Circadian rhythm and disease: Relationship, new insights, and future perspectives.

The circadian system is responsible for internal functions and regulation of the organism according to environmental cues (zeitgebers). Circadian rhythm dysregulation or chronodisruption has been associated with several diseases, from mental to autoimmune diseases, and with life quality change. Following this, some therapies have been developed to correct circadian misalignments, such as light therapy and chronobiotics. In this manuscript, we describe the circadian-related diseases so far investigated, and studies reporting relevant data on this topic, evidencing this relationship, are included. Despite the actual limitations in published work, there is clear evidence of the correlation between circadian rhythm dysregulation and disease origin/development, and, in this way, clock-related therapies emerge as great progress in the clinical field. Future improvements in such interventions can lead to the development of successful chronotherapy strategies, deeply contributing to enhanced therapeutic outcomes.

Beneficial effects of voluntary wheel running on activity rhythms, metabolic state, and affect in a diurnal model of circadian disruption.

Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the "circadian syndrome" and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms.

Strategies for circadian rhythm disturbances and related psychiatric disorders: a new cue based on plant polysaccharides and intestinal microbiota.

Circadian rhythm is essential to human physiological homeostasis and health. The oscillation of host circadian rhythm affects the composition and function of intestinal microbiota, meanwhile, the normal operation of host circadian rhythm depends on the diurnal changes of intestinal microbiota. The imbalance of intestinal micro-ecology or the disorder of host circadian rhythm may lead to psychiatric disorders, while the intervention of plant polysaccharides is a possible way to alleviate circadian rhythm disturbance and the related psychiatric diseases. This review discusses the interaction between host circadian rhythm and intestinal microbiota and their effects on psychiatric disorders, and proposes a possible strategy of plant polysaccharides to alleviate circadian rhythm disorders and related psychiatric disorders by regulating intestinal micro-ecology.

Night shift work and the risk of metabolic syndrome: Findings from an 8-year hospital cohort.

OBJECTIVES: Studies concerning the risk of metabolic syndrome associated with night work have shown inconsistent findings, due to imprecise working time data and cross-sectional design. We used register-based daily working time data to examine the risk of incident metabolic syndrome associated with night shift work. METHODS: Working time data collected between 2010 and 2018 of 5775 Taiwanese hospital workers were used to identify night shift workers and to calculate the number of night shifts. Metabolic syndrome was identified by annual occupational health examination results, which were linked to the working time data. Logistic regression models and generalized estimating equations were used to examine the association between night shift work and metabolic syndrome and the 5 components of metabolic syndrome. RESULTS: Night shift work is associated with a higher risk of developing metabolic syndrome (adjusted OR = 1.36, 95% CI = 1.04 to 1.78) and high waist circumference (adjusted OR = 1.27, 95% CI = 1.07 to 1.78) compared to day work. Among night shift workers, increased number of night shifts was associated with high blood pressure (adjusted OR = 1.15, 95% CI = 1.01 to 1.31). CONCLUSIONS: Night shift work is associated with metabolic risk factors. Long-term effects of circadian rhythm disruption on metabolic disturbances needs to be further studied.

Social Jetlag and Related Risks for Human Health: A Timely Review.

The term social jetlag is used to describe the discrepancy between biological time, determined by our internal body clock, and social times, mainly dictated by social obligations such as school or work. In industrialized countries, two-thirds of the studying/working population experiences social jetlag, often for several years. Described for the first time in 2006, a considerable effort has been put into understanding the effects of social jetlag on human physiopathology, yet our understanding of this phenomenon is still very limited. Due to its high prevalence, social jetlag is becoming a primary concern for public health. This review summarizes current knowledge regarding social jetlag, social jetlag associated behavior (e.g., unhealthy eating patterns) and related risks for human health.

Evidence for a dysfunction and disease-promoting role of the circadian clock in the diabetic retina.

Diabetic retinopathy is a major complication of chronic hyperglycemia and a leading cause of blindness in developed countries. In the present study the interaction between diabetes and retinal clocks was investigated in mice. It was seen that in the db/db mouse - a widely used animal model of diabetic retinopathy - clock function and circadian regulation of gene expression was disturbed in the retina. Remarkably, elimination of clock function by Bmal1-deficiency mitigates the progression of pathophysiology of the diabetic retina. Thus high-fat diet was seen to induce histopathology and molecular markers associated with diabetic retinopathy in wild type but not in Bmal1-deficient mice. The data of the present study suggest that Bmal1/the retinal clock system is both, a target and an effector of diabetes mellitus in the retina and hence represents a putative therapeutic target in the pathogenesis of diabetic retinopathy.

