Significance: A substantial proportion of mammalian physiology is organized around the dayight cycle, being regulated by the co-ordinated action of numerous cell-autonomous circadian oscillators throughout the body. Disruption of internal timekeeping, by genetic or environmental perturbation, leads to metabolic dysregulation, whereas changes in metabolism affect timekeeping. Recent Advances: While gene expression cycles are essential for the temporal coordination of normal physiology, it has become clear that rhythms in metabolism and redox balance are cell-intrinsic phenomena, which may regulate gene expression cycles reciprocally, but persist in their absence. For example, a circadian rhythm in peroxiredoxin oxidation was recently observed in isolated human erythrocytes, fibroblast cell lines in vitro, and mouse liver in vivo. Critical Issues: Mammalian timekeeping is a cellular phenomenon. While we understand many of the cellular systems that contribute to this biological oscillation's fidelity and robustness, a comprehensive mechanistic understanding remains elusive. Moreover, the formerly clear distinction between "core clock components" and rhythmic cellular outputs is blurred since several outputs, for example, redox balance, can feed back to regulate timekeeping. As with any cyclical system, establishing causality becomes problematic. Future Directions: A detailed molecular understanding of the temporal crosstalk between cellular systems, and the coincidence detection mechanisms that allow a cell to discriminate clock-relevant from irrelevant stimuli, will be essential as we move toward an integrated model of how this daily biological oscillation works. Such knowledge will highlight new avenues by which the functional consequences of circadian timekeeping can be explored in the context of human health and disease.
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