Circadian Biology and Phase Response: Fundamental Mechanisms and Clinical Applications

Abstract

The circadian clock, located in the mammalian hypothalamus, regulates biological rhythms with a period of approximately 24 h, influencing nearly all body functions. Its timing is synchronised daily by external cues, primarily light, which align internal rhythms with the environmental cycle. Through this entrainment, the circadian system orchestrates physiological processes such as the sleep–wake cycle, feeding behaviour, gene expression and body temperature regulation. Melatonin, secreted by the pineal gland, also plays a key role as a synchroniser by facilitating sleep onset. Changes in environmental time cues, such as those experienced by shift workers, can disrupt the body’s natural 24-h rhythms. This situation can lead to fatigue, significantly impacting accident rates and productivity, and, in the long term, to an increased risk of various health conditions. A Phase Response Curve (PRC) illustrates how the clock’s phase is affected by stimuli administered at different points in the circadian cycle. In particular, both light and melatonin can induce phase shifts, but the direction and magnitude of this shift depend on the timing of administration. Understanding the PRC enables the design of interventions to realign circadian rhythms and improve adaptation to shift work. This review explores the physiological and clinical effects of circadian disruption in shift workers and discusses strategies to mitigate its impact.