Ketogenic Oscillations and Neurometabolic Healthspan

总结 热量限制，间歇性禁食，时间限制喂养/进食，禁食模仿饮食，以及燃料- 与运动有关的转换都显示出改善新陈代谢和大脑健康的证据。资助的研究 通过父母补助金将是第一个直接解决酮代谢的具体作用后， 间歇性代谢转换带来的代谢、能量、神经调节和认知益处， 其具有多效性作用，包括增强酮代谢。虽然专注于神经代谢 与衰老相关的下降，没有一项通过父母资助的研究直接解决了这个问题。 阿尔茨海默病（AD）中的营养波动、燃料转换或酮代谢。然而，广泛 文献显示AD中发生异常的能量代谢，包括在治疗期间葡萄糖利用减少。 神经变性轻度认知功能障碍/AD也与胰岛素敏感性受损相关， 与对照组相比，VO 2 max，这两个因素都与线粒体功能有关。受损的逻辑延伸 葡萄糖代谢是一个未充分研究的假设，生酮饮食可以在药理学上有益于AD 科目因此，多项试验针对生酮饮食治疗神经退行性疾病中的认知下降， 疾病，以及其他引起间歇性代谢转换的干预方法也很重要。 对AD治疗感兴趣，包括间歇性禁食。本补充申请的中心假设是 综合酮代谢是改善AD结果的原因， 代谢转换单一的具体目标是使用公认的AD小鼠模型来确定振荡是否 在生酮通量通过间歇性禁食不仅提供燃料的大脑，而且还提高分子和 组织病理学结果。rTg 4510（tauP 301 L双转基因）小鼠模型将用于研究 与阿尔茨海默病有关的神经系统缠结。间歇性禁食与ad的效果 将在肝生酮小鼠中定量自由进食对照对代谢和组织病理学结局的影响。 充足性，并与遗传程序性生酮不足的小鼠进行比较。切削刃 代谢组学和代谢通量分析将用于量化脑葡萄糖和酮的利用， 分子和组织病理学方法将用于揭示AD发病机制的影响。影响：The 生酮疗法对健康寿命的益处通常被认为是通过酮代谢发生的， 但这从未被证实过为补编提出的实验将确定酮合成是否 在AD的临床相关干预中起机制作用。而且这 这项工作将为那些不能进行这种生活方式干预， 对这些患者而言，其他形式的酮疗法可能对预防或治疗AD有显著益处。

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.