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：
10438668
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438668
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 Lead 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 base 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.

项目概要/摘要现代社会 24/7 的生活方式扰乱了自然的昼夜节律，并带来了严重的健康问题。流行病学和实验室证据表明，昼夜节律紊乱会对多种生物产生不利影响。功能并增加疾病风险。生物钟是一个细胞振荡器网络，是生物计时器以~24小时节律驱动输出基因表达和生理功能。在老化过程中，生物钟和时钟控制的节律显示减弱的振荡幅度，伴随着生理和行为衰退。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，一些可以延长健康寿命和/或长寿的饮食干预措施，包括活动阶段（TRF）中的热量限制和时间限制喂养，被发现可以增强昼夜节律基因振荡和输出代谢。与遗传证据一起，这些观察结果强烈表明表明稳健的昼夜节律振荡在健康衰老中发挥着至关重要的调节作用。我们之前鉴定出川陈皮素 (NOB)，一种多甲氧基化膳食黄酮类化合物，作为生物钟增强化合物。我们发现NOB激活 ROR（特别是 alpha 和 gamma 亚型，由 Rora 和 Rorc 编码），细胞的关键组成部分振荡器，提高代谢疾病小鼠的昼夜节律幅度并改善能量稳态。重要的是，在自然衰老的小鼠中，我们最近表明 NOB-ROR 轴增强了代谢体内平衡并部分通过骨骼肌中的线粒体激活促进能量消耗，最终促进健康老龄化和生存。因此，NOB（一种膳食类黄酮）和 TRF 会差异化修饰昼夜节律核心振荡器和喂养节律，执行重叠功能以改善衰老过程中的健康状况。在此提案中，我们假设 NOB 和 TRF 协同增强核心振荡器和输出节奏通过影响分子振荡器的机制来维持强大的生物钟并促进健康衰老线粒体功能。在目标 1 中，基于我们强有力的初步研究，我们将确定随意的作用单细胞振荡器中的 NOB 处理和转录/表观遗传调节可增强昼夜节律振幅在老年小鼠中。在目标 2 中，我们将确定一体化 NOB.TRF 团的功能和机制，以以协调一致的方式协调激活老年小鼠的昼夜节律和生理机能。在目标 3 中，我们将描述 NOB 和 TRF 调节线粒体呼吸的昼夜节律机制。在一起，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，以及确定综合饮食方案作为激活生物钟和延长健康寿命的新策略。这创新包括双成分饮食方案，协调增强生物钟振幅，促进健康老龄化以及线粒体呼吸复合物结构和心磷脂合成的新型昼夜节律调节。鉴于与生活方式相关的紧迫健康挑战，我们的研究可能最终促进实施通过严格的昼夜节律进行有效的饮食干预，以改善老年生活质量。