Energy Balance and Control of Body Weight: Possible Effects of Meal Timing and Circadian Rhythm Dysregulation.

Conservation of the energy equilibrium can be considered a dynamic process and variations of one component (energy intake or energy expenditure) cause biological and/or behavioral compensatory changes in the other part of the system. The interplay between energy demand and caloric intake appears designed to guarantee an adequate food supply in variable life contexts. The circadian rhythm plays a major role in systemic homeostasis by acting as "timekeeper" of the human body, under the control of central and peripheral clocks that regulate many physiological functions such as sleep, hunger and body temperature. Clock-associated biological processes anticipate the daily demands imposed by the environment, being synchronized under ideal physiologic conditions. Factors that interfere with the expected demand, including daily distribution of macronutrients, physical activity and light exposure, may disrupt the physiologic harmony between predicted and actual behavior. Such a desynchronization may favor the development of a wide range of disease-related processes, including obesity and its comorbidities. Evidence has been provided that the main components of 24-h EE may be affected by disruption of the circadian rhythm. The sleep pattern, meal timing and meal composition could mediate these effects. An increased understanding of the crosstalk between disruption of the circadian rhythm and energy balance may shed light on the pathophysiologic mechanisms underlying weight gain, which may eventually lead to design effective strategies to fight the obesity pandemic.

Early Life Stress and Chronobiological Rhythms Desynchronization: Possible Impact on Mood Symptoms and Suicidal Ideation in Bipolar Disorder.

ABSTRACT: The study aimed at investigating the potential impact of early stressful events on the clinical manifestations of bipolar disorder (BD). A sample of 162 adult individuals with BD was assessed using the Structural Clinical Interview for DSM-5, the Beck Depression Inventory-II, the Young Mania Rating Scale, the Early Trauma Inventory Self Report-Short Form, the Biological Rhythms Interview of Assessment in Neuropsychiatry, the Insomnia Severity Index, and the Scale for Suicide Ideation. A significant path coefficient indicated a direct effect of early life stressors on biological rhythms (coeff. = 0.26; p < 0.001) and of biological rhythms on depressive symptoms (coeff. = 0.5; p < 0.001), suicidal risk (coeff. = 0.3; p < 0.001), and insomnia (coeff. = 0.34; p < 0.001). Data suggested that the desynchronization of chronobiological rhythms might be one mediator of the association between early life stress and the severity of mood symptoms/suicidal ideation in BD. Addressing circadian rhythm alterations in subjects exposed to early stressors would help in preventing consequences of those stressors on BD.

Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.

Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice.

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A1/A2A receptor signalling through the activation of the Ca2+ -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.

Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans.

Circadian disruption has been identified as a risk factor for health disorders such as obesity, cardiovascular disease, and cancer. Although epidemiological studies suggest an increased risk of various cancers associated with circadian misalignment due to night shift work, the underlying mechanisms have yet to be elucidated. We sought to investigate the potential mechanistic role that circadian disruption of cancer hallmark pathway genes may play in the increased cancer risk in shift workers. In a controlled laboratory study, we investigated the circadian transcriptome of cancer hallmark pathway genes and associated biological pathways in circulating leukocytes obtained from healthy young adults during a 24-hour constant routine protocol following 3 days of simulated day shift or night shift. The simulated night shift schedule significantly altered the normal circadian rhythmicity of genes involved in cancer hallmark pathways. A DNA repair pathway showed significant enrichment of rhythmic genes following the simulated day shift schedule, but not following the simulated night shift schedule. In functional assessments, we demonstrated that there was an increased sensitivity to both endogenous and exogenous sources of DNA damage after exposure to simulated night shift. Our results suggest that circadian dysregulation of DNA repair may increase DNA damage and potentiate elevated cancer risk in night shift workers.

Sleep quality does not mediate the negative effects of chronodisruption on body composition and metabolic syndrome in healthcare workers in Ecuador.

