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Myocardial Effects of Caloric Restriction in Primates


The rhesus macaque (Macaca mulatta) presents an excellent model for human aging due to its genetic, anatomical and physiological similarities to humans. The recent completion of two parallel long- term studies on the effects of Caloric Restriction (CR) on the health and lifespan of rhesus monkeys at the University of Wisconsin Madison (UWM) and National Institute on Aging (NIA) marked a major step toward understanding the aging process in higher primates. Interestingly, while the UWM study observed a significant increase in lifespan with chronic CR, the NIA group did not observe an effect of CR on longevity. However, a comprehensive side-by-side comparison of the two studies revealed several notable differences in study design, and these differences may have contributed to the results observed. Taken together, these two long-term primate CR studies revealed that the health and survival benefits of CR could be conserved in rhesus monkeys, and thus could be translatable to humans. The hearts from the monkeys in these studies present a highly unique opportunity for the investigation of the possible cardiac benefits of CR. We have assembled a collaboration with the primate CR investigators and obtained 51 (UWM) and 28 (NIA) left-ventricle samples from the two-independent primate caloric restriction studies. Here we propose to investigate the relationship of age-associated pathological factors in myocardium and caloric restriction (CR) in rhesus monkeys. Moreover, a comparison of the levels of myocardial hypertrophy and fibrosis in conjunction with the details of the NIA and UWM study conditions may provide insights into the effectiveness of specific dietary regimens in achieving the benefits of CR. We have assembled the tools and resources to study these samples and suggest that this is an opportunity to obtain unique answers with these post-mortem specimens. Our Aims are: AIM 1: To test the hypothesis that (A) chronic CR is associated with a decrease in myocardial hypertrophy and fibrosis, and (B) that this relationship is linked to increased lifespan in rhesus macaques. We propose to quantify myocardial hypertrophy and fibrosis in left ventricle samples obtained from monkeys of the UWM and NIA study via randomized, blinded image analysis. AIM 2: To test the hypothesis that caloric restriction in primates results in the inhibition of mTOR signaling in the heart. Mammalian target of rapamycin (mTOR) signaling is a key regulator of cell metabolism, growth, proliferation, and survival. The mTOR pathway is activated during various cellular processes and is deregulated in human diseases such as cancer and type 2 diabetes. We will study mTOR activation in the myocardium of primates with and without CR.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.