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.

项目摘要 - 项目1 阐明生酮寿命机制的生物标志物和机制。 在中年小鼠中启动的等归量生酮饮食（KD）重新编程新陈代谢，降低了P46SHC 并保留晚期功能，包括记忆，认知和肌肉功能的许多参数，以及 显着增加了寿命1,2。更好地了解依赖酮的寿命机制及其 生物标志物可能会导致这种营养干预的更有效剂量，以延迟其衰老和认知 小鼠的下降，人类的延伸。我们的目标包括确定KD的寿命机制和 生物标志物，通过RNASEQ和组织和血液中的蛋白质表达（AIMS1和2）。通过识别基因 增加或减少最大的，我们确定了最大的响应性生物标志物。通过重叠这些 具有ProJ 2（Pelicci）结果的生物标志物，这将确定与衰老相关的表观遗传标记和 KD逆转了哪些与衰老相关的表观遗传标记，我们将确定那些都是的生物标志物 与衰老相关和KD响应性。这些将有助于机械定义支持KD的基因 保留功能寿命。这些与衰老相关和KD响应生物标志物也将服务于ProJ4 拉姆齐的目标是评估IKD和KS策略的相对益处 功能寿命'。在AIM 3中，我们测试了KD寿命效应的三种可能性候选机制，即升高 靶向β-羟基丁酸受体HCAR2，FFAR3和p46SHC表达的酮酮 调节硫醇酶和生酮发生。功能寿命表型的逆转将表明突出 HCAR2，FFAR3和P46SHC参与该机制，可以进一步指定 通过项目3（BAAR）的线粒体和乙酰化和KAT机制。在AIM 4中，我们测试了最近确定的 阿尔茨海默氏症细胞模型中的SHC抑制剂和阿尔茨海默氏病的PSAPP小鼠模型（核心 c）。这套集成的实验集的完成将定义KD的相关生物标志物，并且 将明确测试KD的三种可能性机制。它还将确定小分子SHC是否 抑制剂保护AD的细胞和动物模型，这可能导致新的药理学策略 阿尔茨海默氏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 亲生战略。该项目的总体产品将支持对什么的机械理解 治疗性酮症与功能性寿命，其工作方式，其生物标志物的作用以及潜力有关 AD中SHC抑制剂的益处。