Biological Mechanisms Underlying the Adverse Health Consequences of Human Circadian Misalignment from Night Shift Work

The waking and working times of night shift workers are displaced relative to the natural light/dark cycle, putting behavioral patterns in misalignment with the circadian regulation of biological processes. This state of circadian misalignment constitutes a circadian health problem, with widespread negative consequences for metabolic, cardiovascular, and mental health, as well as elevated risk of cancer. Scientific advances over the past decade have shed light on key aspects of the underlying biological mechanisms. With a focus on recent human studies, this paper reviews novel insights into what drives the adverse health consequences of circadian misalignment due to night shift work. Misalignment between the central circadian pacemaker and externally driven behavioral patterns during night shift work produces a rapid uncoupling of peripheral rhythms, reflected in the cargo of exosomes and other signaling mechanisms, and causes conflict between central and peripheral regulatory mechanisms. This endogenous internal desynchrony has been shown to be linked to shifted meal timing and, in part, may be mediated by the gut microbiome. Endogenous internal desynchrony leads to insulin resistance – a manifestation of metabolic dysfunction. It perturbs the cardiometabolic and immune systems, and also erodes mental health. At the cellular level, mistimed DNA repair mechanisms leave residual DNA damage after exposure to a night shift schedule – which, over time, may result in genomic instability and ultimately carcinogenesis. A systems biology perspective serves to elucidate how the effects of endogenous circadian disruption from night shift work increase the risk of acute and chronic illnesses. Internal desynchrony, endogenous in nature, is a common underlying cause. Time-restricted eating may help to address metabolic dysfunction due to night shift work; countermeasures for other negative health outcomes, including cancer and mental health disorders, remain to be developed.