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The regulation of health and longevity by branched-chain amino acids

支链氨基酸对健康和长寿的调节

基本信息

批准号：
10348688
负责人：
Dudley William Lamming
金额：
$ 44.38万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348688
关键词：
Address Age Aging Agonist Amino Acids Animal Model Biological Biological Assay Biosensor Body Composition Branched-Chain Amino Acids Caloric Restriction Calories Cardiovascular Diseases Cells Complex Consumption Data Development Diabetes Mellitus Diet Dietary Component Dietary Intervention Dietary Proteins Disease Drosophila genus Elderly Energy Metabolism FRAP1 gene Frequencies Genetic Glucose Clamp Goals Gold Health Health Promotion Hepatocyte Human Inbred Mouse Individual Intervention Islets of Langerhans Isoleucine Laboratories Lead Leucine Long-Term Effects Longevity Macronutrients Nutrition Malignant Neoplasms Measures Mediating Mediator of activation protein Metabolic Metabolism Molecular Morbidity - disease rate Mus NADH Pathway interactions Persons Pharmacologic Substance Pharmacological Treatment Pharmacology Phenotype Phosphotransferases Physical Performance Physiological Physiology Play Population Protein Kinase Protein-Restricted Diet Proteins Reducing diet Regulation Role Signal Transduction Sirolimus Societies System Testing Thinness Time United States Valine Work age related aged anti aging burden of illness cohort dietary dietary restriction experimental study fitness frailty glucose metabolism glucose output glucose production glucose uptake glycemic control healthy aging heart function improved insight insulin secretion interest islet mortality novel preservation prevent response sensor

项目摘要

Project Summary Age-related diseases are the major causes of morbidity and mortality in Western society. Calorie restriction (CR), a dietary intervention which extends lifespan while delaying or preventing age-related disease, is one plausible approach to lessen the burden of these diseases, but reduced-calorie diets are notoriously difficult to sustain. Recent studies have highlighted an important role for dietary protein in health and longevity, with low protein (LP) diets shown to promote longevity and to mimic the metabolic benefits of CR. We have found that specifically reducing dietary consumption of the three branched-chain amino acids (BCAAs) – leucine, isoleucine, and valine – promotes metabolic health in both young and aged mice, and promotes longevity in progeroid mice. Determining the effect of Low BCAA diets on longevity, and identifying the physiological and molecular mechanisms by which dietary BCAAs influence metabolism, will provide mechanistic insight into the regulation of healthy aging. Eventually, this will permit the development of new pharmacological approaches to prevent or delay age-related diseases. Here, we will rigorously test the hypothesis that a Low BCAA diet can promote health and longevity in mice, examining the effect of long-term Low BCAA diet on lifespan, metabolic health, cardiac function and frailty. We will determine if reduced consumption of the BCAAs mediates the metabolic effects of CR and LP diets. Finally, we will examine the cell autonomous effects of the BCAAs and their catabolites on the function and metabolism of primary hepatocytes and pancreatic islets ex vivo using novel metabolic sensors, and test candidate molecular mediators of these effects. The proposed work will examine the role of the branched-chain amino acids on health and longevity for the first time, and address long-standing questions regarding how dietary quality – the specific composition of the diet – impacts healthy aging. Importantly, we will gain new insight into the physiological and molecular mechanisms that drive the potent effects of CR and LP diets. In the long term, this work will enable our laboratory and others to develop a mechanistic understanding of how dietary branched-chain amino acids and other macronutrients regulate health and disease vulnerability, and to identify new targets for the pharmacological treatment of age-related diseases and the promotion of healthy aging.

项目摘要在西方社会，与年龄有关的疾病是导致疾病和死亡的主要原因。卡路里限制(CR)，一种在延缓或预防与年龄相关的疾病的同时延长寿命的饮食干预措施，是减轻这些疾病负担的一种看似合理的方法，但众所周知，低卡路里饮食很难维持下去。最近的研究强调了饮食蛋白质在健康和长寿中的重要作用，低蛋白(LP)饮食被证明可以延长寿命，并模仿CR的新陈代谢益处。我们有研究发现，特别是减少饮食中三种支链氨基酸(BCAA)的摄入量- 亮氨酸、异亮氨酸和缬氨酸-促进年轻和老年小鼠的代谢健康，并促进孕期小鼠的寿命。确定低支链氨基酸饮食对寿命的影响，并确定饮食中支链氨基酸影响新陈代谢的生理和分子机制将提供对健康衰老调控的机械论洞察。最终，这将允许开发新的预防或延缓年龄相关疾病的药理学方法。在这里，我们将严格检验低支链氨基酸饮食可以促进健康和长寿的假设小鼠，检测长期低支链氨基酸饮食对寿命、代谢健康、心功能和脆弱。我们将确定支链氨基酸消费量的减少是否会调节CR和LP的代谢效应节食。最后，我们将研究支链氨基酸及其分解代谢产物对功能的细胞自主影响和利用新型代谢传感器的原代肝细胞和胰岛的体外代谢，并进行测试这些效应的候选分子介体。这项拟议的工作将研究支链氨基酸对健康和长寿的作用第一次，并解决了长期存在的关于饮食质量如何--具体构成--的问题饮食--影响健康衰老。重要的是，我们将对生理学和分子生物学有新的认识驱动CR和LP饮食有效效果的机制。从长远来看，这项工作将使我们的实验室和其他人开发了对饮食支链氨基酸和其他大量营养素调节健康和疾病的脆弱性，并确定新的目标药物治疗老年性疾病，促进健康老龄化。