Circadian rhythms control a variety of biological processes in living systems, ranging from bacteria to humans . Perhaps the most obvious function regulated by circadian rhythms is the daily sleep and wake cycle in animals. However, many other physiological processes are regulated by circadian rhythms, including body temperature, feeding behaviour, hormone secretion, drug and xenobiotic metabolism, glucose homeostasis, and cell-cycle progression. When circadian cycles are disrupted, either by genetic or environmental insults, disorders of diverse physiological processes can occur 3 . Links between circadian physiology and other physiological processes therefore have implications for human biology because it is likely that genetic variation in circadian clock genes can contribute significantly to physiological variation, and therefore potentially to variation in disease susceptibility. In addition, in modern societies, humans are increasingly ignoring natural circadian cues, so it is important to understand how the resulting perturbations of our circadian biology might affect our physiology and susceptibility to diseaseboth to understand the disease processes and to identify new targets for treatment.In this Review, we bring together findings from recent studies that have begun to provide a molecular understanding of how circadian biology influences physiological processes that are relevant to human disease. We first briefly describe the generally accepted models of how our circadian rhythms are regulated at the neural, genetic and molecular levels, an understanding that has come from extensive work in model organisms. We then highlight recent findings from genetic studies of human circadian disorders, which illustrate the striking conservation of clock-gene function in model organisms and humans, and we also highlight the implications of human clockgene variation for human circadian biology. We will also discuss recent studies that have revealed a number of surprisingly direct molecular links with the cell cycle, metabolism and behavioural disorders, providing a basis for understanding how the circadian system impinges on diverse aspects of mammalian physiology that are of relevance for human diseases and their treatment, including regenerative medicine and cancer, obesity and diabetes, and mental health.
Neural control of mammalian circadian rhythms
The ability of living systems to sustain approximately 24-hour rhythms in the absence of environmental cues shows that most daily oscillations are not responses to the diurnal cycle, but rather are generated by an internal clock (BOX 1). The 'master' internal clock in mammals is located in the hypothalamic suprachiasmatic nucleus, or SCN -this is composed of bilateral nuclei containing approximately 10,000 neurons each 4,5 (FIG. ). The primary environmental synchronizer of circadian rhythms in mammals is the daily light-dark cycle. A novel class of intrinsically photosensitive retinal ganglion cells that express the photopigment melanopsin