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：
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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要与年龄相关的疾病是美国许多老年人发病和死亡的主要原因。同时患有多种与年龄相关的疾病；而几乎每种疾病的风险都在上升；随着年龄的增长，它们也会相互作用，例如，糖尿病和肥胖是神经退行性疾病的危险因素。包括阿尔茨海默病 (AD)，这是一种可以延长寿命的饮食干预措施。延缓或预防与年龄相关的疾病，是减轻多种年龄相关疾病负担的一种可行方法。相关疾病同时存在，但众所周知，低热量饮食很难维持。强调了膳食蛋白质在健康和长寿中的重要作用，蛋白质限制 (PR) 显示促进长寿并模仿 CR 对代谢、虚弱和认知的益处。在项目初期，我们发现专门减少三者的饮食消耗支链氨基酸 (BCAA) – 亮氨酸、异亮氨酸和缬氨酸 – 对缓解体弱和虚弱具有特定性别的益处我们确定 PR 对 C57BL/6J 小鼠的代谢和分子影响既包括性别，也包括性别。菌株依赖性，并且提议介导 PR 效果的特定激素的作用可能更重要支链氨基酸的数量比之前怀疑的要有限，而且性别和品系之间也存在差异。对代谢具有独特的作用，限制异亮氨酸对于代谢是必要且充分的在初步实验中，我们还发现异亮氨酸限制具有性别二态性。 PR 对遗传异质小鼠的健康寿命和寿命有影响，并且 PR 对阿尔茨海默病小鼠模型的认知和疾病病理学。在这里，我们将严格检验分级限制异亮氨酸促进健康长寿的能力在 DBA/2J 和 C57BL/6J 两性小鼠中，检查对代谢健康、虚弱、认知和我们将确定特定的作用。激素 FGF21 在异亮氨酸限制的代谢反应中的作用最后，我们将测试个体是否受到限制。 BCAA 对于 PR 饮食预防或延缓 AD 的能力来说是必要且充分的。拟议的工作将研究 BCAA 异亮氨酸对多种健康和长寿的作用首次研究遗传背景，并回答有关膳食成分如何影响长期存在的问题重要的是，我们将对驱动其有效影响的机制有新的见解。异亮氨酸限制对健康衰老的影响，并开辟了新的领域，以确定单个支链氨基酸如何影响从长远来看，这项工作将使我们的实验室和其他人能够开发出一种机制。了解膳食支链氨基酸和其他常量营养素如何调节健康和疾病脆弱性，并确定药物治疗的新目标，以促进健康老龄化。