Tuning up an aged clock: Circadian clock regulation in metabolism and aging

Circadian rhythms provide temporal variation of a broad range of behavioral and physiological functions, which is precisely controlled by the internal molecular gear, the circadian clock. However, circadian clock functions decline concomitantly with aging-dependent functional deterioration, such as metabolic dysfunction. Metabolic deterioration is widely accepted as one of the hallmarks of aging and leads to various types of aging-associated diseases, such as type 2 diabetes, cardiovascular disease, cancer, and Alzheimer's disease. Importantly, recent transcriptomic, epigenomic, proteomic, and metabolomic data indicates that the circadian clock governs daily fluctuation of metabolic activity and in turn is functionally reliant on metabolic and epigenetic modifications. This suggests that the activation of the circadian clock defends organisms from metabolic aging, eventually resulting in systemic healthy aging. This notion is strongly supported by mounting evidence indicating that dietary interventions robustly affect the circadian clock machinery and subsequent clock-controlled metabolic pathways. In the 21st century, the expansion of an aged population is one of the most important health problem worldwide, making a strategy to promote healthy aging critical. In this review, we summarize the latest evidence regarding an intertwined link between aging and the circadian clock, and propose potential anti-aging therapies centered on the circadian clock.