Circadian disruption and human health

Abstract

Circadian disruption is pervasive and can occur at multiple organizational levels, contributing to poor health outcomes at individual and population levels. Evidence points to a bidirectional relationship, in that circadian disruption increases disease severity and many diseases can disrupt circadian rhythms. Importantly, circadian disruption can increase the risk for the expression and development of neurologic, psychiatric, cardiometabolic, and immune disorders. Thus, harnessing the rich findings from preclinical and translational research in circadian biology to enhance health via circadian-based approaches represents a unique opportunity for personalized/precision medicine and overall societal well-being. In this Review, we discuss the implications of circadian disruption for human health using a bench-to-bedside approach. Evidence from preclinical and translational science is applied to a clinical and population-based approach. Given the broad implications of circadian regulation for human health, this Review focuses its discussion on selected examples in neurologic, psychiatric, metabolic, cardiovascular, allergic, and immunologic disorders that highlight the interrelatedness between circadian disruption and human disease and the potential of circadian-based interventions, such as bright light therapy and exogenous melatonin, as well as chronotherapy to improve and/or modify disease outcomes.

Figure 1. Schematic of the interrelationships between circadian disruption and human disease.

As depicted on the top left, circadian disruption can result from misalignment of external factors (such as the natural light/dark cycle, social and work requirements, and behaviors such as sleep and meal timing) with the master circadian clock located in the suprachiasmatic nucleus (SCN), as well as with endogenous circadian clocks in other tissues. Common examples of chronic external-internal misalignment include social jet lag, shift work, and misalignment due to inappropriately timed light exposure (evening or night). The top right image depicts the SCN and the peripheral clocks throughout the body. The SCN integrates light and nonphotic stimuli to synchronize the timing of other brain and body clocks with the environment and behaviors. Disturbances at these various organizational levels result in circadian disruption. Disturbance in the phase and amplitude of circadian rhythms can occur at the molecular, cellular, and organismal levels. On the bottom are examples of the impact of circadian disruption and the bidirectionality between circadian disruption and the classical circadian sleep-wake disorders and other chronic medical disorders.

Figure 2. A multimodal approach to address circadian disruption and its effect on health.

Diagnostic approaches, including current tools, rely primarily on self-reported and behavioral measures and require time-intensive multiple sampling of biomarkers to obtain a 24-hour profile. However, tools in development seek to assess circadian phase using a single time sample of multiple rhythms. Circadian-based therapies, such as timed bright light exposure and exogenous melatonin, are commonly used to align the phase of external/behavioral rhythms with endogenous central and peripheral clocks. In addition, time-restricted feeding can enhance alignment among peripheral clocks and improve metabolic health. In development are multimodal approaches to target central and peripheral clocks with dynamic circadian lighting, time-restricted feeding and drugs to align and stabilize circadian entrainment, and chronopharmacotherapy to optimize efficacy and tolerability of medications. CRSWD, circadian rhythm sleep wake disorder.