BACKGROUND AND AIMS: The objective of the present work was to determine to what extent sleep quality may mediate the association between chronodisruption (CD) and metabolic syndrome (MS), and between CD and body composition (BC). METHODOLOGY: Cross-sectional study which included 300 adult health workers, 150 of whom were night shift workers and thereby exposed to CD. Diagnosis of MS was made based on Adult Treatment Panel III criteria. Sleep quality was measured using the Pittsburgh Sleep Quality Index. Body mass index (BMI), fat mass percentage, and visceral fat percentage were measured as indicators of body composition (BC). Data were analyzed using logistic, linear regression and structural equation models. RESULTS: The odds of health workers exposed to CD to suffer MS was 22.13 (IC95 8.68-66.07) when the model was adjusted for age, gender, physical activity and energy consumption. CD was also significantly associated with an increase in fat mass and visceral fat percentages, but not to BMI. Surprisingly, there was not enough evidence supporting the hypothesis that sleep quality contributes to the association between CD and MS or between CD and BC. CONCLUSIONS: Sleep quality does not mediate the negative effects of CD on MS nor on BC.

Impact of Circadian Desynchrony on Spermatogenesis: A Mini Review.

The purpose of this mini review is to provide data about pre-clinical and clinical evidence exploring the impact of circadian desynchrony on spermatogenesis. Several lines of evidence exist demonstrating that disruption of circadian rhythms may interfere with male fertility. Experimental knock-out or knock-down of clock genes, physiologically involved in the regulation of circadian rhythms, are associated with impairments of fertility pathways in both animal and human models. Moreover, disruption of circadian rhythms, due to reduction of sleep duration and/or alteration of its architecture can negatively interfere in humans with circulating levels of male sexual hormones as well as with semen parameters. Unfortunately, current evidence remains low due to study heterogeneity.

Association between circadian disruption and diseases: A narrative review.

Circadian rhythms play an important role in a wide range of human physiology and pathology. Individuals increasingly experience situations such as night-shift work schedules, likely leading to circadian disruption. Recent studies have also demonstrated that patients with other diseases often show symptoms of circadian disruption as manifested by the sleep-wake cycle and other biological rhythms. Circadian disruption often results in changes to the phase, period, and amplitude of the sleep-wake cycle, melatonin rhythm, and core body temperature. Several cardiometabolic, psychiatric, and neurodegenerative diseases are closely related to circadian disruption. Several interventions are also available, including phototherapy, exogenous melatonin, and exercise. The cumulative findings suggest that circadian disruption can increase risk for some cardiometabolic diseases. Circadian disruption also acts as a concomitant symptom of several psychiatric and neurodegenerative diseases. More attention should be paid to evaluating the impact of circadian disruption on these related diseases, as well as the benefits of the mitigation interventions for both circadian disruption and related diseases.

Melanopsin Cell Dysfunction is Involved in Sleep Disruption in Parkinson's Disease.

BACKGROUND: Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) signal the environmental light to mediate circadian photoentrainment and sleep-wake cycles. There is high prevalence of circadian and sleep disruption in people with Parkinson's disease, however the underlying mechanisms of these symptoms are not clear. OBJECTIVE: Based on recent evidence of anatomical and functional loss of melanopsin ganglion cells in Parkinson's disease, we evaluate the link between melanopsin function, circadian, and sleep behavior. METHODS: The pupil light reflex and melanopsin-mediated post-illumination pupil response were measured using chromatic pupillometry in 30 optimally medicated people with Parkinson's disease and 29 age-matched healthy controls. Circadian health was determined using dim light melatonin onset, sleep questionnaires, and actigraphy. Ophthalmic examination quantified eye health and optical coherence tomography measured retinal thickness. RESULTS: The melanopsin-mediated post-illumination pupil response amplitudes were significantly reduced in Parkinson's disease (p < 0.0001) and correlated with poor sleep quality (r2 = 33; p < 0.001) and nerve fiber layer thinning (r2 = 0.40; p < 0.001). People with Parkinson's disease had significantly poorer sleep quality with higher subjective sleep scores (p < 0.05) and earlier melatonin onset (p = 0.01). Pupil light (outer retinal) response metrics, daily light exposure and outer retinal thickness were similar between the groups (p > 0.05). CONCLUSION: Our evidence-based data identify a mechanism through which inner retinal ipRGC dysfunction contributes to sleep disruption in Parkinson's disease in the presence of normal outer retinal (rod-cone photoreceptor) function. Our findings provide a rationale for designing new treatment approaches in Parkinson's disease through melanopsin photoreceptor-targeted light therapies for improving sleep-wake cycles.

Circadian Rhythm Sleep-Wake Disorders.

