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; 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.

恒河猕猴（Macaca Mulatta）为人类衰老提供了出色的模型 与人类的遗传，解剖学和生理相似性。最近完成了两个平行长的 关于热量限制（CR）对恒河猴健康和寿命的影响的术语研究 威斯康星大学麦迪逊大学（UWM）和国家老化研究所（NIA）标志着迈出的重要一步 了解高级灵长类动物的衰老过程。有趣的是，而UWM研究观察到 慢性CR的寿命显着增加，NIA组没有观察到CR对寿命的影响。 但是，两项研究的全面并排比较揭示了几个显着差异 在研究设计中，这些差异可能导致了观察到的结果。总的来说，这些 两项长期的灵长类动物研究表明，CR的健康和生存益处可以保留 在恒河猴中，因此可以翻译成人类。这些猴子的心 研究为调查CR的可能心脏益处提供了一个高度独特的机会。我们 已经与灵长类动物CR调查人员合作，获得了51（UWM）和28（NIA） 来自两种独立的灵长类动物热量限制研究的左腹膜样品。在这里我们建议 研究心肌和热量中与年龄相关的病理因素的关系 恒河猴中的限制（CR）。此外，比较心肌肥大和 纤维化与NIA和UWM研究条件的细节结合使用，可能会提供有关该的见解 特定饮食方案在实现CR的好处方面的有效性。我们组装了工具， 研究这些样本的资源，并建议这是一个获得独特答案的机会 这些验尸标本。我们的目标是： 目的1：检验（a）慢性CR与心肌减少有关的假设 肥大和纤维化，（b）这种关系与恒河猴的寿命增加有关 猕猴。我们建议在获得的左心室样品中量化心肌肥大和纤维化 从UWM和NIA研究的猴子通过随机，盲图像分析。 目的2：检验假设的假设，即灵长类动物的热量限制会导致抑制 MTOR在心脏中发出信号。雷帕霉素（MTOR）信号传导的哺乳动物靶标是细胞的关键调节剂 代谢，生长，增殖和生存。 MTOR途径在各种细胞中被激活 在癌症和2型糖尿病等人类疾病中进行了过程，并受到了管制。我们将学习mtor 有或没有CR的灵长类动物心肌的激活。