Microbial Reconstitution Improves Aging-Driven Lacrimal Gland Circadian Dysfunction.

Lacrimal glands are highly susceptible to aging and exhibit age-related structural and functional alterations. However, the mechanisms by which aging affects the lacrimal glands are not well-established. The current study explores the crosstalk between the aging process, gut microbiota, and circadian rhythm in age-associated lacrimal gland dysfunction. C57BL/6J mice were divided into young, old, and fecal microbiota transplant (FMT)-treated old groups. The gut bacterial community diversity was analyzed by 16S rRNA sequencing. Exorbital lacrimal glands (ELGs) were collected at 3-hour intervals over a 24-hour circadian cycle, and total RNA was subjected to high-throughput sequencing. Rhythmic transcriptional data were analyzed using the Jonckheere-Terpstra-Kendall algorithm and bioinformatics analysis technology. Immunostaining was used to identify lymphocytic infiltration, lipid deposition, and nerve innervation in the ELGs. Compared with young mice, old mice underwent a significant gut microbial community shift. The rhythmically transcriptomic profile was significantly reprogrammed over a 24-hour cycle in the old ELG group. Intervention with serial FMT from young donors for 1 month rejuvinated the gut microbial community of the old mice. Most alterations in rhythmic transcriptomic profiling were improved. Furthermore, chronic inflammation, lipid deposition, and aberrant neural response of the aging lacrimal glands were significantly reduced. Thus, the study shows that reconstitution of age-associated gut dysbiosis with FMTs from young donors improves aging-driven lacrimal gland circadian dysfunction.

Adiponectin improves amyloid-ß 31-35-induced circadian rhythm disorder in mice.

Adiponectin is an adipocyte-derived hormone, which is closely associated with the development of Alzheimer's disease (AD) and has potential preventive and therapeutic significance. In the present study, we explored the relationship between adiponectin and circadian rhythm disorder in AD, the effect of adiponectin on the abnormal expression of Bmal1 mRNA/protein induced by amyloid-ß protein 31-35 (Aß31-35), and the underlying mechanism of action. We found that adiponectin-knockout mice exhibited amyloid-ß deposition, circadian rhythm disorders and abnormal expression of Bmal1. Adiponectin ameliorated the abnormal expression of the Bmal1 mRNA/protein caused by Aß31-35 by inhibiting the activity of glycogen synthase kinase 3ß (GSK3ß). These results suggest that adiponectin deficiency could induce circadian rhythm disorders and abnormal expression of the Bmal1 mRNA/protein, whilst exogenous administration of adiponectin may improve Aß31-35-induced abnormal expression of Bmal1 by inhibiting the activity of GSK3ß, thus providing a novel idea for the treatment of AD.

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.

Night shift work and cardiovascular disease biomarkers in female nurses.

BACKGROUND: Night shift work is associated with cardiovascular disease, but its associations with cardiovascular disease biomarkers are unclear. We investigated these associations in a study of female nurses. METHODS: We used data from the Nurses' Health Study II for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, C-reactive protein (CRP), and fibrinogen. The sample sizes for our analysis ranged from 458 (fibrinogen) to 3574 (total cholesterol). From questionnaires, we determined the number of night shifts worked in the 2 weeks before blood collection and total years of rotating night shift work. We used quantile regression to estimate differences in biomarker levels by shift work history, adjusting for potential confounders. RESULTS: Nurses working 1 to 4 recent night shifts had median HDL cholesterol levels 4.4 mg/dL (95% confidence interval [CI]: 0.3, 7.5) lower than nurses without recent night shifts. However, working ≥5 recent night shifts and years of rotating night shift work were not associated with HDL cholesterol. There was no association between recent night shifts and CRP, but median CRP levels were 0.1 (95% CI: 0.0, 0.2), 0.2 (95% CI: 0.1, 0.4), and 0.2 (95% CI: 0.0, 0.4) mg/L higher among nurses working rotating night shifts for 1 to 5, 6 to 9, and ≥10 years compared with nurses never working rotating night shifts. These associations were attenuated when excluding postmenopausal women and women taking statins. We observed no associations between night shift work and other biomarkers. CONCLUSIONS: We found suggestive evidence of adverse short-term and long-term effects of night shift work on select cardiovascular disease biomarkers.

Internal clock and the surgical ICU patient.

