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.

项目概要/摘要 在衰老过程中，生物钟和时钟控制的节律显示出振荡幅度减弱， 伴随着生理和行为的下降，昼夜节律失调更加明显。 阿尔茨海默病 (AD)，人们越来越认识到睡眠和昼夜节律周期紊乱是一种疾病 重要的是，干预研究支持积极的可改变功能。 我们之前发现了一种天然化合物Nobiletin (NOB)作为时钟- 增强分子，激活细胞振荡器中的 ROR 核受体以增加昼夜节律 同样，一些饮食干预措施可以改善代谢健康并促进健康衰老。 延长健康寿命和/或寿命，包括活动中的热量限制和时间限制喂养 阶段（TRF），还被发现可以增强昼夜节律基因振荡和输出代谢。 研究支持 NOB 和 TRF 对 AD 的有益作用；然而，它们的协同功能和 机制仍不清楚。 在母 R01 补助金 (R01AG065984) 中，标题为“Concerted Improvement of core and output rates to 促进健康老龄化”，我们研究了 NOB 和 TRF 的协同功能，以加强时钟和延迟 当前的行政补充提案是针对 NOT-AG-20- 的。 034. 基于我们最近的初步结果显示 NOB 对改善病理学和 在 AD 小鼠模型中的行为中，我们发现 TRF 与 NOB 协同作用以协调激活 减缓 AD 相关衰退的昼夜节律功能 在目标 1 中，我们将确定 TRF.NOB 的作用。 APP/PS1 小鼠的病理和行为下降 在目标 2 中，我们将研究昼夜节律生理学。 周期，并确定海马体和皮质中昼夜节律和 AD 基因表达的变化。 该项目在实验设计和方法方面与父项目非常一致，重要的是 开始解决有关 NOB 和 TRF 对抗 AD 神经退行性变的作用的关键知识差距 最终目标是确定时钟是否以及如何被这种强大的双时钟激活。 基于我们对 NOB 的系列研究以及有希望和有前景的干预措施。 易于转化的 TRF 策略，这些研究将揭示针对 AD 的候选治疗策略 这些创新包括 AD 的 NOB.TRF 方案的概念范例，以及 考虑到应对 AD 基因表达的迫切需要，关键大脑区域的新型环周机制。 人口迅速老龄化、24/7 随意的生活方式扰乱了自然昼夜节律，以及 AD危机迫在眉睫，这种多功能且可行的干预措施将产生立竿见影和持久的影响 老年人和 AD 患者的生活质量。