Concerted Enhancement Of Core And Output Rhythms To Promote Healthy Aging

协同增强核心节律和输出节律，促进健康老龄化

• 批准号: 10284687
• 负责人: Zheng Chen
• 金额: $ 38.67万
• 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/10284687
• 关键词: APP-PS1; Acids; Address; Administrative Supplement; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Attenuated; Automobile Driving; Behavior; Behavioral; Biological Assay; Brain region; Breeding; C57BL/6 Mouse; Caloric Restriction; Circadian Dysregulation; Circadian Rhythms; Cognition; Cognitive; DNA Sequence Alteration; Degenerative Disorder; Dietary Flavonoid; Dietary Intervention; Disease; Disease Progression; Eating; Elderly; Energy Metabolism; Ensure; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Experimental Designs; Fasting; Feeding behaviors; Funding; Future; Gene Expression; Genes; Genetic; Goals; Grant; Health; Hippocampus (Brain); Homeostasis; Impaired cognition; Intermittent fasting; Intervention; Intervention Studies; Knowledge; Life Style; Light; Longevity; Metabolic; Metabolic Diseases; Metabolism; Methodology; Mitochondria; Modality; Modernization; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Nuclear Receptors; Orphan; Output; Parents; Pathologic; Pathology; Pathway interactions; Peripheral; Phase; Physiological; Physiology; Pollution; Public Health; Quality of life; Regimen; Regulator Genes; Reporting; Respiration; Retinoids; Role; Running; Sleep; Sleep disturbances; Societies; Testing; Time-restricted feeding; Transgenic Mice; age related; aged; aging population; base; circadian; circadian pacemaker; cognitive function; dietary restriction; disorder risk; feeding; fitness; healthspan; healthy aging; human old age (65+); improved; innovation; insight; mortality; mouse model; nobiletin; novel; object recognition; parent project; receptor; respiratory; response; shift work; synergism; tau Proteins; therapeutic candidate; β-amyloid burden

PROJECT SUMMARY / ABSTRACT During aging, the circadian clock and clock-controlled rhythms display attenuated oscillatory amplitude, concomitant with physiological and behavioral decline. The circadian dysregulation is more pronounced in Alzheimer's Disease (AD), where disrupted sleep and circadian cycles are increasingly appreciated as a potential disease-driving factor. Importantly, intervention studies support a positive modifiable function of the clock to promote healthy aging. We previously identified a natural compound Nobiletin (NOB) as a clock- enhancing molecule which activates the ROR nuclear receptors in the cellular oscillator to increase circadian amplitude, improve metabolic health and promote healthy aging. Likewise, several dietary interventions that prolong healthy lifespan and/or longevity, including caloric restriction and time-restricted feeding in the active phase (TRF), were also found to enhance circadian gene oscillation and output metabolism. Preliminary studies support beneficial roles of NOB and TRF against AD; however, their synergistic function and mechanism remain unknown. In the parent R01 grant (R01AG065984) entitled “Concerted enhancement of core and output rhythms to promote healthy aging”, we investigate a concerted function of NOB and TRF to strengthen the clock and delay peripheral age-related decline. The current administrative supplement proposal is in response to NOT-AG-20- 034. Building on our recent preliminary results showing beneficial effects of NOB to improve pathology and behavior in an AD mouse model, we hypothesize that TRF synergizes with NOB to coordinately activate circadian functions to decelerate AD-related decline. In Aim 1, we will determine the role of TRF.NOB against pathological and behavioral decline in APP/PS1 mice. In Aim 2, we will investigate circadian physiological cycles, and determine changes in circadian and AD gene expression in the hippocampus and the cortex. This project is well aligns with the parent project in experimental design and methodologies, and importantly will begin to address a key knowledge gap regarding a role of NOB and TRF against neurodegeneration in AD mice. The ultimate goal is to determine whether and how the clock can be activated by this powerful dual- modality intervention to delay AD progression. Based on our serial studies on NOB and the promising and readily translatable TRF strategy, these studies will reveal a candidate therapeutic strategy against AD pathology/behavior. The innovations include a conceptual paradigm of the NOB.TRF regimen for AD, and novel circadian mechanisms in key brain regions for AD gene expression. Given the pressing needs to counter the rapidly aging population, the 24/7 ad libitum lifestyle that disrupts natural circadian rhythms, and the imminent crisis of AD, such a versatile and feasible intervention will have an immediate and long-lasting impact on the quality of life in the elderly and AD patients.

项目摘要/摘要 在衰老过程中，生物钟和钟控节律显示出衰减的振荡幅度， 伴随着生理和行为的衰退。昼夜节律失调在 阿尔茨海默病(AD)，睡眠中断和昼夜节律被越来越多地认为是一种 潜在的致病因素。重要的是，干预研究支持了一种积极的可修改功能 促进健康衰老的时钟。我们之前发现了一种天然化合物诺比莱汀(Nob)，它是一种时钟-- 激活细胞振荡器中的ROR核受体以增加昼夜节律的增强分子 幅度，改善新陈代谢健康，促进健康衰老。同样，几种饮食干预措施 延长健康寿命和/或长寿，包括限制热量摄入和限制进食时间 时相(TRF)，也被发现促进昼夜节律的基因振荡和输出代谢。初步 研究支持NOB和TRF对抗AD的有益作用；然而，它们的协同作用和 机制仍不清楚。 在父R01授权(R01AG065984)中，标题为“协调增强核心和输出节律 促进健康老龄化“，我们调查了NOB和TRF的协同作用，以加强时钟和延迟 外周年龄相关性下降。目前的行政补充提案是对NOT-AG-20- 034.根据我们最新的初步结果显示，NOB对改善病理和 在AD小鼠模型中，我们假设TRF与Nob协同激活 昼夜节律起着减缓AD相关衰退的作用。在目标1中，我们将确定TRF.NOB对 APP/PS1小鼠病理和行为能力下降。在目标2中，我们将研究生理昼夜节律 循环，并确定海马区和皮质中昼夜节律和AD基因表达的变化。这 项目在实验设计和方法上与父项目保持良好的一致性，并且重要的是将 开始解决关于Nob和TRF在AD中对抗神经变性的作用的关键知识缺口 老鼠。最终目标是确定时钟是否以及如何被这种强大的双重功能激活- 通道干预以延缓AD进展。基于我们对Nob的系列研究，以及前景看好的 TRF策略易于翻译，这些研究将揭示治疗AD的候选策略 病理学/行为这些创新包括NOB.TRF方案的概念范例，以及 AD基因表达的关键脑区的新的昼夜节律机制。考虑到迫切需要反击 快速老龄化的人口，打乱自然昼夜节律的全天候随意生活方式，以及 迫在眉睫的AD危机，这样一种多才多艺、切实可行的干预措施，将产生立竿见影、持久的影响 对老年人和AD患者的生活质量的影响。