Caloric restriction has been shown in numerous studies in rodents to extend the maximal life span, retard age-associated physiological changes and delay or prevent most age associated disease. If these findings are to be extrapolated to human beings, it will first be necessary to test varying dietary regimens in some higher species and evaluate the effect on an age-related disease process, particularly as it relates to human health. As such, age related disease such as atherosclerosis would be a valuable end point to study. To diminish atherosclerosis, the caloric restriction should alter pathogenic mechanisms contributing to the disease process. Therefore, the proposed research will evaluate a well characterized non-human primate model for human atherosclerosis and study dietary intervention in the form of caloric restriction compared to unrestricted diet with equivalent cholesterol content. We will evaluate for changes secondary to the dietary restriction on insulin resistance, arterial collagen glycation/advanced glycation, and adipose tissue distribution, particularly for intra-abdominal fat, all of which have been strongly implicated in contributing to cardiovascular disease. The changes in our parameters secondary to dietary intervention will be related to atherosclerosis extent of the coronary arteries assessed at study completion. To diminish atherosclerosis, caloric restriction should alter pathogenic mechanisms contributing to the disease process. Therefore, our specific hypothesis is that caloric restriction over a sustained period when compared with an ad libitum diet with equivalent cholesterol content, may diminish atherosclerosis by reducing age-associated increases in vascular levels of early/advanced glycated products (e.g. protein cross-linking), improving peripheral insulin sensitivity, and reducing intra-abdominal fat. To evaluate our hypothesis, we plan to study a non-human primate model of atherosclerosis using dietary intervention in the form of caloric restriction. At study baseline, animals will have an iliac artery removed to quantitate advanced glycated products (pentosidine, carboxymethyllysine). In addition an assessment of insulin sensitivity and computed tomographic scans will be done to quantitate intra-abdominal fat. The animals will then be randomized to receive either an ad libitum or caloric restricted diet. Both diets will have identical cholesterol content to evaluate the effect of caloric restriction on atherosclerosis. Animals will be followed for four years, with longitudinal assessment of insulin sensitivity, skin glycation/advanced glycation, and amount of intra-abdominal fat. At the end of a four year period, animals will be necropsied, vascular tissue removed for assessment of advanced glycation, and atherosclerosis extent evaluated. The primary objective of the proposed study is to evaluate the association between physiologic and glycation measures with atherosclerosis and to compare the glycation, insulin resistance and adiposity measures in monkeys between caloric restricted and ad libitum diet groups. The principal measure of the degree of atherosclerosis will be the mean coronary artery intimal area.
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