Myocardial Effects of Caloric Restriction in Primates

恒河猴（Macaca mulatta）是人类衰老的极好模型， 与人类在遗传、解剖和生理上的相似性。最近完成了两个平行的长- 热量限制对恒河猴健康和寿命影响的长期研究 威斯康星州麦迪逊大学（UWM）和国家老龄化研究所（NIA）标志着朝着 了解高等灵长类动物的衰老过程有趣的是，虽然UWM研究观察到 尽管NIA组的慢性CR患者的寿命显著增加，但NIA组未观察到CR对寿命的影响。 然而，对这两项研究进行全面的并排比较，发现了几个显著的差异 在研究设计中，这些差异可能导致了观察到的结果。综上所述各项 两项长期的灵长类CR研究表明，CR的健康和生存益处可以被保留， 在恒河猴中，因此可以翻译给人类。这些猴子的心脏 研究为研究CR可能的心脏益处提供了非常独特的机会。我们 与灵长类CR研究人员合作，获得了51（UWM）和28（NIA） 来自两个独立灵长类动物热量限制研究的左心室样本。在此，我们建议 探讨心肌增龄相关病理因素与热量的关系 限制（CR）在恒河猴。此外，比较心肌肥厚和 结合NIA和UWM研究条件的详细信息，可以深入了解 特定饮食方案在实现CR益处方面的有效性。我们已经组装好了工具， 资源来研究这些样本，并建议这是一个获得独特答案的机会， 这些尸体样本我们的目标是： 目的1：检验以下假设：（A）慢性CR与心肌细胞凋亡减少相关， 肥大和纤维化，以及（B）这种关系与恒河猴寿命的延长有关 猕猴我们建议量化左心室样本中的心肌肥厚和纤维化， 来自UWM和NIA研究的猴子的图像。 目的2：检验灵长类动物热量限制导致抑制 心脏中的mTOR信号。哺乳动物雷帕霉素靶蛋白（mTOR）信号转导是细胞凋亡的关键调节因子， 代谢、生长、增殖和存活。mTOR通路在各种细胞过程中被激活， 在癌症和2型糖尿病等人类疾病中，它会产生并解除调节。我们将研究mTOR 在有和没有CR的灵长类动物的心肌中的激活。

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.