Hypothalamic Glucoregulation in Aging Rodents by fMRI

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Aging is a significant cause of morbidity, mortality, and health-care costs in the United States and has associations with diabetes and atherosclerosis. Evidence documenting the anti-aging effect of dietary restriction (DR) exists in a wide variety of laboratory animals. Chronically lowered plasma glucose levels in mice, rats and non-human primates of different ages and using a variety of DR regimens have also been clearly demonstrated. Indeed, it has been suggested that lowered plasma glucose may be an important component of the mechanism by which DR retards aging. Further, the extremely crucial role that the hypothalamus plays in processes like feeding and drinking and its intimate involvement in glucoregulation are well known. However, the in vivo specificity and mechanism responsible for the anti-aging action of decreased plasma glucose following DR still remains unknown. Our overall long-term goal is to understand the hypothalamic mechanism(s) accountable for the decreased plasma glucose following DR and the development of effective preventive and therapeutic anti-aging strategies from the knowledge so gained. The objective of this particular application is to monitor in vivo alterations in glucose metabolism of the hypothalamus with aging and their reversal with DR, using functional magnetic resonance imaging (fMRI). The central hypothesis is that aging alters hypothalamic glucoregulation and that DR retards this age-associated change. Data obtained in our earlier study showed that DR lowers plasma glucose levels throughout the course of the day and over the lifespan of rats. The rationale that underlies the proposed research is that, once knowledge of the hypothalamic response is obtained in diet restricted rats with fMRI, the mechanism that is responsible for this can be subsequently determined. We are uniquely well prepared to undertake the proposed project, as our team's research has already yielded novel observations concerning the effects of DR in rats and has also been successful in demonstrating the in vivo hypothalamic fMRI response (signal intensity change which is a reflection of changes in basal blood flow, blood volume, and blood oxygenation associated with underlying neural activity) following glucose administration in both humans and rats. The central hypothesis will be tested and the objective of this application accomplished by pursuing the following specific aims: (a) To determine if glucose metabolism in the rat hypothalamus is altered with aging and whether DR reverses it; and (b) To determine if these age-related changes can be detected in mice so as to be able to use transgenic models in the future. The proposed work is novel and innovative. and is expected to demonstrate that there are significant alterations with aging, in the normal fMRI hypothalamic response induced by intraperitoneal glucose administration. Such outcomes will have a significant impact on our understanding of glucoregulation in DR. Further, they will be extremely valuable in investigating the effects of DR in transgenic models of mice in the future. Finally, the proposed research is expected to make fundamental new contributions to aging research and can eventually be expected to reduce the complications associated with aging.