Elucidating biomarkers and mechanisms of the Ketogenic longevity mechanism

阐明生酮长寿机制的生物标志物和机制

• 批准号: 10685456
• 负责人: Gino A Cortopassi
• 金额: $ 37.54万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10685456
• 关键词: Acetyl-CoA C-Acetyltransferase; Acetylation; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animal Model; Biological Markers; Blood; Brain; Caloric Restriction; Cell model; Cognition; Collaborations; Cytoprotection; Diet; Dietary Intervention; Dose; Elderly; Enzymes; Epigenetic Process; FFAR3 gene; Gastrocnemius Muscle; Gene Chips; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Glycolysis; Goals; Harvest; Heart; Hippocampus; Human; Impaired cognition; Intermittent fasting; Investigation; Ketones; Ketoses; Ketosis; Lipids; Liver; Longevity; Measures; Memory; Metabolic; Metabolic Control; Metabolism; Mitochondria; Modeling; Monitor; Mus; Muscle function; Nonesterified Fatty Acids; Outcome; Pathway Analysis; Phenotype; Protein Array; Proteins; Repression; Skeletal Muscle; Specific qualifier value; Testing; Tetanus Helper Peptide; Therapeutic; Tissues; Work; abeta toxicity; beta-Hydroxybutyrate; experimental study; human data; human old age (65+); in vitro testing; in vivo; inhibitor; ketogenesis; ketogenic diet; ketogentic; middle age; mouse model; novel; overexpression; oxidation; pharmacologic; potential biomarker; preservation; programs; protein expression; receptor; small molecule; therapeutic target; transcriptome sequencing

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.

项目概要 – 项目 1 阐明生酮长寿机制的生物标志物和机制。 中年小鼠启动的等热量生酮饮食 (KD) 可重新编程新陈代谢，降低 p46Shc 并保留晚年功能，包括记忆、认知和肌肉功能的许多参数，以及 显着延长寿命1,2。更好地了解酮症依赖性长寿机制及其 生物标志物可以使这种营养干预措施的剂量更有效，以延缓衰老和认知能力 老鼠的下降，以及人类的下降。我们的目标包括确定 KD 的长寿机制和 生物标志物，通过 RNAseq 以及组织和血液中的蛋白质表达（Aims1 和 2）。通过识别基因 哪个增加或减少最多，我们确定了对 KD 反应最强的生物标志物。通过重叠这些 生物标志物与 Proj 2(Pelicci) 的结果，这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可以被 KD 逆转，我们将识别出那些既可以逆转衰老相关的表观遗传标记， 与衰老相关且具有 KD 响应性。这些将有助于机械地定义支持 KD 的基因 保持功能寿命。这些与衰老相关且 KD 响应的生物标志物也将服务于 Proj4 Ramsey 的目标是评估“治疗性酮症”的 iKD 和 KS 策略的相对益处 功能寿命”。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-羟基丁酸受体 HCAR2、FFAR3 的酮以及 p46Shc 的抑制 调节硫解酶和酮生成。功能性长寿表型的逆转将表明显着 HCAR2、FFAR3 和 p46Shc 参与该机制，可以通过 项目 3 (Baar) 的线粒体和乙酰化以及 KAT 机制。在目标 4 中，我们测试最近识别的 阿尔茨海默病细胞模型和阿尔茨海默病 PSAPP 小鼠模型中的 Shc 抑制剂（含核心 C）。这组综合实验的完成将定义 KD 的衰老相关生物标志物，并且 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 细胞和动物模型中发挥保护作用，这可能会带来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 有利于生存的战略。该项目的整体产品将支持对什么的机械理解 治疗性酮症涉及功能寿命、其工作原理、其生物标志物是什么以及潜力 Shc 抑制剂在 AD 中的益处。