Circadian clock regulation of metabolic pathways in aging

衰老过程中代谢途径的昼夜节律时钟调节

• 批准号: 10901023
• 负责人: Ke Ma
• 金额: $ 44万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 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/10901023
• 关键词: ARNTL gene; Address; Adipose tissue; Age; Aging; Attenuated; Basal metabolic rate; Caloric Restriction; Cell Aging; Cells; Circadian Dysregulation; Circadian desynchrony; Cues; Developmental Process; Elderly; Etiology; Exercise; Fatty acid glycerol esters; Genetic; Goals; Growth; Homeostasis; Impairment; Intervention; Knowledge; Life Style; Longevity; Maintenance; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modality; Modeling; Mus; Muscle; Muscle function; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Outcome; Output; Pathway interactions; Periodicity; Peripheral; Phenotype; Population; Prevention; Regulation; Signal Transduction; Site; Skeletal Muscle; Testing; Tissue Expansion; Tissues; Work; aged; aging population; anti aging; biological adaptation to stress; circadian; circadian pacemaker; circadian regulation; comorbidity; exercise regimen; feeding; functional decline; gain of function; human old age (65+); improved; loss of function; metabolomics; mortality; muscle aging; muscle form; nobiletin; nutrient metabolism; obesity development; overexpression; oxidation; pharmacologic; prevent; sarcopenic obesity; shift work; skeletal muscle growth; skeletal muscle wasting; stem cells; targeted treatment; tool; transcriptomics

Project Summary Sarcopenic obesity (SO), the loss of skeletal muscle mass and function with obesity in old age, are debilitating co-morbidities contributing to increased mortality in this population. Our current understanding of the mechanisms underlying these metabolic deficits and targeted therapeutic options are limited. Circadian clock exerts temporal control in key metabolic processes that underlie cellular senescence in aging, and its disruption leads to the development of obesity, Type II diabetes and early aging. Despite the importance of circadian regulation involved in metabolic homeostasis, how aging impacts clock metabolic output and their potential contribution to aging-associated metabolic decline remains unknown. Prior studies indicate intricate interplays between circadian clock and aging, with loss of clock leading to an early aging phenotype and aged stem cells inducing re-programming of circadian pathways. In addition, our work revealed that muscle and adipose tissue clock are required for developmental and metabolic processes that determined their metabolic capacity in nutrient oxidation and storage respectively, while new results from shiftwork-induced clock disruption revealed progressive muscle atrophy with adipose tissue expansion resembling SO. Based on further findings of significant clock dampening with impaired output signaling in aged skeletal muscle and adipose tissue, we hypothesize that circadian clock and its rhythmic metabolic output are required to maintain metabolic capacity in skeletal muscle and adipose tissue to prevent SO in aging. Employing transcriptomics and metabolomics approaches and leveraging unique tissue-selective clock loss- and gain-of-function models, we will comprehensively define clock-controlled pathways underlying SO, and most importantly, further interrogate clock-targeting strategies through genetic, lifestyle and pharmacological interventions. With the wide-spread circadian misalignment in the elderly, the outcome of this project may uncover previously unexplored circadian etiologies underlying SO and identify potential clock-targeting interventions to address these debilitating metabolic co-morbidities of aging.

项目摘要 肌肉萎缩性肥胖症（SO）是老年人骨骼肌质量和功能的丧失， 导致该人群死亡率增加的合并症。我们目前对 这些代谢缺陷的潜在机制和靶向治疗选择是有限的。生物钟 在关键的代谢过程中发挥时间控制作用，这些代谢过程是衰老过程中细胞衰老的基础， 导致肥胖、II型糖尿病和过早衰老。尽管昼夜节律的重要性 参与代谢稳态的调节，衰老如何影响时钟代谢输出及其潜力 对衰老相关的代谢下降的贡献仍然未知。先前的研究表明， 生物钟和衰老之间的联系，生物钟的丢失导致早期衰老表型和衰老的干细胞 诱导昼夜节律途径的重新编程。此外，我们的研究还发现， 生物钟是发育和代谢过程所必需的，这些过程决定了它们的代谢能力， 营养氧化和存储分别，而新的结果从shiftwork引起的时钟中断揭示 进行性肌肉萎缩伴类似SO的脂肪组织扩张。根据进一步的调查结果， 在老年骨骼肌和脂肪组织中， 假设生物钟及其节律性代谢输出是维持代谢能力所必需， 骨骼肌和脂肪组织，以防止SO老化。使用转录组学和代谢组学 方法和利用独特的组织选择性时钟损失和功能增益模型，我们将 全面定义SO背后的时钟控制途径，最重要的是，进一步询问 通过遗传、生活方式和药物干预来实现生物钟靶向策略。随着广泛传播的 老年人的昼夜节律失调，这个项目的结果可能会揭示以前未探索的昼夜节律 病因的基础SO和确定潜在的时钟靶向干预措施，以解决这些衰弱 衰老的代谢共病。