Mechanisms Underlying Improved Health Span on a Short-Term Ketogenic Diet

短期生酮饮食改善健康寿命的机制

• 批准号: 10153626
• 负责人: Keith Baar
• 金额: $ 36.45万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153626
• 关键词: APP-PS1; Acetylation; Address; Adherence; Age; Aging; Alzheimer' s Disease; American; Area; Biology of Aging; Brain; Centenarian; Data; Development; Diet; Dietary Intervention; Disease; Elderly; Enzymes; Event; Exercise; Goals; Hawaiian population; Health; Height; Human; Impaired cognition; Impairment; Incidence; Institutionalization; Intervention; Investigation; Ketosis; Kynurenine; Kynurenine-oxoglutarate aminotransferase; Laboratories; Lead; Learning; Life; Link; Longevity; Memory; Metabolism; Mitochondria; Molecular; Molecular Target; Motor; Mus; Muscle; Muscle Mitochondria; Muscle Weakness; Muscle function; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurotoxins; Nursing Homes; Nutritional; Peroxisome Proliferator-Activated Receptors; Physical activity; Play; Population; Protein Acetylation; Publishing; Quality of life; Quinolinic Acid; Research; Role; Skeletal Muscle; Testing; Therapeutic; Time; Transferase; Work; age related; age-related muscle loss; cost; dietary; drug development; exercise program; healthspan; improved; improved functioning; innovation; ketogenic diet; men; middle age; mimetics; mortality; muscle form; novel; novel strategies; prevent

Summary — Project 3 Mechanisms Underlying Improved Health Span on a Short Term Ketogenic Diet A decrease in mitochondrial mass and function in muscle and neurodegeneration are common complications of aging. Both of these conditions are linked to a decline in physical activity. Even though muscle and brain function are essential to health and quality of life, the molecular chain of events that lead to these devastating conditions and interventions, outside of life long exercise, that slow them remain poorly understood. We have recently shown that a long term ketogenic diet can prevent age-associated loss of muscle and brain function. Since strict diets, like exercise programs, are difficult to maintain throughout life, this study aims to determine whether a short term intervention started late in life is equivalent to the longer term treatment and determine the mechanism underlying the benefits so that novel, less arduous, interventions can be developed to improve the longevity and quality of life in millions of Americans. Specifically, we will look at the role played by acetylation in the effects of a ketogenic diet on mitochondrial mass in muscle and the kynurenine amino transferases (KATs) in the development of neurocognitive decline with age and Alzheimer's disease. Since interventions that improve muscle mitochondrial function improve brain function, the objective of this work is to determine whether a ketogenic diet increases enzymes that prevent a neurotoxin from reaching the brain. Building on previously published research in this area, and strong preliminary data, we have developed the working hypothesis that a ketosis shifts metabolism in a manner similar to exercise resulting in enhanced muscle mitochondrial function and an increase in KATs, enzymes that decrease the amounts of the neurotoxin quinolinic acid in the brain and slow neurodegeneration with age or Alzheimer's disease. We will test this hypothesis by completing these three specific aims: 1) Determine whether ketosis can mimic exercise and reverse the age-related impairments in muscle and brain function; 2) Determine whether an increase in KAT in muscle as a result of ketosis is required and sufficient for the improvement in brain function; and 3) Determine whether increasing acetylation and KAT in muscle can improve learning, memory, and motor function in mice with Alzheimer's disease. This highly innovative proposal explores the molecular mechanism underlying an essential question in aging biology using a completely novel approach where diet is used to prevent hallmarks of aging. The significance of this research is three-fold: 1) It will contribute to a basic understanding of the molecular events leading to age-associated loss of muscle and brain function; 2) It will validate a simple nutritional strategy to improve muscle and brain with aging and thus improve quality of life and reduce mortality in the population; and 3) It will provide a novel molecular target for the development of drugs to slow the progress of Alzheimer's disease. Successful completion of this application is one step towards the long-term objective of our laboratory: to increase quality of life through improved muscle and brain function.

摘要 - 项目3 短期生酮饮食中的健康跨度改善的机制 线粒体质量和肌肉和神经退行性的功能的降低是常见的并发症 衰老。这两种情况都与体育锻炼的下降有关。即使肌肉和大脑 功能对于健康和生活质量至关重要，这是导致这些毁灭性的事件的分子链 在长期运动之外的情况下，疾病和干预措施使他们放慢脚步仍然很少理解。我们有 最近表明，长期的生酮饮食可以防止与年龄相关的肌肉和脑功能丧失。 由于严格的饮食（如锻炼计划）在一生中都难以维持，因此该研究旨在确定 短期干预是否在生活后期开始是否等同于长期治疗和确定 益处的基础机制，因此可以开发出新颖，不那么艰巨的干预措施来改善 数百万美国人的寿命和生活质量。具体来说，我们将研究 生酮饮食对肌肉和雌激素氨基中线粒体肿块作用的乙酰化化 随着年龄和阿尔茨海默氏病的神经认知下降的发展，转移（KAT）。自从 改善肌肉线粒体功能改善大脑功能的干预措施，这项工作的目的是 确定生酮饮食是否会增加酶，以防止神经毒素进入大脑。 在该领域先前发表的研究以及强大的初步数据的基础上，我们开发了 酮症的工作假设以类似于运动的方式改变了新陈代谢 增强的肌肉线粒体功能和Kats的增加，酶降低了 随着年龄的年龄或 阿尔茨海默氏病。我们将通过完成这三个特定目的来检验这一假设：1）确定 酮症是否可以模仿运动并扭转与年龄相关的肌肉和脑功能障碍； 2） 确定是否需要酮症中的Kat增加肌肉的增加，并且足以满足 改善大脑功能； 3）确定肌肉中乙酰化和kat的增加是否可以 通过阿尔茨海默氏病改善小鼠的学习，记忆和运动功能。这种高度创新的 提案探讨了使用A 完全新颖的方法，用于防止饮食来防止衰老的标志。这项研究的意义 是三倍：1）它将有助于对分子事件的基本理解，从而导致年龄相关 肌肉和大脑功能的丧失； 2）它将验证一种简单的营养策略来改善肌肉和大脑 随着衰老的质量而改善生活质量并降低人口的死亡率； 3）它将提供小说 用于开发药物的分子靶标，以减慢阿尔茨海默氏病的进展。成功的 该应用程序的完成是朝着我们实验室的长期目标迈出的一步：提高质量 通过改善肌肉和大脑功能的生活。