Mechanisms of Intermittent Fasting and Longevity in C. elegans

线虫间歇性禁食和长寿的机制

• 批准号: 9911557
• 负责人: Pallas Yao
• 金额: $ 3.95万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911557
• 关键词: Aging; Animal Model; Biology; CREB1 gene; CREBBP gene; Caenorhabditis elegans; Cells; Cellular biology; Chronic; Communication; Data; Dietary Intervention; Disease Resistance; Dominant-Negative Mutation; Eating; Energy Intake; Energy Metabolism; Experimental Designs; FRAP1 gene; Fasting; Fluorescence; Genes; Genetic; Genetic Epistasis; Genetic Transcription; Goals; Growth; Immunity; Impairment; Intermittent fasting; International; Intestines; Knock-in; Laboratories; Longevity; Longevity Pathway; Malnutrition; Measures; Mediating; Mentors; Metabolic; Metabolism; Methods; Mitochondria; Morphology; Muscle; NADH; Neuraxis; Neurons; Nutrient; Organelles; Output; Pathway interactions; Peer Review; Peripheral; Positioning Attribute; Public Health Schools; Refractory; Regimen; Regulation; Resources; Role; Signal Transduction; Specificity; Study models; System; Techniques; Testing; Therapeutic; Therapeutic Studies; Tissues; Training; Transcription Coactivator; Work; Writing; career; clinical implementation; confocal imaging; dietary restriction; feeding; flexibility; food restriction; graduate student; healthy aging; in vivo; inhibitor/antagonist; insight; insulin signaling; journal article; mutant; novel; novel strategies; novel therapeutics; side effect; skills; symposium; transcription factor; two-photon; undergraduate student

ABSTRACT Manipulating evolutionarily conserved mechanisms of nutrient signaling and energy metabolism promotes healthy aging in many species. While the most robust and well-studied model is dietary restriction (DR), a chronic reduction in caloric intake without malnutrition, its therapeutic potential is limited by negative associated side effects and difficulty of clinical implementation. The search to generate more viable therapies from this research has uncovered alternative dietary interventions that could promote healthy aging, independent of reduced overall caloric intake. One such regimen is intermittent fasting (IF), which suggests that simply altering the timing of food intake can increase longevity and disease resistance, independent of caloric intake. These mechanisms are relatively understudied, but evidence suggests that IF modulates longevity in mechanisms that are distinct from those of chronic DR. Studying IF-longevity could therefore elucidate novel approaches to target aging, and IF as a therapy itself may be more translatable than chronic DR. The central aim of this proposal is therefore to utilize the genetically tractable and transparent model organism C. elegans to identify novel mechanisms underlying IF and longevity. Here, I show new data to suggest the transcription factor CREB and mitochondrial dynamics are indispensable for lifespan extension by IF. This project will dissect the mechanisms by which CREB mediates IF-longevity on the level of transcription, organelle biology and metabolism. I will interrogate the potential role of CREB as a cell non-autonomous modulator of IF-longevity from the central nervous system and investigate if mitochondrial dynamics lies functionally downstream of CREB to mediate IF- longevity. The spatial and functional requirement of mitochondrial remodeling for IF-longevity will be determined to elucidate whether CREB and mitochondrial dynamics are required in the same tissue. Two-photon excited fluorescence of endogenous NADH and FAD levels will then be used as a non-invasive method to measure metabolic state in vivo. I will use this technique to simultaneously extract information on mitochondrial network morphology and how it corresponds to metabolic changes during IF and manipulation of CREB activity. Overall, these studies will provide new mechanistic insight into IF biology, which can be harnessed to develop new therapeutics against aging. Pallas’ position as a graduate student in Dr. William Mair’s laboratory at the Harvard T.H. Chan School of Public Health gives her access to all the resources necessary to complete this project. As part of the training plan, Pallas will develop her career plan, writing and communication skills through participation in local and national/international scientific conferences, peer reviewing journal articles, and mentoring undergraduate students. The goal is to further develop her scientific acumen in experimental design in order to move her further toward independence as she transitions into a postdoctoral position.

抽象的 操纵养分信号传导和能量代谢的进化配置的机制 促进许多物种的健康衰老。虽然最强大，最有良好的模型是饮食限制 （DR），无营养不良的慢性降低热量摄入量，其治疗潜力受阴性的限制 相关的副作用和临床实施困难。搜索以生成更可行的疗法 从这项研究中，发现了替代性饮食干预措施，这些干预措施可以促进健康的衰老，独立 这样一种方案是间歇性禁食（如果），这表明简单地改变 食物摄入的时机可以增加寿命和抗病性，而与热量摄入无关。这些 机制是相对理解的，但是证据表明，如果调节寿命，机制的寿命 与慢性DR不同。因此，研究IF-Longevity可以阐明新颖的方法 衰老，如果作为治疗本身可能比慢性DR更翻译。该提议的核心目的是 因此，要利用一般易于疗法和透明的模型有机体C.秀丽隐杆线索识别新颖 IF和寿命的基础机制。在这里，我显示了新数据，以建议转录因子CREB和 线粒体动力学对于if的寿命扩展是必不可少的。该项目将剖析机制 通过这种情况，CREB在转录，细胞器生物学和代谢水平上介导了If-Longevity。我会 询问CREB作为中央IF-Longevity的单元非自主调节剂的潜在作用 神经系统并研究线粒体动力学是否在CREB的下游功能，以介导if- 长寿。将确定线粒体重塑的空间和功能需求 阐明在同一组织中是否需要CREB和线粒体动力学。双光子激动 内源性NADH和FAD水平的荧光将被用作一种非侵入性方法来测量 体内代谢状态。我将使用此技术同时提取线粒体网络上的信息 形态及其对应于IF和操纵CREB活性期间的代谢变化。全面的， 这些研究将为生物学提供新的机械洞察力，可以利用生物学来发展新的机理 反对衰老的治疗剂。帕拉斯（Pallas）在哈佛大学威廉·梅尔（William Mair）的实验室中担任研究生 T.H. Chan公共卫生学院使她可以访问完成该项目所需的所有资源。作为 培训计划的一部分，帕拉斯将通过参与制定她的职业计划，写作和沟通技巧 在本地和国家/国际科学会议上，同行评审期刊文章和心理 本科生。目的是进一步发展她在实验设计中的科学敏锐度，以便 当她转变为博士后职位时，她将她进一步向独立发展。