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。 中年小鼠开始的等热量生酮饮食(KD)重新编程新陈代谢，降低p46Shc 并保留晚年的功能，包括记忆、认知和肌肉功能的许多参数，以及 显著延长寿命1.更好地理解酮症依赖的长寿机制及其 生物标志物可能导致这种营养干预的更有效的剂量，因为它延缓衰老和认知 在小鼠中呈下降趋势，进而在人类中也是如此。我们的目标包括确定KD的长寿机制和 生物标记物，通过组织和血液中的RNAseq和蛋白质表达(目标1和2)。通过识别基因 哪些增加或减少最多，我们确定对KD反应最大的生物标志物。通过将这些重叠起来 具有项目2(Pelicci)结果的生物标记物，它将确定与衰老相关的表观遗传标记和 哪些与衰老相关的表观遗传标记被KD逆转，我们将鉴定那些既是 衰老相关和KD反应。这些将有助于机械地定义支持KD的基因 功能寿命的保存。这些与衰老相关和KD反应的生物标志物也将服务于Proj4 Ramsey的目标是评估IKD和KS治疗酮症的相对收益 “功能寿命”。在目标3中，我们测试了KD的长寿效应的三种可能的候选机制，即上升 靶向β-羟丁酸受体HCAR2、FFAR3的酮，以及p46Shc的抑制 调节硫解酶和酮的生成。功能长寿表型的逆转将表明显著 HCAR2、FFAR3和p46Shc在该机制中的参与，可以通过 线粒体和乙酰化以及KAT机制，由项目3(Baar)完成。在目标4中，我们测试了最近确定的 SHC抑制剂在阿尔茨海默病细胞模型和阿尔茨海默病PSAPP小鼠模型中的作用(与Core c)。这套综合实验的完成将确定KD的衰老相关生物标记物，以及 将明确测试KD的三种可能机制。它还将确定小分子Shc 抑制剂在AD细胞和动物模型中的保护作用，这可能导致一种新的治疗AD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 支持生存的战略。项目的整体产品将支持对什么是机械的理解 治疗性酮症与功能寿命、作用方式、生物标志物和潜在功能有关。 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.