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: 9764223
• 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 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764223
• 关键词: Age; Age of Onset; Aging; 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; Ingestion; 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; Process; 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）由于其 与人类在遗传、解剖学和生理学上的相似性。最近完成了两个并行的长 关于热量限制（CR）对恒河猴健康和寿命影响的学期研究 威斯康星大学麦迪逊分校 (UWM) 和国家老龄化研究所 (NIA) 标志着迈出了重要一步 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 虽然慢性 CR 可以显着延长寿命，但是 NIA 组没有观察到 CR 对寿命的影响。 然而，两项研究的全面并排比较揭示了一些显着差异 在研究设计中，这些差异可能对观察到的结果有所贡献。综合起来，这些 两项长期灵长类 CR 研究表明 CR 对健康和生存的益处可以得到保留 在恒河猴中，因此可以转化为人类。这些猴子的心 研究为研究 CR 可能对心脏带来的益处提供了一个非常独特的机会。我们 与灵长类 CR 研究人员合作，获得了 51 (UWM) 和 28 (NIA) 来自两项独立的灵长类动物热量限制研究的左心室样本。在此我们建议 探讨心肌年龄相关病理因素与热量的关系 恒河猴的限制（CR）。此外，比较心肌肥厚水平和 纤维化与 NIA 和 UWM 研究条件的细节相结合可能会提供对纤维化的深入了解 特定饮食方案在实现 CR 益处方面的有效性。我们已经组装好工具并 研究这些样本的资源并表明这是一个获得独特答案的机会 这些尸检标本。我们的目标是： 目标 1：检验 (A) 慢性 CR 与心肌功能下降相关的假设 肥大和纤维化，并且 (B) 这种关系与恒河猴的寿命延长有关 猕猴。我们建议量化获得的左心室样本中的心肌肥厚和纤维化 通过随机、盲法图像分析，从 UWM 和 NIA 研究的猴子中获得。 目标 2：检验灵长类动物热量限制会抑制 心脏中的 mTOR 信号传导。哺乳动物雷帕霉素靶点 (mTOR) 信号传导是细胞的关键调节因子 新陈代谢、生长、增殖和生存。 mTOR 通路在各种细胞过程中被激活 它在癌症和 2 型糖尿病等人类疾病中发挥着重要作用，并且不受控制。我们将研究mTOR 有和没有 CR 的灵长类动物心肌中的激活。