficiency. The specific aims are to use thee interventions to assess the role of DR-induced hyperadrenocorticism in: (1) The prolongation of life and attenuation of pathological changes by DR. Longevity studies will measure life span in ad libitum (AL) fed and DR CRH-/- and CRH+/+ MICE, and in CORT supplemented control groups. Comprehensive pathological profiles will be obtained to assess the role of CORT in probably cause of death, and in age-specific incidence and progression of disease. (2) The anti-inflammatory action of DR. The time-course of carrageenan-induced foot pad edema and its resolution will be used as the index of inflammation in the aforementioned experimental animal groups. (3) The anti-proliferative actions of DR. Cell proliferation will be measured in pituitary, thymus, spleen, liver, epidermis, testis, and intestinal epithelia using proliferating cell nuclear antigen and bromodeoxyuridine immunoreactivity. (4) The hypoglycemic/hypoinsulinemic effects of DR. Blood glucose and insulin concentrations will be measured in the aforementioned experimental animal groups throughout life span. They hypothesize that the CRH-/- mice under DR will fail to show the characteristic hypoglycemia and hypoinsulinemia of DR but that CORT supplementation of CRH+/+ DR mice and CRH-/- AL mice to DR levels will restore these effects. The results of these studies will provide the most conclusive evidence to data on whether hyperadrenocorticism plays a role in the anti-aging action of DR and, if so, on the underlying mechanisms through which it acts.