Ketogenic Oscillations and Neurometabolic Healthspan

生酮振荡和神经代谢健康寿命

• 批准号: 10294352
• 负责人: Peter A Crawford
• 金额: $ 38.52万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10294352
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapy; Brain; Caloric Restriction; Diet; Disease Outcome; Eating; Energy Metabolism; Exercise; Fasting; Funding; Glucose; Health; Hepatic; Impaired cognition; Impairment; Individual; Intermittent fasting; Intervention; Ketones; Link; Literature; Liver; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nutrient; Outcome; Pathogenesis; Play; Role; Testing; Time-restricted feeding; VO2max; Work; brain health; clinically relevant; cognitive benefits; experimental study; glucose metabolism; healthspan; improved; indexing; insulin sensitivity; interest; ketogenic diet; ketogentic; lifestyle intervention; metabolomics; mild cognitive impairment; mouse model; neurofibrillary tangle formation; neuroregulation; parent grant; pleiotropism; prevent; therapeutic target

SUMMARY Caloric restriction, intermittent fasting, time restricted feeding/eating, fasting mimicking diet, and the fuel- switching linked to exercise have all shown evidence of improving metabolic and brain health. Studies funded through the parent grant will be the first to directly address the specific roles of ketone metabolism upon the metabolic, energetic, neuromodulatory, and cognitive benefits conferred by intermittent metabolic switching, which has pleiotropic effects, including augmentation of ketone metabolism. Although focused on neurometabolic declines associated with aging, none of the studies funded through the parent grant directly addresses the role of nutrient oscillations, fuel switching, or ketone metabolism in Alzheimer’s Disease (AD). However, extensive literature shows aberrant energy metabolism occurs in AD, including reduced glucose utilization during neurodegeneration. Mild cognitive impairment/AD also is associated with impaired insulin sensitivity and reduced VO2max compared to controls, factors both linked to mitochondrial function. A logical extension of impaired glucose metabolism is the understudied hypothesis that a ketogenic diet could symptomatically benefit AD subjects. Thus, multiple trials are targeting ketogenic diets to treat cognitive decline in neurodegenerative diseases, and other interventional approaches that provoke intermittent metabolic switching are also of great interest for AD therapy, including intermittent fasting. The central hypothesis of this supplemental application is that integrated ketone metabolism is responsible for the improvement in AD outcomes attributable to intermittent metabolic switching. The single Specific Aim is to use an accepted mouse model of AD to determine if oscillations in ketogenic flux via intermittent fasting not only provide fuel to the brain, but also improve molecular and histopathological outcomes. The rTg4510 (tauP301L bitransgenic) mouse model will be used to study the formation of neurofibrillary tangles associated with Alzheimer's disease. The effects of intermittent fasting, versus ad libitum-fed control, on metabolic and histopathological outcomes will be quantified in mice with hepatic ketogenic sufficiency and compared to those of mice with genetically programmed ketogenic insufficiency. Cutting edge metabolomics and metabolic flux analyses will be used to quantify brain glucose and ketone utilization, and molecular and histopathological approaches will be used to reveal effects on AD pathogenesis. IMPACT: The benefits of ketogenic therapies on health span are commonly presumed to occur through ketone metabolism, but this has never been proven. The experiments proposed for the Supplement will determine if ketone synthesis in liver for utilization in brain plays a mechanistic role in clinically relevant interventions for AD. Moreover, this work will elucidate specific therapeutic targets for individuals who cannot perform this lifestyle intervention but for whom other forms of ketone therapy might confer significant benefit to prevent or treat AD.

概括 热量限制，间歇性禁食，时间限制喂食/进食，禁食模仿饮食以及燃料 - 与运动相关的转换都显示出改善代谢和大脑健康的证据。研究资助 通过父母赠款将是第一个直接解决酮代谢在 代谢，能量，神经调节和认知益处由间歇代谢转换赋予 具有多效作用，包括增强酮代谢。虽然专注于神经代谢 与衰老相关的下降，由父母赠款资助的研究都没有直接解决角色 阿尔茨海默氏病（AD）中营养素振荡，燃料转换或酮代谢的。但是，广泛 文献显示在AD中发生异常的能量代谢，包括减少的葡萄糖利用率 神经变性。轻度认知障碍/AD也与胰岛素敏感性受损相关并降低 VO2MAX与对照组相比，两者都与线粒体功能相关。受损的逻辑扩展 葡萄糖代谢是一种理解的假设，即生酮饮食可以使AD受益 主题。这是针对生酮饮食以治疗神经退行性的认知下降的多次试验 疾病和其他引起间歇代谢转换的介入方法也很棒 广告疗法的兴趣，包括间歇性禁食。这种补充应用的核心假设是 综合的酮代谢是导致间歇性归因于广告结果的改善 代谢切换。单一的特定目的是使用AD的接受鼠标模型来确定振荡是否振荡 在生酮通量中，通过间歇性禁食不仅为大脑提供燃料，还可以改善分子和 组织病理学结果。 RTG4510（TAUP301L BITRANSGENIC）小鼠模型将用于研究形成 与阿尔茨海默氏病有关的神经纤维缠结的缠结。间歇性禁食的影响，与广告 肝脏病酮的小鼠将定量对代谢和组织病理学结局的自由喂养对照 足够的和与一般编程的生酮不足的小鼠相比。前沿 代谢组学和代谢通量分析将用于量化脑葡萄糖和酮利用率，以及 分子病理学方法和组织病理学方法将用于揭示对AD发病机理的影响。影响： 生酮疗法对健康跨度的好处通常是通过酮代谢而出现的 但这从未得到证明。为补充提出的实验将确定酮合成是否合成 在肝脏中，用于脑部的肝脏在AD的临床相关干预措施中起着机械作用。而且，这 工作将为无法执行这种生活方式干预但 其他形式的酮疗法可能会涉及预防或治疗广告的重要好处。