The circadian clock at the intersection of metabolism and aging – emerging roles of metabolites

The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops, which modulates an approximately 24-h cycle of endocrine and metabolic rhythms within cells and tissues. While circadian clocks regulate metabolic processes and related physiology, emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined. In this review, we highlight the concept of metabolites, including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake, as time cues that drive changes in circadian rhythms, which in turn influence metabolism and aging. Furthermore, we discuss the roles of functional metabolites as circadian cues, paving a new direction on potential intervention targets of circadian disruption, pathological aging, as well as metabolic diseases that are clinically important.