Circadian clock regulation of metabolic pathways in aging

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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.