Circadian Pathways Linking Metabolic Homeostasis and Gene Regulation During Aging

点击翻译按钮获取中文摘要

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.