Circadian Pathways Linking Metabolic Homeostasis and Gene Regulation During Aging

项目总结/摘要 老龄化的特点是逐渐衰退，包括一些标志性的过程。尤其是， 能量代谢中与年龄相关的异常导致营养感测和线粒体功能失调， 导致了生理和行为的全面衰退。生物钟是一个细胞网络， 振荡器驱动输出基因表达与~24小时的节奏，并在能源中发挥着重要作用 体内平衡在老化过程中，时钟和时钟控制的输出节律也显示衰减的振荡 振幅和弹性，有助于代谢下降。视黄酸受体相关孤儿（Retinoid acid receptor related orphan） 核受体的一个亚家族是昼夜节律振荡器的关键组成部分，其功能是维持细胞内的细胞周期。 稳定的振荡幅度和通过转录和表观遗传机制驱动昼夜节律基因表达。 我们以前从化学筛选中鉴定出一种ROR的天然激动剂，并证明了其重要作用。 在代谢调节和衰老生理学中的作用。最近，我们用骨骼肌特异性 小鼠中ROR（α和γ亚型）的敲除（Ror mDKO），以及成年小鼠的表型表征 Ror mDKO小鼠（最大8月龄）显示对骨骼肌代谢和功能的强烈影响。 基于这些令人兴奋的初步结果，我们假设生物钟，特别是ROR， 通过基因调控机制调节衰老相关的代谢功能，并在以下方面发挥关键和可改变的作用： 健康和寿命。在目的1中，利用上述老年Ror mDKO小鼠，我们将评估 ROR在健康寿命和寿命中的作用。在目标2中，结合生理学、分子学和组学方法， 我们将确定ROR协调能量代谢和线粒体的调节途径， 在老年对照和Ror mDKO小鼠中的功能，并描绘转录和表观遗传机制。在aim中 3，我们将进行两种昼夜生活方式干预，即限时喂养（TRF）和定时运动 (TE)分别对应于时间上受控的能量摄入和消耗，并且评估是否 这些生活方式干预对健康老龄化的影响需要ROR。拟议的研究将共同 提供了关键的机械见解时钟之间的串扰代谢和基因调控的作用， 老化的标志，并将ROR作为激活时钟的新型治疗策略的可操作目标， 延缓衰老，延长健康寿命。这些创新包括一个概念范式， 机制协调衰老标志，一种新的KO小鼠系，和昼夜生活方式干预，以促进 骨骼肌健康和整体健康。我们已经组建了一个优秀的合作研究团队， 在衰老、昼夜节律、新陈代谢、基因方面具有互补的专业知识和良好的记录 监管/表观遗传学和干预措施。考虑到与生活方式有关的紧迫健康挑战和 老龄化社会，拟议的研究可能会产生深刻的基础和转化影响，最终导致 提高老年人的生活质量。

PROJECT SUMMARY / ABSTRACT Aging is characterized by a progressive decline encompassing a number of hallmark processes. Particularly, age-related abnormalities in energy metabolism entail dysregulated nutrient sensing and mitochondrial function, contributing to the overall decline in physiology and behavior. The circadian clock is a network of cellular oscillators driving output gene expression with ~24 hr rhythmicity, and plays a fundamental role in energy homeostasis. During aging, the clock and clock-controlled output rhythms also display attenuated oscillatory amplitude and resilience, contributing to metabolic decline. The ROR (Retinoid acid receptor-related Orphan Receptor) subfamily of nuclear receptors are key components of the circadian oscillator that function to sustain robust oscillatory amplitude and drive circadian gene expression via transcriptional and epigenetic mechanisms. We previously identified a natural agonist of RORs from chemical screening and demonstrated an important role of RORs in metabolic regulation and aging physiology. More recently, we generated skeletal muscle specific knockout of RORs (alpha and gamma subtypes) in mice (Ror mDKO), and phenotypic characterization of adult Ror mDKO mice (up to 8 months of age) revealed a strong effect on skeletal muscle metabolism and function. Based on these exciting preliminary results, we hypothesize that the circadian clock, particularly RORs, regulate aging-related metabolic functions via gene regulatory mechanisms, and play a pivotal and modifiable role in healthspan and lifespan. In Aim 1, utilizing the aforementioned Ror mDKO mice at old ages, we will evaluate the role of RORs in healthspan and lifespan. In Aim 2, combining physiological, molecular and omics approaches, we will determine regulatory pathways by which RORs orchestrate energy metabolism and mitochondrial function in aged control and Ror mDKO mice, and delineate transcriptional and epigenetic mechanisms. In Aim 3, we will perform two circadian lifestyle interventions, namely time-restricted feeding (TRF) and timed exercise (TE) corresponding to temporally controlled energy intake and expenditure respectively, and evaluate whether RORs are required for healthy aging effects of these lifestyle interventions. Together, the proposed studies will provide key mechanistic insights on the role of the clock in the crosstalk among metabolic and gene regulatory hallmarks of aging, and pinpoint RORs as an actionable target for novel therapeutic strategies to activate clocks, delay aging and prolong healthspan. The innovations include a conceptual paradigm where circadian mechanisms orchestrate aging hallmarks, a novel KO mouse line, and circadian lifestyle interventions to promote skeletal muscle health and overall healthspan. We have assembled an excellent team of co-Investigators with complementary expertise and demonstrated track record in aging, circadian rhythms, metabolism, gene regulation/epigenetics, and interventions. Given the pressing lifestyle-related health challenges and a rapidly aging society, the proposed study may have profound basic and translational impact, eventually leading to improved quality of life in the elderly population.