Investigations of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional longevity and treatment of Alzheimer's disease

项目摘要--总体 治疗功能性酮症的靶点、机制和最佳给药方案的研究 阿尔茨海默病的长寿与治疗 我们最近首次在任何地方证明了等卡路里连续生酮饮食延长了 小鼠的认知、记忆和肌肉功能，并显著提高平均寿命13%1。 同一期的细胞新陈代谢，其他的显示间歇性生酮饮食(IKD)保留了许多 小鼠的晚年生活功能。这些同时发表的发现具有深刻的机械性(对于 了解衰老的生物学)和翻译(对美国公共卫生)的影响。从机械上讲，他们 提出“酮症延缓衰老”的假说。PPG应用程序旨在识别机械设备 治疗性酮症延缓小鼠衰老的靶点和生物标志物，并与 老年学概念，即延缓衰老的干预措施应该延缓与年龄相关的疾病，在这种情况下是AD， 通过识别小鼠的KD机制和生物标志物，这项研究将为以下工作奠定基础 未来的人体研究。为了服务于这些机械性和翻译性的目标，我们提出了以下四点 项目。1，Cortopassi，涉及对酮类长寿机制的机械剖析，使用 转录学、蛋白质阵列和基因敲除小鼠，以及治疗阿尔茨海默病的Shc拮抗剂。2，Pelicci， 绘制衰老的表观遗传后果图，KD如何逆转它们，以及这些重叠的程度 与衰老和阿尔茨海默氏症。3，Baar，阐述了Kat和乙酰化机制，通过这些机制改善了肌肉 在野生型和阿尔茨海默病小鼠模型中，功能延缓了大脑的衰老。4，Ramsey，指出了 保护晚年功能和长寿所必需的‘酮治疗包络’，以及关于 阿尔茨海默病小鼠模型。这些项目都是互动的，如正文所示。它们还得到了 杰出的动物核心C，由Kent Lloyd DVM博士和Lee-way jin医学博士领导，拥有出色的经验 在小鼠生物学和阿尔茨海默氏症方面，生物统计核心B、金永美和一口井提供了出色的支持- 有组织的行政核心A。这个项目的完成将导致新的内部机制进入 治疗性酮病的长寿机制，并确认酮治疗效果的生物标志物可能 与老年美国人和阿尔茨海默病患者的功能和长寿有关。

Project Summary – Overall 'Investigation of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional longevity and treatment of Alzheimer's disease' We recently demonstrated, for the first time anywhere, that the isocaloric continuous Ketogenic diet extends cognitive and memory and muscle functions in mice, and significantly increases median longevity by 13%1. In the same issue of Cell Metabolism, others showed that the intermittent Ketogenic diet (iKD) preserves many late life functions in mice. These simultaneously-published findings have profound mechanistic (for understanding the biology of aging) and translational (for US public health) implications. Mechanistically, they suggest the hypothesis that 'ketosis delays aging'. The PPG application is designed to identify mechanistic targets and biomarkers by which therapeutic ketosis delays aging in mice, and are consistent with the geroscience concept, i.e. that interventions that delay aging should delay age related disease, in this case AD, Alzheimer's. By identifying the KD mechanisms and biomarkers in mice, this study will lay the ground work for future human studies. In order to serve these mechanistic and translational goals, we propose these four projects. 1, Cortopassi, involves the mechanistic dissection of the ketolongevity mechanism, using transcriptomics, protein arrays and knockout mice, and Shc antagonists for Alzheimer's disease. 2, Pelicci, maps the epigenetic consequences of aging, and how the KD reverses them, and to what extent these overlap with aging and Alzheimer's. 3, Baar, addresses KAT and acetylation mechanisms by which improved muscle function delays brain aging in wild-type and Alzheimer's mouse model. 4, Ramsey, identifies the 'ketotherapeutic envelope' necessary for preservation of late-life functions and longevity, and with respect to an Alzheimer's mouse model. These Projects are all interactive as shown in the text. They are also supported by an outstanding Animal Core C, led by Kent Lloyd DVM PHD and Lee-Way Jin MD PHD with stellar experience in mouse biology and Alzheimer's disease, brilliant support by Biostatistics Core B, Kyoungmi Kim, and a well- organized Administrative Core A. The completion of this project will lead to new mechanistic inside into the therapeutic ketosis longevity mechanism, and identify biomarkers of ketotherapeutic effect that could be relevant to preservation of functions and longevity in aging Americans, and those with Alzheimer's disease.