PURPOSE OF REVIEW: This article provides an overview of circadian physiology and discusses common presentations and treatment strategies for the circadian rhythm sleep-wake disorders. RECENT FINDINGS: Circadian rhythms are present throughout the body, and appreciation for the role that circadian dysregulation plays in overall health is increasing, with mounting associations between circadian disruption and cardiometabolic disease risk. SUMMARY: It is important to recognize the ubiquitous role that circadian rhythms play throughout the brain and body. An understanding of circadian neurophysiology will provide insight into the means by which patients with a variety of neuropathologies at the level of the retina, optic nerve, or hypothalamus may also be at risk for circadian dysfunction.

Circadian alterations in patients with neurodegenerative diseases: Neuropathological basis of underlying network mechanisms.

Circadian organization of physiology and behavior is an important biological process that allows organisms to anticipate and prepare for daily changes and demands. Disruptions in this system precipitates a wide range of health issues. In patients with neurodegenerative diseases, alterations of circadian rhythms are among the most common and debilitating symptoms. Although a growing awareness of these symptoms has occurred during the last decade, their underlying neuropathophysiological circuitry remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these health issues. Recent studies have examined the neuropathological status of the different neural components of the circuitry governing the generation of circadian rhythms in neurodegenerative diseases. In this review, we will dissect the potential contribution of dysfunctions in the different nodes of this circuitry to circadian alterations in patients with neurodegenerative diseases. A deeper understanding of these mechanisms will provide not only a better understanding of disease neuro-pathophysiology, but also hold the promise for developing effective and mechanisms-based therapies.

Effects of the COVID-19 lockdown on human sleep and rest-activity rhythms.

In modern societies, human rest-activity rhythms and sleep result from the tensions and dynamics between the conflicting poles of external social time (e.g., work hours and leisure activities) and an individual's internal biological time. A mismatch between the two has been suggested to induce 'social jetlag' [1] and 'social sleep restriction', that is, shifts in sleep timing and differences in sleep duration between work days and free days. Social jetlag [2,3] and sleep restrictions [4] have repeatedly been associated with negative consequences on health, mental wellbeing, and performance. In a large-scale quasi-experimental design, we investigated the effects of the phase with the most rigorous COVID-19 restrictions on the relationship between social and biological rhythms as well as sleep during a six-week period (mid-March until end of April 2020) in three European societies (Austria, Germany, Switzerland). We found that, on one hand, the restrictions reduced the mismatch between external (social) and internal (biological) sleep-wake timing, as indexed by significant reductions in social jetlag and social sleep restriction, with a concomitant increase in sleep duration. Sleep quality on the other hand was slightly reduced. The improved individual sleep-wake timing can presumably be attributed to an increased flexibility of social schedules, for instance due to more work being accomplished from home. However, this unprecedented situation also led to a significant increase in self-perceived burden, which was attendant to the decrease in sleep quality. These adverse effects may be alleviated by exposure to natural daylight as well as physical exercise.

Sleep in university students prior to and during COVID-19 Stay-at-Home orders.

Sleep health has multiple dimensions including duration, regularity, timing, and quality [1-4]. The Coronavirus 2019 (COVID-19) outbreak led to Stay-at-Home orders and Social Distancing Requirements in countries throughout the world to limit the spread of COVID-19. We investigated sleep behaviors prior to and during Stay-at-Home orders in 139 university students (aged 22.2 ± 1.7 years old [±SD]) while respectively taking the same classes in-person and remotely. During Stay-at-Home, nightly time in bed devoted to sleep (TIB, a proxy for sleep duration with regard to public health recommendations [5]) increased by ∼30 min during weekdays and by ∼24 mins on weekends and regularity of sleep timing improved by ∼12 min. Sleep timing became later by ∼50 min during weekdays and ∼25 min on weekends, and thus the difference between weekend and weekday sleep timing decreased - hence reducing the amount of social jetlag [6,7]. Further, we find individual differences in the change of TIB devoted to sleep such that students with shorter TIB at baseline before the first COVID-19 cases emerged locally had larger increases in weekday and weekend TIB during Stay-at-Home. The percentage of participants that reported 7 h or more sleep per night, the minimum recommended sleep duration for adults to maintain health [5] - including immune health - increased from 84% to 92% for weekdays during Stay-at-Home versus baseline. Understanding the factors underlying such changes in sleep health behaviors could help inform public health recommendations with the goal of improving sleep health during and following the Stay-at-Home orders of the COVID-19 pandemic.