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Concerted enhancement of core and output rhythms to promote healthy aging

协调增强核心节律和输出节律，促进健康老龄化

基本信息

批准号：
10668956
负责人：
Zheng Chen
金额：
$ 39万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668956
关键词：
Acids Address Affect Aging Architecture Area Attenuated Automobile Driving Behavioral Bioenergetics Biological Biological Assay Biological Process Bioluminescence C57BL/6 Mouse Caloric Restriction Cardiolipins Cell Nucleus Cells Chemosensitization Chromatin Circadian Dysregulation Circadian Rhythms Circadian gene expression Complex Databases Dietary Component Dietary Flavonoid Dietary Intervention Energy Metabolism Epidemiology Epigenetic Process Feeding behaviors Filtration Gene Expression Genes Genetic Genetic Transcription Genus Hippocampus Goals Hand Strength Health High Fat Diet Histones Homeostasis Impairment Intervention Laboratories Life Style Light Lipids Literature Longevity Measures Metabolic Metabolic Diseases Metabolism Methodology Mining Mitochondria Modernization Molecular Monitor Mus Organ Orphan Output Periodicity Peripheral Phase Physiological Physiology Pollution Population Public Health Publishing Quality of life Regimen Reporter Reporting Research Personnel Respiration Retinoids Role Running Skeletal Muscle Sleep Societies Thermogenesis Time Time-restricted feeding Tissues age related aged circadian circadian pacemaker circadian regulation cofactor combat dietary disorder risk epigenetic regulation feeding fitness gel electrophoresis healthspan healthy aging human old age (65+)implementation facilitation improved innovation insight metabolic fitness mortality nobiletin novel novel strategies promoter receptor respiratory shift work

项目摘要

PROJECT SUMMARY / ABSTRACT The 24/7 lifestyle in modern society disrupts natural circadian rhythms and poses a serious health concern. Epidemiological and laboratory evidence indicates that circadian disturbances adversely affect various biological functions and increase disease risk. The circadian clock, a network of cellular oscillators, is the biological timer driving output gene expression and physiological functions with ~24h rhythmicity. During aging, the clock and clock-controlled rhythms display attenuated oscillatory amplitude, concomitant with physiological and behavioral decline. Importantly, environmental/dietary interventions support a positive modifiable function of the clock to promote healthy aging. For example, several dietary interventions that prolong healthy lifespan and/or longevity, including caloric restriction and time-restricted feeding in the active phase (TRF), were found to enhance circadian gene oscillation and output metabolism. Together with genetic evidence, these observations strongly suggest a crucial regulatory role of robust circadian oscillation in healthy aging. We previously identified Nobiletin (NOB), a polymethoxylated dietary flavonoid, as a clock-enhancing compound. We found that NOB activates RORs (specifically the alpha and gamma subtypes, encoded by Rora and Rorc), key components of the cellular oscillator, to elevate circadian amplitude and improve energy homeostasis in metabolic disease mice. Importantly, in naturally aged mice, we recently showed that the NOB-ROR axis strengthens metabolic homeostasis and promotes energy expenditure in part via mitochondrial activation in skeletal muscle, ultimately bolstering healthy aging and survival. Therefore, NOB (a dietary flavonoid) and TRF differentially modify circadian core oscillator and feeding rhythms, performing overlapping functions to improve fitness during aging. In this proposal, we hypothesize that NOB and TRF synergistically enhance core oscillators and output rhythms to maintain a robust clock and promote healthy aging, via mechanisms impinging on molecular oscillators and mitochondrial function. In Aim 1, building on our strong preliminary studies, we will determine roles of ad libitum NOB treatment in single-cell oscillators and transcriptional/epigenetic regulation to enhance circadian amplitude in aged mice. In Aim 2, we will determine function and mechanism of an integrated NOB.TRF regiment to coordinately activate circadian rhythms and physiology in aged mice in a concerted manner. In Aim 3, we will delineate the circadian mechanisms via which NOB and TRF regulate mitochondrial respiration. Together, the proposed studies will provide key mechanistic insights into the role of circadian rhythms during aging, and pinpoint an integrated dietary regimen as a novel strategy to activate clocks and extend healthspan. The innovations include a dual-component dietary regimen coordinately enhance clock amplitude for healthy aging and a novel circadian regulation of mitochondrial respiratory complex architecture and cardiolipin synthesis. Given the pressing lifestyle-related health challenges, our study may ultimately facilitate implementation of an efficacious dietary intervention to improve quality of life at old ages through robust circadian timing.

项目总结/摘要现代社会的24/7生活方式扰乱了自然的昼夜节律，并造成了严重的健康问题。流行病学和实验室证据表明，昼夜节律紊乱会对各种生物学特性产生不利影响。功能和增加疾病风险。生物钟是一个由细胞振荡器组成的网络，以~ 24 h的节律性驱动输出基因表达和生理功能。在衰老过程中，时钟控制的节律显示衰减的振荡幅度，伴随着生理和行为下降重要的是，环境/饮食干预支持生物钟的积极可调节功能，促进健康老龄化。例如，几种延长健康寿命和/或长寿的饮食干预，包括热量限制和活动期限时喂养（TRF），昼夜基因振荡和输出代谢。加上遗传学证据，这些观察结果强烈地表明，表明在健康老龄化中，昼夜节律振荡起着至关重要的调节作用。我们之前鉴定出诺必列汀 (NOB)，一种多甲氧基化的膳食类黄酮，作为生物钟增强化合物。我们发现NOB激活了 ROR（特别是由Rora和Rorc编码的α和γ亚型），细胞免疫的关键组分，振荡器，以提高昼夜节律振幅并改善代谢疾病小鼠的能量稳态。重要的是，在自然衰老的小鼠中，我们最近发现NOB-ROR轴增强了代谢，体内平衡，并通过骨骼肌中的线粒体活化部分促进能量消耗，最终支持健康的衰老和生存。因此，NOB（一种膳食类黄酮）和TRF差异性地改变昼夜核心振荡器和喂养节奏，执行重叠的功能，以改善老化过程中的健身。在这个提议中，我们假设NOB和TRF协同增强核心振荡器和输出节律通过撞击分子振荡器的机制，线粒体功能在目标1中，基于我们强大的初步研究，我们将确定自由采食的作用单细胞振荡器中的NOB处理和转录/表观遗传调节以增强昼夜节律振幅老年小鼠在目标2中，我们将确定一个整合的NOB.TRF团的功能和机制，以协调的方式协调激活老年小鼠的昼夜节律和生理学。在目标3中，我们描述NOB和TRF调节线粒体呼吸的昼夜机制。统称拟议的研究将为衰老过程中昼夜节律的作用提供关键的机制见解，指出一个综合的饮食养生法作为一种新的策略，以激活时钟和延长健康寿命。的创新包括一种双组分饮食养生法，以及线粒体呼吸复合体结构和心磷脂合成的新的昼夜节律调节。考虑到紧迫的生活方式相关的健康挑战，我们的研究最终可能有助于实施一项有效的饮食干预，以改善生活质量，在老年人通过强大的昼夜节律。