Project 3: Peripheral and Central Molecular Clocks in Feeding, Sleep and Metabolic Aging

项目 3：进食、睡眠和代谢衰老中的外周和中枢分子钟

• 批准号: 10208662
• 负责人: FRED W TUREK
• 金额: $ 40.65万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208662
• 关键词: ARNTL gene; Ablation; Address; Age; Aging; Anabolism; Animals; Attenuated; Behavior; Behavioral; Bioenergetics; Calorimetry; Cardiometabolic Disease; Cell Respiration; Cells; ChIP-seq; Chronology; Circadian Dysregulation; Circadian Rhythms; Cre-LoxP; Data; Deterioration; Eating; Enzymes; Fasting; Feeding Patterns; Female; Gene Deletion; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Health; Hepatic; High Fat Diet; Homeostasis; Human; Individual; Intervention; Life; Light; Link; Longevity; Maintenance; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Methodology; Molecular; Monitor; Morbidity - disease rate; Mus; Nutrient; Obesity; Pathology; Pathway interactions; Periodicity; Peripheral; Pharmacology; Phase; Phenotype; Physiological; Physiology; Play; Process; Program Research Project Grants; RNA; RNA analysis; Rest; Role; SIRT1 gene; Schedule; Science; Sirtuins; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Supplementation; System; Testing; Time; Tissues; age effect; age related; aged; anti aging; base; cell type; circadian; circadian behavioral rhythms; circadian pacemaker; feeding; food restriction; glucose metabolism; healthspan; improved; insight; insulin secretion; male; molecular clock; mortality; mouse model; next generation sequencing; prevent; programs

The integrated goal of this program project application is to apply approaches in both humans (Projects 1 and 2) and experimental male and female mouse models (Project 3) to determine the impact of circadian phase- restricted feeding on age-related disorders of sleep, circadian rhythms, and metabolism. In Project #3, we aim to dissect the molecular mechanisms by which circadian phase-restricted feeding acts as a countermeasure to prevent the age-related decay in circadian robustness, sleep, and metabolic health by exploiting integrated systems level physiological analyses and genome-based approaches. New preliminary data using whole animal calorimetry, feeding monitoring, and RNA analyses support the concept that feeding time plays a key role in the integration of energetics and metabolism throughout life, and that mis-timing in behavioral, energetic, and transcriptional rhythms in relationship to the light cycle represents a hallmark of aging. Our lab and others have also shown that circadian control of NAD+ biosynthesis impacts both core clock function and activity of the sirtuins, key enzymes involved in gene regulation and energetic homeostasis during aging. Yet, a gap remains in understanding whether decay in peripheral clock control of NAD+ biosynthesis and sirtuin function during aging contributes to alterations in circadian behavioral rhythms, sleep, and metabolic homeostasis. We have also recently performed integrated RNA and chromatin immunoprecipitation sequencing (Science, Nov 2015) to reveal cell-type specific functions of the molecular clock in glucose metabolism, and we aim to apply these methodologies to further investigate the global effects of mis-timed feeding on peripheral clock transcription cycles and the impact of such cycles on circadian behavior and sleep homeostasis. We will further perform both chronologic and lifespan-extension analyses to dissect the role of the clock-NAD+-SIRT pathway and application of next-generation sequencing as a discovery platform will uncover how dampened oscillations of clock- controlled metabolic gene regulation contributes to alterations in cell-type specific metabolic dysfunction, and in turn, to alterations in circadian behavior and sleep. Finally, we will also assess whether NAD+ biosynthesis in peripheral tissues is both necessary and sufficient to prevent the age-related decline in sleep and metabolic function. Collectively, results of Project #3 will determine whether circadian phase-restricted feeding is an effective means to attenuate misalignment between oscillations in bioenergetics, metabolic, and transcriptional pathways important in aligning oxidative and reductive phases of physiology with the sleep-wake cycle and will establish new mechanistic insights into feeding time manipulation as an anti-aging intervention in humans.

该计划项目应用的综合目标是将方法应用于人类（项目 1 和 2） 和实验性雄性和雌性小鼠模型（项目 3）以确定昼夜节律阶段的影响 限制喂养会导致与年龄相关的睡眠、昼夜节律和新陈代谢紊乱。在项目#3中，我们的目标是 剖析昼夜节律阶段限制喂养作为对抗措施的分子机制 通过利用综合疗法，防止昼夜节律稳健性、睡眠和代谢健康方面与年龄相关的衰退 系统级生理分析和基于基因组的方法。使用整个动物的新初步数据 热量测定、饲喂监测和 RNA 分析支持饲喂时间在 整个生命过程中能量学和新陈代谢的整合，以及行为、精力和新陈代谢的错误时机 与光周期相关的转录节律是衰老的一个标志。我们的实验室和其他实验室有 还表明，NAD+ 生物合成的昼夜节律控制会影响核心生物钟功能和生物钟活动 Sirtuins 是参与衰老过程中基因调节和能量稳态的关键酶。但仍存在差距 了解衰老过程中 NAD+ 生物合成和 Sirtuin 功能的外周时钟控制是否衰退 有助于改变昼夜行为节律、睡眠和代谢稳态。我们还有 最近进行了整合 RNA 和染色质免疫沉淀测序（Science，2015 年 11 月） 揭示分子钟在葡萄糖代谢中的细胞类型特定功能，我们的目标是应用这些 进一步研究错时喂养对外周时钟转录的整体影响的方法 周期以及此类周期对昼夜节律行为和睡眠稳态的影响。我们将进一步做好这两项工作 按时间顺序和寿命延长分析来剖析时钟-NAD+-SIRT 通路的作用和应用 下一代测序作为发现平台将揭示如何抑制时钟振荡 受控的代谢基因调控有助于改变细胞类型特异性代谢功能障碍，并且 反过来，昼夜节律行为和睡眠的改变。最后，我们还将评估 NAD+ 生物合成是否在 外周组织对于防止与年龄相关的睡眠和代谢下降既必要又充分 功能。总的来说，项目 #3 的结果将决定昼夜节律阶段限制喂养是否是一种 减少生物能量学、代谢和转录振荡之间失调的有效方法 对于调整生理氧化和还原阶段与睡眠-觉醒周期和意志的重要途径 建立关于喂养时间控制作为人类抗衰老干预措施的新机制见解。