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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要衰老的特点是逐渐衰退，包括许多标志性过程。特别，与年龄相关的能量代谢异常导致营养感应和线粒体功能失调，导致生理和行为的整体下降。生物钟是一个细胞网络振荡器以约 24 小时的节律驱动输出基因表达，并在能量方面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出振荡衰减幅度和弹性，导致代谢下降。 ROR（视黄酸受体相关孤儿药物）受体）核受体亚家族是昼夜节律振荡器的关键组成部分，其功能是维持强大的振荡幅度并通过转录和表观遗传机制驱动昼夜节律基因表达。我们之前通过化学筛选鉴定了 ROR 的天然激动剂，并证明了其重要作用 ROR 在代谢调节和衰老生理学中的作用。最近，我们生成了骨骼肌特异性小鼠 ROR（α 和 γ 亚型）敲除 (Ror mDKO) 以及成年小鼠的表型特征 Ror mDKO 小鼠（8 个月以下）显示出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，调节通过基因调控机制调节衰老相关的代谢功能，并在衰老过程中发挥关键和可改变的作用健康寿命和寿命。在目标 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控途径在衰老对照和 Ror mDKO 小鼠中发挥作用，并描述转录和表观遗传机制。瞄准 3、我们会进行两项昼夜生活方式干预，即限时进食（TRF）和定时运动（TE）分别对应于暂时控制的能量摄入和消耗，并评估是否这些生活方式干预措施对健康老龄化的影响需要 ROR。总之，拟议的研究将提供关于时钟在代谢和基因调控之间的串扰中的作用的关键机制见解衰老的标志，并将 ROR 确定为激活生物钟的新型治疗策略的可行目标，延缓衰老，延长健康寿命。这些创新包括一个概念范式，其中昼夜节律机制协调衰老标志、新型 KO 小鼠系和昼夜节律生活方式干预措施，以促进骨骼肌健康和整体健康寿命。我们组建了一支优秀的联合研究人员团队在衰老、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调控/表观遗传学和干预措施。鉴于与生活方式相关的紧迫健康挑战以及快速发展的老龄化社会，拟议的研究可能会产生深远的基础和转化影响，最终导致改善老年人口的生活质量。