Circadian Pathways Linking Metabolic Homeostasis and Gene Regulation During Aging

连接衰老过程中代谢稳态和基因调控的昼夜节律途径

• 批准号: 10901043
• 负责人: Zheng Chen
• 金额: $ 38.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901043
• 关键词: Acids; Adult; Age Months; Aging; Agonist; Architecture; Attenuated; Automobile Driving; Behavior; Bioenergetics; Biological Process; Caloric Restriction; Candidate Disease Gene; Cardiolipins; Chemicals; Circadian Dysregulation; Circadian Rhythms; Circadian gene expression; Complex; Deterioration; Dietary Intervention; Eating; Elderly; Energy Intake; Energy Metabolism; Epigenetic Process; Exercise; Fc Receptor; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Health; Health Promotion; Histones; Homeostasis; Intervention; Knock-out; Knockout Mice; Life Style; Link; Longevity; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methodology; Mitochondria; Modernization; Molecular; Mus; Muscle; Muscle function; Nuclear; Nuclear Receptors; Organ; Orphan; Output; Paper; Pathway interactions; Periodicity; Phenotype; Physiological; Physiology; Play; Population; Process; Public Health; Publishing; Quality of life; Regulation; Regulator Genes; Regulatory Pathway; Research Personnel; Respiration; Retinoids; Role; Series; Skeletal Muscle; Societies; Time; Time-restricted feeding; Tissues; Wild Type Mouse; age effect; age related; aged; aging population; circadian; circadian pacemaker; cofactor; detection of nutrient; healthspan; healthy aging; human old age (65+); improved; innovation; insight; insulin signaling; lifestyle intervention; new therapeutic target; nobiletin; novel; novel therapeutic intervention; promoter; receptor; receptor function; resilience; respiratory; response; screening; skeletal muscle metabolism; transcriptome sequencing; transcriptomics; translational impact

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.

项目摘要 /摘要 衰老的特征是逐步下降，包括许多标志性的过程。特别， 能量代谢与年龄相关的异常情况导致营养感应和线粒体功能失调， 导致生理和行为的总体下降。昼夜节律是蜂窝的网络 振荡器以约24小时的节奏驱动输出基因表达，并且在能量中起着基本作用 稳态。在衰老期间，时钟和时钟控制的输出节奏也显示出衰减的振荡 振幅和韧性，导致代谢下降。 ROR（类视视视视视网麻酸受体相关的孤儿 受体）亚科核受体是昼夜节振荡器的关键组成部分，可维持 通过转录和表观遗传机制，可靠的振荡振幅和驱动昼夜节律的表达。 我们以前从化学筛选中确定了一种自然的RORS激动剂，并证明了重要的作用 代谢调节和衰老生理学中的ROR。最近，我们产生了骨骼肌特异性 小鼠（ROR MDKO）的ROR（Alpha和Gamma subtypes）的敲除和成人的表型表征 ROR MDKO小鼠（长达8个月大）揭示了对骨骼肌肉的代谢和功能的强烈影响。 基于这些令人兴奋的初步结果，我们假设昼夜节律，尤其是RORS 与衰老相关的代谢功能通过基因调节机制，并在 HealthSpan和寿命。在AIM 1中，使用上述ROR MDKO小鼠在老年时代，我们将评估 ROR在HealthSpan和寿命中的作用。在AIM 2中，结合了生理，分子和幻象方法， 我们将确定调节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，以及描述转录和表观遗传机制。目标 3，我们将执行两种昼夜节律的生活方式干预措施，即时间限制（TRF）和定时运动 （TE）分别对应于时间控制的能量摄入和支出，并评估是否是否 这些生活方式干预措施的健康衰老效果需要ROR。拟议的研究一起将 提供有关时钟在代谢和基因调节中串扰中的作用的关键机械见解 衰老的标志，并将RORS视为激活时钟的新型治疗策略的可行目标， 延迟衰老并延长健康状态。这些创新包括一个概念范式 机制协调衰老标志，新颖的KO鼠标线和昼夜节律的生活方式干预措施以促进 骨骼肌健康和整体健康范围。我们已经组建了一支优秀的共同投资者团队 互补的专业知识并展示了衰老，昼夜节律，代谢，基因的往绩 调节/表观遗传学和干预措施。考虑到紧迫的生活方式相关的健康挑战，并且迅速 拟议的研究衰老社会可能会产生深远的基本和翻译影响，最终导致 老年人口的生活质量改善。