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

摘要-项目3 短期生酮饮食改善健康状况的机制 肌肉中线粒体质量和功能的减少和神经变性是常见的并发症。 衰老的问题。这两种情况都与体力活动减少有关。即使肌肉和大脑 功能对健康和生活质量是必不可少的，导致这些毁灭性事件的分子链 除了终生锻炼之外，减缓它们的条件和干预措施仍然鲜为人知。我们有 最近的研究表明，长期生酮饮食可以防止与年龄相关的肌肉和大脑功能丧失。 由于严格的饮食，如锻炼计划，很难在一生中保持下去，这项研究旨在确定 在晚年开始的短期干预是否等同于长期的治疗和确定 潜在的利益机制，从而可以开发新的、不那么费力的干预措施来改善 数百万美国人的寿命和生活质量。具体地说，我们将研究一下 生酮饮食对肌肉线粒体质量和犬尿氨酸氨基酸乙酰化的影响 转移酶(KATS)在神经认知功能随年龄增长和阿尔茨海默病发展中的作用。自.以来 改善肌肉线粒体功能的干预措施改善了大脑功能，这项工作的目标是 确定生酮饮食是否增加了阻止神经毒素到达大脑的酶。 基于以前在这方面发表的研究和强大的初步数据，我们开发了 工作假说，酮症以类似于运动的方式改变新陈代谢，导致 肌肉线粒体功能增强和KATS增加，这些酶可以降低 大脑中神经毒素喹啉酸的含量以及随年龄或年龄增长而缓慢的神经退行性变 阿尔茨海默氏症。我们将通过完成以下三个具体目标来验证这一假设：1)确定 酮症是否可以模拟运动，逆转与年龄相关的肌肉和大脑功能损害；2) 确定酮病引起的肌肉中Kat增加是否是必需的，并且是否足以满足 改善大脑功能；以及3)确定增加肌肉中的乙酰化和Kat是否可以 改善阿尔茨海默病小鼠的学习、记忆和运动功能。这个极具创新性的 Proposal使用一种方法探索了衰老生物学中一个基本问题背后的分子机制 全新的方法，饮食被用来防止衰老的标志。这项研究的意义 有三个方面：1)它将有助于对导致年龄相关的分子事件的基本理解 肌肉和大脑功能的丧失；2)它将验证一种改善肌肉和大脑的简单营养策略 随着老龄化，从而改善生活质量，降低人口死亡率；以及3)它将提供一种新的 分子靶点用于开发延缓阿尔茨海默病进展的药物。成功 完成这项申请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来改善生命。

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.