PURPOSE OF REVIEW: The alteration of circadian rhythms in the postoperative period has been demonstrated to influence the outcomes. With this narrative review we would revise how anesthesia, surgery and intensive care can interfere with the circadian clock, how this could impact on the postsurgical period and how to limit the disruption of the internal clock. RECENT FINDINGS: Anesthesia affects the clock in relation to the day-time administration and the type of anesthetics, N-methyl-D-aspartate receptor antagonists or gamma-aminobutyric acid receptors agonists. Surgery causes stress and trauma with consequent alteration in the circadian release of cortisol, cytokines and melatonin. ICU represents a further challenge for the patient internal clock because of sedation, immobility, mechanical ventilation and alarms noise. SUMMARY: The synergic effect of anesthesia, surgery and postoperative intensive care on circadian rhythms require a careful approach to the patient considering a role for therapies and interventions aimed to re-establish the normal circadian rhythms. Over time, approach like the Awakening and Breathing Coordination, Delirium Monitoring and Management, Early Mobility and Family engagement and empowerment bundle can implement the clinical practice.

Sleep-wake and circadian disturbances in Parkinson disease: a short clinical guide.

Sleep-wake and circadian disturbances are very frequent and often troublesome symptoms in patients suffering from Parkinson disease. Therefore, a concept for the evaluation and therapy of such disturbances must be considered and implemented by all physicians involved in Parkinson care. The present review shall offer a short and condensed guide for the clinician. It summarizes the epidemiology of sleep-wake and circadian disturbances in Parkinson disease, sheds some light into translational studies forwarding knowledge about underlying pathophysiological concepts, and discusses diagnostic approaches and current therapeutic recommendations, albeit the latter being mostly based on insufficient evidence. As most treatments for Parkinson-related sleep-wake disturbances are still off-label, we need more prospective randomized trials for being able to optimize and personalize treatment for every single patient.

Chronotype, nursing activity, and gender: A systematic review.

AIM: To synthesize evidence about the effect of individual circadian preference (chronotype) and gender in the development of sleep and mood problems in nursing professionals. BACKGROUND: Shift workers are more prone to having unhealthy habits and unfavourable clinical conditions than nonshift workers. These associations are mediated by chronotype and gender differences have also been detected. DESIGN: A quantitative systematic review. DATA SOURCES: Electronic searches were performed in MEDLINE, Scopus, ScienceDirect, and Web of Science from 1 July 2012 - 1 July 2017. REVIEW METHODS: A systematic review was conducted using the Cochrane Collaboration guidelines and two quality assessment tools: the National Heart, Lung and Blood Institute and GRADE. Inclusion criteria were quantitative studies where the sample consists entirely of nurses, analysing circadian rhythms or individual chronotype or gender and sleep/mood disturbances in nursing activity. The review was reported using the PRISMA statement. RESULTS: A total of 23 studies were included in the review (five cohort studies and 18 cross-sectional studies). Data on gender-specific attention were scarce (two studies) and showed a higher incidence of sleep problems. Female nurses with eveningness-oriented personality seem to be more prone to having sleep disorders, insomnia, fatigue, and anxiety than male and morningness ones. CONCLUSIONS: Evidence seems to show that female nurses with an evening-oriented preference suffer more problems of insomnia, sleepiness, fatigue, and anxiety. The impact of our results may affect nurses, patient safety and the quality of clinical practice.

The Period 2 Enhancer Nobiletin as Novel Therapy in Murine Models of Circadian Disruption Resembling Delirium.

OBJECTIVES: Delirium occurs in approximately 30% of critically ill patients, and the risk of dying during admission doubles in those patients. Molecular mechanisms causing delirium are largely unknown. However, critical illness and the ICU environment consistently disrupt circadian rhythms, and circadian disruptions are strongly associated with delirium. Exposure to benzodiazepines and constant light are suspected risk factors for the development of delirium. Thus, we tested the functional role of the circadian rhythm protein Period 2 (PER2) in different mouse models resembling delirium. DESIGN: Animal study. SETTING: University experimental laboratory. SUBJECTS: Wildtype, Per2 mice. INTERVENTIONS: Midazolam, lipopolysaccharide (lipopolysaccharide), constant light, nobiletin, or sham-treated animals. MEASUREMENTS AND MAIN RESULTS: Midazolam significantly reduced the expression of PER2 in the suprachiasmatic nucleus and the hippocampus of wild-type mice. Behavioral tests following midazolam exposure revealed a robust phenotype including executive dysfunction and memory impairment suggestive of delirium. These findings indicated a critical role of hippocampal expressed PER2. Similar results were obtained in mice exposed to lipopolysaccharide or constant light. Subsequent studies in Per2 mice confirmed a functional role of PER2 in a midazolam-induced delirium-like phenotype. Using the small molecule nobiletin to enhance PER2 function, the cognitive deficits induced by midazolam or constant light were attenuated in wild-type mice. CONCLUSIONS: These experiments identify a novel role for PER2 during a midazolam- or constant light-induced delirium-like state, highlight the importance of hippocampal PER2 expression for cognitive function, and suggest the PER2 enhancer nobiletin as potential therapy in delirium-like conditions associated with circadian disruption.

