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

研究酮症治疗的靶标、机制和最佳给药方式，以实现功能性长寿和阿尔茨海默氏病的治疗

• 批准号: 10203670
• 负责人: Gino A Cortopassi
• 金额: $ 5.83万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203670
• 关键词: Acetyl-CoA C-Acetyltransferase; Acetylation; Address; Adopted; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Animal Model; Animals; Applications Grants; Binding; Biological Markers; Biology; Biology of Aging; Biometry; Biostatistics Core; Blood; Brain; Carbohydrates; Cell model; Cells; Cellular Metabolic Process; Cognitive; Companions; Country; Diet; Dietary Fats; Disease; Dissection; Dose; Elderly; Epigenetic Process; Fatty acid glycerol esters; Future; Genes; Geroscience; Goals; Health; Health Care Costs; Human; Intervention; Investigation; Ketones; Ketosis; Knockout Mice; Longevity; Maps; Measures; Memory; Metabolic; Metabolism; Modeling; Mus; Muscle; Muscle function; Mutant Strains Mice; Nerve Degeneration; Nonesterified Fatty Acids; Paper; Phenotype; Population; Program Research Project Grants; Protein Acetylation; Protein Array; Public Health; Publishing; Resistance; Stress; Testing; Text; Therapeutic; Time; Tissues; Translations; Work; age related; aged; aging brain; base; beta-Hydroxybutyrate; cognitive function; design; dietary supplements; disability; epidemiology study; epigenetic marker; epigenome; experience; functional improvement; healthy aging; human study; improved; improved functioning; inhibitor/antagonist; ketogenic diet; ketogentic; metabolomics; middle age; mortality; mouse model; novel; preservation; programs; receptor; targeted biomarker; transcriptome sequencing; transcriptomics; translation to humans

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.

项目概要-总体 研究功能性酮症治疗的靶点、机制和最佳给药 老年痴呆症的治疗 我们最近首次证明，等热量连续生酮饮食可以延长 小鼠的认知、记忆和肌肉功能，并将中位寿命显著延长13%1。在 同样的问题细胞代谢，其他人表明，间歇生酮饮食（iKD）保留了许多 小鼠的晚年功能。这些错误发表的发现具有深刻的机制（对于 理解衰老的生物学）和翻译（对美国公共卫生）的影响。机械地，他们 提出了“酮症延缓衰老”的假设。PPG应用程序旨在识别机械性 靶点和生物标志物，通过这些靶点和生物标志物治疗酮症延缓小鼠衰老，并且与 老年科学概念，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， 老年痴呆通过确定小鼠KD机制和生物标志物，这项研究将为 未来的人类研究为了服务于这些机制和转化目标，我们提出了这四个 项目1，Cortopassi，涉及酮长寿机制的机械解剖，使用 转录组学、蛋白质阵列和敲除小鼠，以及阿尔茨海默病的Shc拮抗剂。2，佩里奇， 绘制了衰老的表观遗传后果，以及KD如何逆转它们，以及这些重叠的程度 与衰老和老年痴呆症有关3，巴尔，地址KAT和乙酰化机制，通过改善肌肉 功能延缓野生型和阿尔茨海默氏症小鼠模型的脑老化。4，拉姆齐，确定了 “酮治疗信封”的必要保存晚年的功能和长寿，并就一个 阿尔茨海默氏症小鼠模型。这些项目都是互动的，如文本所示。它们还由 一个杰出的动物核心C，由肯特劳埃德DVM PHD和李威金MD PHD与恒星的经验 在小鼠生物学和阿尔茨海默氏病方面，生物统计学核心B、金敬美和一个很好- 组织的行政核心A。这个项目的完成将导致新的机械化的内部进入 治疗酮症长寿机制，并确定酮治疗效果的生物标志物， 与老年美国人和阿尔茨海默病患者的功能和寿命的保护有关。