Concerted enhancement of core and output rhythms to promote healthy aging

项目摘要/摘要 现代社会全天候的生活方式扰乱了自然的昼夜节律，并构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产生不利影响。 功能和增加疾病风险。生物钟是细胞振荡器的网络，是生物计时器。 以~24小时的节律性驱动输出基因表达和生理功能。在衰老过程中，时钟和 钟控节律显示出衰减的振荡幅度，伴随着生理和行为 拒绝。重要的是，环境/饮食干预支持时钟的积极可修改功能，以 促进健康老龄化。例如，几种延长健康寿命和/或长寿的饮食干预措施， 包括卡路里限制和活动期限时饲喂(TRF)，被发现可以提高 昼夜节律的基因振荡和输出代谢。结合遗传证据，这些观察结果有力地证明了 表明强健的昼夜节律振荡在健康衰老中起着至关重要的调节作用。我们之前发现了诺比莱汀 (NOB)，一种多甲氧基化的饮食类黄酮，作为一种时钟增强化合物。我们发现Nob激活了 RORS(特别是阿尔法和伽马亚型，由RORA和RORC编码)，细胞的关键成分 振荡器，以提高昼夜节律幅度和改善代谢疾病小鼠的能量平衡。 重要的是，在自然衰老的小鼠中，我们最近显示NOB-ROR轴加强新陈代谢 动态平衡，并促进能量消耗，最终部分通过激活骨骼肌中的线粒体 支持健康衰老和生存。因此，Nob(一种膳食类黄酮)和TRF具有不同的修饰作用 昼夜节律的核心振荡器和摄食节律，执行重叠的功能，以改善衰老期间的健康。 在这个建议中，我们假设NOB和TRF协同增强核心振荡器和输出节律 为了维持强大的时钟并促进健康衰老，通过影响分子振荡器和 线粒体功能。在目标1中，基于我们强有力的初步研究，我们将确定临时自由裁量权的作用 NOB处理单细胞振荡器和转录/表观遗传调节以提高昼夜节律幅度 在衰老的小鼠身上。在目标2中，我们将确定一个综合NOB TRF团的功能和机制，以 协同激活衰老小鼠的昼夜节律和生理。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。团结在一起， 拟议的研究将为昼夜节律在衰老过程中的作用提供关键的机械性见解，以及 准确地确定综合饮食方案，作为一种激活时钟和延长健康寿命的新策略。这个 创新包括双组分饮食方案协调提高时钟幅度，促进健康衰老 以及线粒体呼吸复合体结构和心磷脂合成的新的昼夜调节。 考虑到与生活方式相关的紧迫健康挑战，我们的研究最终可能会促进 有效的饮食干预，通过强健的昼夜节律提高老年生活质量。

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.