MATHEMATICAL MODELS OF INTERMEDIARY METABOLISM IN AGING

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The goal of this SERCA proposal is to provide the opportunity for career development in the area of mathematical modeling of intermediary metabolism in aging for Dr. Joanne K. Kelleher. The candidate has over ten years experience in laboratory research in intermediary metabolism and an interest in mathematical modeling and aging. The candidate was a NIA post- doctoral fellow and has co-authored a paper describing the application of mathematical models to the field of aging research. Two areas of modeling research have been selected for detailed study in the initial years of the proposal. 1) 'Minimal modeling' is a method for selecting the most concise model capable of describing the physiological system. This process may be essential if models are to be of practical use in understanding complex homoestated systems. 2) 'Control analysis' is a method for analyzing metabolic pathways replacing the notion of "rate limiting steps". Control analysis produces quantitative estimates of the extent to which flux through the entire pathway is controlled by each reaction. While it is recognized that modeling methods are not without short comings, the thesis of this proposal is that application of modeling techniques to the altered metabolic homeostasis of aging will be extremely useful. Experimental investigation will focus on the stimulation of gluconeogenesis by glucagon in isolated rat hepatocytes from adult (6 mo) and aged (24 mo) rats. The sensitivity of hepatocytes to glucagon will be investigated. The long term goal of this candidate is to bring expertise in modeling methodologies to the study of human aging.