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

• 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
• 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

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.

项目摘要/摘要