Ketogenic Oscillations and Neurometabolic Healthspan

摘要 卡路里限制，间歇性禁食，限时喂食，禁食模拟饮食，以及燃料- 与锻炼相关的改变都显示出改善新陈代谢和大脑健康的证据。获资助的研究 通过父母的资助，将是第一个直接解决酮代谢对 间歇性代谢转换带来的代谢、能量、神经调节和认知方面的好处， 它具有多效性，包括增强酮的代谢。尽管重点放在神经代谢上 衰老相关的衰退，没有一项由父母资助的研究直接解决了这一角色 阿尔茨海默病(AD)中营养振荡、燃料转换或酮代谢的影响。然而，广泛的 文献显示阿尔茨海默病患者能量代谢异常，包括在 神经退行性变。轻度认知障碍/阿尔茨海默病也与胰岛素敏感性受损和 与对照组相比，最大摄氧量都与线粒体功能有关。受损人士的合理延伸 葡萄糖代谢是一个未被充分研究的假说，即生酮饮食可能对阿尔茨海默病有症状 研究对象。因此，多项试验的目标是生酮饮食来治疗神经退行性疾病的认知能力下降。 疾病和其他引起间歇性代谢转换的干预性方法也很重要 对AD治疗感兴趣，包括间歇性禁食。这一补充应用程序的中心假设是 由于间歇性阿尔茨海默病预后的改善，综合酮代谢是原因之一 新陈代谢转换。唯一的具体目标是使用被接受的AD小鼠模型来确定是否存在振荡 在生酮中，通过间歇禁食不仅为大脑提供能量，而且还改善了分子和 组织病理学结果。将使用rTg4510(tauP301L双转基因)小鼠模型来研究这种形成 与阿尔茨海默病有关的神经原纤维缠结。间歇性禁食与广告的效果 Libitum喂养的对照对肝生酮小鼠代谢和组织病理学结果的影响将被量化 并与遗传程序性生酮不足的小鼠进行比较。尖端 代谢组学和代谢流量分析将用于量化大脑葡萄糖和酮类的利用，以及 分子和组织病理学方法将被用来揭示AD发病机制中的作用。影响： 生酮疗法对健康寿命的好处通常被认为是通过酮代谢产生的， 但这一点从未得到证实。为补充材料提出的实验将确定酮的合成 益肝益脑在AD的临床干预中起着重要的机制作用。此外，这一点 这项工作将为无法进行这种生活方式干预的个人阐明具体的治疗目标，但 对他们来说，其他形式的酮疗法可能会对预防或治疗阿尔茨海默病有重大好处。

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.