Depressive symptoms and actigraphy-measured circadian disruption predict head and neck cancer survival.

OBJECTIVE: Depressive symptoms have demonstrated prognostic significance among head and neck cancer patients. Depression is associated with circadian disruption, which is prognostic in multiple other cancer types. We hypothesized that depressive symptoms would be associated with circadian disruption in head and neck cancer, that each would be related to poorer 2-year overall survival, and that relationships would be mediated by tumor response to treatment. METHODS: Patients (N = 55) reported on cognitive/affective and somatic depressive symptoms (PHQ-9) and wore an actigraph for 6 days to continuously record rest and activity cycles prior to chemoradiation. Records review documented treatment response and 2-year survival. Spearman correlations tested depressive symptoms and circadian disruption relationships. Cox proportional hazard models tested the predictive capability of depressive symptoms and circadian disruption, separately, on survival. RESULTS: Depressive symptoms were significantly associated with circadian disruption, and both were significantly associated with shorter survival (somatic: hazard ratio [HR] = 1.325, 95% confidence interval [CI] = 1.089-1.611, P = .005; rest/activity rhythm: HR = 0.073, 95% CI = 0.009-0.563, P = .012; nighttime restfulness: HR = 0.910, 95% CI = 0.848-0.977, P = .009). Tumor response to treatment appeared to partly mediate the nighttime restfulness-survival relationship. CONCLUSIONS: This study replicates and extends prior work with new evidence linking a subjective measure of depression and an objective measure of circadian disruption-2 known prognostic indicators-to shortened overall survival among head and neck cancer patients. Continued examination should elucidate mechanisms by which depressive symptomatology and circadian disruption translate to head and neck cancer progression and mortality.

Effects of Light Treatment on Sleep, Cognition, Mood, and Behavior in Alzheimer's Disease: A Systematic Review.

BACKGROUND: Bright light treatment is a therapeutic intervention mainly used to treat sleep and circadian disturbances in Alzheimer's disease (AD) patients. Recently, a handful of studies also focused on the effect on cognition and behavior. Conflicting findings are reported in the literature, and no definite conclusions have been drawn about its specific therapeutic effect. SUMMARY: The aim of this review is to provide a critical evaluation of available evidence in this field, highlighting the specific characteristics of effective bright light treatment. Eligible studies were required to assess at least one of the following outcome measures: sleep, cognition, mood, and/or behavior (e.g., depression, agitation). A total of 32 articles were included in this systematic review and identified as research intervention studies about light treatment in AD. The quality of the papers was evaluated based on the US Preventive Service Task Force guidelines. Key Messages: Overall, the current literature suggests that the effects of light treatment in AD patients are mixed and may be influenced by several factors, but with a general trend toward a positive effect. Bright light seems to be a promising intervention treatment without significant adverse effects; therefore, further well-designed randomized controlled trials are needed taking into account the highlighted recommendations.

Circadian dysfunction and fluctuations in gait initiation impairment in Parkinson's disease.

In people with Parkinson's disease (PD), anticipatory postural adjustments may be prolonged, reduced in amplitude, or absent, contributing to impaired gait initiation. In addition to motor symptoms, disturbance of the circadian rhythm (CR) is one of the common non-motor symptoms of PD. The purpose of this study was to investigate whether time of day modulates the magnitude of gait initiation impairment, and furthermore, if there is any relationship between CR dysfunction and impaired postural control in PD. Seven consecutive 24-h periods of wrist actigraphy (as a measure of CR), and then gait initiation studies (at two different times, 9:00 a.m. and 2:30 p.m., of the same day) were conducted in two cohorts of ten subjects each: people with PD, and age-matched control subjects. We found that in the PD group, the amplitude of medial/lateral center of pressure (CoP) excursions were significantly reduced in the afternoon as compared with the morning session across all trials (p < 0.05). Actigraphy results showed that CR amplitude was significantly decreased (p < 0.05) in the PD group, which suggests that the PD group suffered from CR disruption. More importantly, changes in medial/lateral CoP displacement were correlated with abnormal CR amplitude in the PD group. These findings provide novel evidence that diurnal fluctuations in treatment-resistant motor symptoms of PD, such as postural and gait initiation deficits, are associated with CR dysfunction. This study supports the idea that therapeutic correction of circadian misalignment should be considered in combination with pharmaceutical and rehabilitation treatments of motor symptoms in PD.

Chronobiological theories of mood disorder.

