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

• 批准号: 10539009
• 负责人: Dudley William Lamming
• 金额: $ 197.4万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539009
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amino Acids; Animals; Biological; Blood Glucose; Body Composition; Body Weight decreased; Branched-Chain Amino Acids; Caloric Restriction; Calories; Cardiovascular Diseases; Cognition; Consumption; Data; Diabetes Mellitus; Diet; Dietary Component; Dietary Intervention; Dietary Proteins; Disease; Drosophila genus; Elderly; Energy Metabolism; FGF21 gene; Fasting; Genetic; Glucose Clamp; Health; Health Promotion; Hormones; Human; Hyperinsulinism; Incidence; Individual; Intervention; Isoleucine; Lead; Leucine; Life Expectancy; Link; Longevity; Macronutrients Nutrition; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Molecular Analysis; Morbidity - disease rate; Mouse Strains; Mus; Neurodegenerative Disorders; Obesity; Pathology; Persons; Pharmacological Treatment; Physical Performance; Physiologic Thermoregulation; Physiological; Play; Population; Process; Protein-Restricted Diet; Proteins; Regulation; Risk; Risk Factors; Rodent; Role; Sex Differences; Telemetry; Testing; Time; United States; Valine; Weight Gain; Work; age related; aging brain; cognitive benefits; cohort; dietary; energy balance; experimental study; fibroblast growth factor 21; fitness; frailty; glucose metabolism; glucose production; glucose uptake; glycemic control; healthspan; healthy aging; improved; insight; longitudinal human study; male; metabolic phenotype; mortality; mouse model; obesity risk; overexpression; pharmacologic; preservation; prevent; protein intake; randomized, clinical trials; response; sex; sexual dimorphism; therapy development

Project Summary Age-related diseases are the major causes of morbidity and mortality in the US. Many elderly people suffer from multiple age-related diseases simultaneously; while the risk of almost every individual disease rises with age, they also interact. For example, diabetes and obesity are risk factors for neurodegenerative diseases including Alzheimer’s disease (AD). 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 multiple age- related diseases simultaneously, but reduced-calorie diets are notoriously difficult to sustain. Recent studies have highlighted an important role for dietary protein in health and longevity, with protein restriction (PR) shown to promote longevity and to mimic the metabolic, frailty, and cognitive benefits of CR. During the initial project period, we found that specifically reducing dietary consumption of the three branched-chain amino acids (BCAAs) – leucine, isoleucine, and valine – has sex-specific benefits for frailty and lifespan in C57BL/6J mice. We determined that the metabolic and molecular effects of PR are both sex and strain dependent, and that the role of a specific hormone proposed to mediate the effects of PR may be more limited than previously suspected and also differ between sexes and strains. Finally, we found that the BCAAs have distinct roles on metabolism, with restriction of isoleucine being necessary and sufficient for the metabolic benefits of PR. In preliminary experiments, we have also found that isoleucine restriction has sexually dimorphic effects on healthspan and longevity in genetically heterogenous mice, and that PR has beneficial effects on cognition and disease pathology in a mouse model of Alzheimer’s disease. Here, we will rigorously test the ability of graded restriction of isoleucine to promote health and longevity in DBA/2J and C57BL/6J mice of both sexes, examining the effects on metabolic health, frailty, cognition and lifespan as well as the effects on pathology and at the molecular level. We will identify the role of a specific hormone, FGF21, in the metabolic response to isoleucine restriction. Finally, we will test if restriction of individual BCAAs is necessary and sufficient for the ability of a PR diet to prevent or delay AD. The proposed work will examine the role of the BCAA isoleucine on health and longevity in multiple genetic backgrounds for the first time and answer long-standing questions regarding how dietary composition impacts healthy aging. Importantly, we will gain new insight into the mechanisms that drive the potent effects of isoleucine restriction on healthy aging, and break new ground identifying how individual BCAAs impact the progression of AD. In the long term, this work will enable our lab and others to develop a mechanistic understanding of how dietary BCAAs and other macronutrients regulate health and disease vulnerability, and to identify new targets for pharmacological treatments to promote healthy aging.

项目摘要 与年龄相关的疾病是美国发病率和死亡率的主要原因。许多老年人 简单地患有多种与年龄有关的疾病；而几乎每种单个疾病的风险都会上升 随着年龄的增长，它们也相互作用。例如，糖尿病和肥胖是神经退行性疾病的危险因素 包括阿尔茨海默氏病（AD）。卡路里限制（CR），一种饮食干预，延长了寿命 延迟或预防与年龄相关的疾病是一种合理的方法，可以减轻多年年龄的燃烧 相关疾病很容易，但众所周知，减少的饮食很难维持。最近的研究 在健康和寿命中强调了饮食蛋白的重要作用，其中显示了蛋白质限制（PR） 促进寿命并模仿CR的代谢，脆弱和认知益处。 在最初的项目期间，我们发现特别减少了这三种的饮食消费 分支链氨基酸（BCAA） - 亮氨酸，异亮氨酸和缬氨酸 - 对脆弱和 C57BL/6J小鼠中的寿命。我们确定PR的代谢和分子作用既是性别，又是性别 菌株依赖性，并且提议介导PR影响的特定骑马的作用可能更多 在性别和菌株之间的限制比以前怀疑和不同。最后，我们发现BCAA 在新陈代谢上具有独特的作用，对于代谢而言，异亮氨酸的限制是必要的和足够的 公关的好处。在初步实验中，我们还发现异亮氨酸限制具有性二态 对一般异质小鼠的健康范围和寿命的影响，PR对 阿尔茨海默氏病小鼠模型中的认知和疾病病理学。 在这里，我们将严格测试异亮氨酸分级限制以促进健康和寿命的能力 在两性的DBA/2J和C57BL/6J小鼠中，检查了对代谢健康，脆弱，认知和 寿命以及对病理和分子水平的影响。我们将确定特定的作用 Horseone，FGF21，对异亮氨酸限制的代谢反应。最后，我们将测试个人是否限制 BCAA对于PR饮食预防或延迟AD的能力是必要且足够的。 拟议的工作将研究BCAA异亮氨酸在多重健康中的健康和寿命中的作用 第一次遗传背景，并回答有关饮食成分的长期问题 影响健康的衰老。重要的是，我们将对推动潜在影响的机制获得新的见解 异亮氨酸对健康衰老的限制，并打破新的地面，以确定个体BCAA如何影响 AD的进展。从长远来看，这项工作将使我们的实验室和其他人能够开发机械 了解饮食BCAA和其他大量营养素如何调节健康和疾病脆弱性，以及 确定药物治疗的新目标以促进健康的衰老。