Myocardial Effects of Caloric Restriction in Primates

灵长类动物热量限制对心肌的影响

• 批准号: 9507133
• 负责人: RICHARD T LEE
• 金额: $ 8.45万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9507133
• 关键词: Age; Age of Onset; Aging; Aging-Related Process; Anatomy; Animal Model; Atherosclerosis; Autopsy; Birth; Blinded; Caloric Restriction; Calories; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Cycle; Cell physiology; Cellular Metabolic Process; Chronic; Code; Collaborations; Collagen; Development; Diet; Disease; Effectiveness; Energy Intake; FRAP1 gene; Fibrosis; Freezing; Genetic; Growth; Health; Health Benefit; Heart; Heart failure; Human; Hypertrophy; Image Analysis; Inbred SHR Rats; Intervention; Investigation; Left ventricular structure; Life; Life Style; Link; Long-Term Effects; Longevity; Longitudinal Studies; Macaca mulatta; Malnutrition; Molecular; Monkeys; Myocardial; Myocardium; National Institute on Aging; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathologic; Pathway interactions; Physiological; Physiology; Prevalence; Primates; Randomized; Regimen; Research Design; Research Personnel; Resources; Risk; Rodent; Sampling; Sampling Studies; Side; Signal Transduction; Specimen; Testing; Time; Tissue Preservation; United States; Universities; Wisconsin; Yeasts; cancer type; cardiovascular disorder risk; coronary fibrosis; heart function; heart preservation; human disease; human model; insight; interstitial; mortality; nonhuman primate; prevent; programs; tool; translation to humans

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.

恒河猴(Macaca Mulatta)是研究人类衰老的极佳模型，因为它 在基因、解剖学和生理学上与人类相似。最近完成的两个平行的长- 热量限制(CR)对恒河猴健康和寿命影响的长期研究 威斯康星大学麦迪逊分校(UWM)和国家老龄研究所(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的研究观察到 慢性CR患者的寿命显著延长，NIA组没有观察到CR对寿命的影响。 然而，对这两项研究进行全面的并列比较，发现了几个显著的差异 在研究设计中，这些差异可能是导致观察结果的原因之一。这些加在一起， 两项长期的灵长类CR研究表明，CR对健康和生存的好处是可以保留的 在恒河猴身上，因此可以对人类进行翻译。这里面的猴子的心脏 研究为研究CR可能的心脏益处提供了一个非常独特的机会。我们 与灵长类CR调查人员合作，获得了51(UWM)和28(NIA) 来自两个独立的灵长类卡路里限制研究的左心室样本。在此，我们建议 心肌中与年龄相关的病理因素与热量的关系 对恒河猴的限制(CR)。此外，心肌肥厚和心肌肥厚水平的比较 结合NIA和UWM研究条件的细节，纤维化可能会提供对 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和 资源来研究这些样本，并建议这是获得唯一答案的机会 这些尸检样本。我们的目标是： 目的1：检验以下假设：(A)慢性CR与心肌梗死的减少有关 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。我们建议量化获得的左心室样本中的心肌肥大和纤维化。 来自UWM和NIA研究的猴子，通过随机、盲目图像分析。 目的2：检验灵长类动物限制卡路里会导致抑制 心脏中的mTOR信号。哺乳动物雷帕霉素靶标(MTOR)信号转导是细胞的关键调节因子 新陈代谢、生长、增殖和生存。MTOR通路在不同的细胞周期中被激活 在癌症和2型糖尿病等人类疾病中被处理并被解除管制。我们将研究mTOR 有或无CR的灵长类动物心肌中的激活。