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.

项目概要与年龄相关的疾病是西方社会发病和死亡的主要原因。限制（CR），一种饮食干预措施，可以延长寿命，同时延缓或预防与年龄相关的疾病，是减轻这些疾病负担的一种可行方法，但众所周知，低热量饮食最近的研究强调了膳食蛋白质对健康和长寿的重要作用，低蛋白 (LP) 饮食被证明可以延长寿命并模仿 CR 的代谢益处。发现特别减少三种支链氨基酸 (BCAA) 的饮食摄入量 – 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，并促进确定低 BCAA 饮食对长寿的影响，并确定其影响因素。膳食支链氨基酸影响新陈代谢的生理和分子机制将提供最终，这将有助于开发新的机制。预防或延缓与年龄有关的疾病的药理学方法。在这里，我们将严格检验低 BCAA 饮食可以促进健康和长寿的假设小鼠，检查长期低 BCAA 饮食对寿命、代谢健康、心脏功能和我们将确定 BCAA 消耗量的减少是否会介导 CR 和 LP 的代谢效应。最后，我们将检查 BCAA 及其分解代谢物对功能的细胞自主影响。使用新型代谢传感器对原代肝细胞和胰岛进行体外代谢和代谢，并进行测试这些效应的候选分子介质。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，并解决了有关膳食质量（膳食的具体成分）如何的长期存在的问题饮食——影响健康衰老，重要的是，我们将获得对生理和分子的新见解。从长远来看，这项工作将使我们能够实现 CR 和 LP 饮食的有效作用。实验室和其他人对膳食支链氨基酸和其他宏量营养素调节健康和疾病脆弱性，并确定新的目标与年龄相关的疾病的药物治疗和促进健康老龄化。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Strength in diversity: Intra-cellular metabolite sharing enhances longevity.

多样性的优势：细胞内代谢物共享可延长寿命。

DOI：
10.1016/j.cell.2022.12.012
发表时间：
2023
期刊：
Cell
影响因子：
64.5
作者：
Lamming,DudleyW;Anderson,RozalynM
通讯作者：
Anderson,RozalynM

A food with medicine approach to health.

食品与药物的健康之道。

DOI：
10.1016/j.cmet.2021.11.012
发表时间：
2021
期刊：
Cell metabolism
影响因子：
29
作者：
Green,CaraL;Lamming,DudleyW
通讯作者：
Lamming,DudleyW

SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.

DOI：
10.1111/acel.13721
发表时间：
2022-12
期刊：
Aging cell
影响因子：
7.8
作者：
通讯作者：

mTOR gets greasy: lysosomal sensing of cholesterol.

mTOR 变得油腻：溶酶体对胆固醇的感知。

DOI：
10.1038/s41422-022-00740-9
发表时间：
2023
期刊：
Cell research
影响因子：
44.1
作者：
Bar-Peled,Liron;Lamming,DudleyW
通讯作者：
Lamming,DudleyW

Protein restriction slows the development and progression of Alzheimer's disease in mice.

蛋白质限制可减缓小鼠阿尔茨海默病的发生和进展。

DOI：
10.21203/rs.3.rs-3342413/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Babygirija,Reji;Sonsalla,MichelleM;Han,JessicaH;James,Isabella;Green,CaraL;Calubag,MariahF;Mill,Jericha;Wade,Gina;Tobon,Anna;Michael,John;Trautman,MichaelaM;Matoska,Ryan;Yeh,Chung-Yang;Grunow,Isaac;Pak,HeidiH;Rigby,Mic
通讯作者：
Rigby,Mic