Circadian clock regulation of metabolic pathways in aging

项目摘要 骨骼肌肥胖症(SO)是指老年肥胖导致的骨骼肌质量和功能的丧失，使人虚弱 导致该人群死亡率上升的并存疾病。我们目前对这个问题的理解 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 对导致细胞衰老的关键代谢过程施加时间控制，并对其进行破坏 导致肥胖、II型糖尿病和早期衰老。尽管昼夜节律很重要 代谢动态平衡的调节，衰老如何影响时钟代谢输出及其潜力 与衰老相关的代谢衰退的作用尚不清楚。先前的研究表明错综复杂的相互作用 生物钟和衰老之间的关系，生物钟丢失导致早期衰老表型和干细胞老化 诱导昼夜节律通路的重新编程。此外，我们的工作揭示了肌肉和脂肪组织 时钟是发育和代谢过程所必需的，这些过程决定了它们在 营养物质的氧化和储存，而轮班导致的时钟中断的新结果显示 进行性肌肉萎缩伴脂肪组织扩张，与此相似。根据进一步的研究结果 衰老的骨骼肌和脂肪组织中显著的时钟抑制和输出信号受损 假设生物钟及其有节奏的代谢输出是维持体内代谢能力所必需的 骨骼肌和脂肪组织，防止衰老。利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功能损失和增益模型，我们将 全面定义SO背后的时钟控制通路，最重要的是，进一步询问 通过遗传、生活方式和药物干预的时钟定向战略。随着广泛传播的 老年人的昼夜节律失调，该项目的结果可能揭示以前未被探索的昼夜节律 SO的潜在病因，并确定潜在的时钟靶向干预措施，以解决这些衰弱问题 衰老的代谢性共病。

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.