Elucidating biomarkers and mechanisms of the Ketogenic longevity mechanism

项目摘要-项目1 阐明生酮长寿机制的生物标志物和机制。 在中年小鼠中开始的等热量生酮饮食（KD）重新编程代谢，降低p46 Shc， 并保留晚年功能，包括记忆，认知和肌肉功能的许多参数， 显著延长寿命1，2.更好地理解酮症依赖性长寿机制及其 生物标志物可以导致更有效的剂量这种营养干预其延缓衰老和认知 在小鼠中下降，并在人类中延伸。我们的目标包括确定KD的长寿机制， 生物标志物，通过RNAseq和组织和血液中的蛋白质表达（Aims 1和2）。通过识别基因 增加或减少最多，我们确定了最KD响应的生物标志物。通过重叠这些 生物标志物与项目2（Pelicci）的结果，这将确定衰老相关的表观遗传标记， 哪些与衰老相关的表观遗传标记被KD逆转，我们将鉴定那些既 与衰老相关，并对KD有反应。这些将有助于机械地定义支持KD的基因 保持功能寿命。这些衰老相关和KD响应性生物标志物也将用于Proj 4 Ramsey的目标是评估iKD和KS策略治疗酮症在以下方面的相对获益： 功能性长寿在目标3中，我们测试了KD长寿效应的三种可能的候选机制，即 靶向β-羟基丁酸酯受体HCAR 2、FFAR 3的酮，以及抑制p46 Shc， 调节硫解酶和酮生成。功能性长寿表型的恢复表明 HCAR 2、FFAR 3和p46 Shc参与了该机制，这可以进一步通过 线粒体和乙酰化和KAT机制，项目3（巴尔）。在目标4中，我们测试最近确定的 阿尔茨海默氏病细胞模型和阿尔茨海默氏病PSAPP小鼠模型中的Shc抑制剂（With Core C）。完成这组综合实验将确定KD的衰老相关生物标志物， 将明确测试KD的三种可能机制。它还将确定小分子Shc是否 抑制剂在AD的细胞和动物模型中起保护作用，这可能导致一种新的药理学策略， 阿尔茨海默病不是基于淀粉样蛋白的溶解，而是基于神经代谢、线粒体和 生存策略该项目的整体产品将支持一个机械的理解， 治疗性酮症是关于功能寿命，它是如何工作的，它的生物标志物是什么，和潜力 Shc抑制剂在AD中的益处

Project Summary – Project 1 Elucidating biomarkers and mechanisms of the Ketogenic longevity mechanism. The isocaloric Ketogenic Diet (KD) initiated in middle-aged mice reprograms metabolism, decreases p46Shc and preserves late-life functions including memory, cognition, and many parameters of muscle function, and significantly increases lifespan1,2. A better understanding of the ketosis-dependent longevity mechanism and its biomarkers could lead to more effective dosing of this nutritional intervention for its delay of aging and cognitive decline in mice, and by extension in humans. Our goals include identifying the KD's longevity mechanism and biomarkers, by RNAseq and protein expression in tissues and blood (Aims1 and 2). By identifying the genes which increase or decrease the most, we identify the most KD-responsive biomarkers. By overlapping these biomarkers with the results of Proj 2(Pelicci), which will determine the aging-relevant epigenetic marks and which aging-relevant epigenetic marks are reversed by KD, we will identify those biomarkers that are both aging-relevant and KD-responsive. These will help to mechanistically define genes that support the KD's preservation of functional longevity. These aging-relevant and KD-responsive biomarkers will also serve Proj4 Ramsey's goals to evaluate the relative benefit of iKD and KS strategies of 'therapeutic ketosis with respect to functional longevity'. In Aim 3, we test three likely candidate mechanisms for KD's longevity effect, i.e. rising ketones that target the beta-hydroxybutyrate receptor HCAR2, FFAR3, and the repression of p46Shc that regulates thiolase and ketogenesis. Reversal of functional longevity phenotype will indicate prominent involvement of HCAR2, FFAR3 and p46Shc in the mechanism, which can be further specified into by the mitochondrial and acetylation and KAT mechanisms by Project 3 (Baar). In Aim 4, we test recently-identified Shc inhibitors in a cell model of Alzheimer's, and the PSAPP mouse model of Alzheimer's disease (With Core C). The completion of this integrative set of experiments will define aging-relevant biomarkers of the KD, and will test three likely mechanisms of the KD explicitly. It will also determine whether small-molecule Shc inhibitors protect in cell and animal models of AD, which could lead to a new pharmacological strategy for Alzheimer's disease not based on dissolution of amyloid, but based on a neuro-metabolic, mitochondrial and pro-survival strategy. The overall product of the Project will support a mechanistic understanding of what therapeutic ketosis is with respect to functional longevity, how it works, what its biomarkers are, and potential benefit of Shc inhibitors in AD.