application) Several mechanisms that may retard aging have been uncovered through research on dietary restriction (DR). This revised application for a competing renewal of the Program Project """"""""Nutritional Probe of the Aging Process"""""""" utilizes transgenic models to directly test potential anti-aging mechanisms of DR. This represents a novel approach and an essential step to understanding the actions of DR. The over-arching hypothesis of this Program Project is that DR extends longevity by enhancing physiological functions involved in maintenance of cellular protection. These investigators have focused on three protective systems that have shown to be altered markedly by DR and that are also amenable to a more direct examination by transgenic manipulation: (1) repair of DNA damage, (2) metabolic regulation of glucose homeostasis, and (3) the glucocorticoid system. Project 1 will test the hypothesis that DR alters aging by reducing the accumulation of DNA damage/mutations using the DNA polymerase knockout mouse model and developing a transgenic mouse model that shows enhanced DNA repair. Project 2 will test the hypothesis that reduced plasma glucose contributes to the increased longevity of rodents fed a DR- diet using transgenic mice that over express GLUT4 glucose transporter protein. Project 3 will test the hypothesis that elevated plasma glucocorticoid levels play a role in the anti-aging action of DR using the CRH (corticosterone releasing hormone) knockout mouse model to prevent the elevated glucocorticoid surge, which is characteristic of DR. The Program Project also will have four Cores: an Administrative Core (Core A), an Animal Core (Core B), a Pathology Core (Core C), and a Developmental Core (Core D). The Animal and Pathology Cores will play a vital role in the Program Project because they will provide the first survival and pathology data on these transgenic mice when fed either ad libitum or a DR-diet. The Developmental Core will generate and characterize transgenic models that allow temporal control of transgene expression to further test the aforementioned and other potential mechanisms in the next generation of DR research.
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