Major depressive disorder (MDD) remains the most prevalent mental disorder and a leading cause of disability, affecting approximately 100 million adults worldwide. The disorder is characterized by a constellation of symptoms affecting mood, anxiety, neurochemical balance, sleep patterns, and circadian and/or seasonal rhythm entrainment. However, the mechanisms underlying the association between chronobiological parameters and depression remain unknown. A PubMed search was conducted to review articles from 1979 to the present, using the following search terms: "chronobiology," "mood," "sleep," and "circadian rhythms." We aimed to synthesize the literature investigating chronobiological theories of mood disorders. Current treatments primarily include tricyclic antidepressants and selective serotonin reuptake inhibitors, which are known to increase extracellular concentrations of monoamine neurotransmitters. However, these antidepressants do not treat the sleep disturbances or circadian and/or seasonal rhythm dysfunctions associated with depressive disorders. Several theories associating sleep and circadian rhythm disturbances with depression have been proposed. Current evidence supports the existence of associations between these, but the direction of causality remains elusive. Given the existence of chronobiological disturbances in depression and evidence regarding their treatment in improving depression, a chronobiological approach, including timely use of light and melatonin agonists, could complement the treatment of MDD.

Time Travels: A 40-Year Journey from Drosophila's Clock Mutants to Human Circadian Disorders (Nobel Lecture).

Living organisms have a biological clock that helps to prepare our physiology for the fluctuations of the day. Key research to elucidate the biological mechanisms of this regular adaptation, referred to as the circadian rhythm, is described by M. W. Young in his Nobel lecture.

Melanopsin retinal ganglion cell loss in Alzheimer disease.

OBJECTIVE: Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction. METHODS: We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid ß (Aß) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls. RESULTS: We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aß accumulation was remarkably evident inside and around mRGCs. INTERPRETATION: We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aß deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.

Alterations of the circadian system in Parkinson's disease patients.

Alterations of circadian rhythms are among the most debilitating non-motor symptoms in Parkinson's Disease (PD). Although a growing awareness towards these symptoms has occurred during the last decade, their underlying neuropathophysiology remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these problems. Recent studies have investigated multiple circadian rhythms at different stages of PD. The advances made have allowed an accurate evaluation of the affected underlying pathways and mechanisms. Here I dissect, over disease progression, the relative causal contribution to health impairments in PD patients of dysfunctions in the different components of the neural network governing circadian rhythms. A deeper understanding of these mechanisms will provide not only a greater understanding of disease neuropathology, but also hold the promise for effective therapies. © 2016 International Parkinson and Movement Disorder Society.

Effect of peripheral circadian dysfunction on metabolic disease in response to a diabetogenic diet.

BMAL1 is a core component of the transcription/translation machinery that regulates central and peripheral circadian rhythms that coordinate behavior and metabolism, respectively. Our objective was to determine the impact of BMAL1 in adipose alone or in combination with liver on metabolic phenotypes. Control, adipose-Bmal1 knockout (ABKO), and liver- and adipose-Bmal1 knockout (LABKO) female mice were placed in TSE System metabolic chambers for metabolic phenotyping. A second cohort of male mice was fed a control or diabetogenic diet, and body weight and composition, glucose tolerance, insulin sensitivity, and serum and hepatic lipids were measured. Both female ABKO and LABKO mice exhibited increased food consumption compared with control mice. ABKO mice also exhibited increased overall activity predominantly during the light phase compared with both control and LABKO mice and were protected from increased weight gain. When the male cohort was challenged with a diabetogenic diet, LABKO mice had increased body weight due to increased fat mass compared with control and ABKO mice. However, these mice did not present further impairments in glycemic control, adipose inflammation, or liver injury. LABKO mice had increased hepatic cholesterol and elevated expression of cholesterol synthesis and uptake genes. Our data indicate that deletion of this allele in adipose or in combination with liver alters feeding behavior and locomotor activity. However, obesity is exacerbated only with the combination of liver and adipose deletion.

Circadian Rhythm Disruption in the Critically Ill: An Opportunity for Improving Outcomes.

OBJECTIVES: Circadian rhythms are severely disrupted among the critically ill. These circadian arrhythmias impair mentation, immunity, autonomic function, endocrine activity, hormonal signaling, and ultimately healing. In this review, we present a modern model of circadian disruption among the critically ill, discuss causes of these circadian arrhythmias, review observational and intervention studies of the effects of circadian-rhythm-restoring factors on medical outcomes, and identify needed key trials of circadian interventions in the critically ill. DATA SOURCES: MEDLINE, EMBASE, PsychINFO, Google Scholar through December 2014. STUDY SELECTION: Articles relevant to circadian rhythms, melatonin, and light in the critically ill were selected. DATA EXTRACTION AND DATA SYNTHESIS: Articles were synthesized for this review of circadian arrhythmia and the use of circadian-rhythm-restoring interventions among the critically ill. CONCLUSIONS: Circadian disruption often demonstrates serial degradation: initially, the amplitude attenuates along with delayed circadian phase. With increasing acuity of illness, circadian rhythmicity may be lost entirely. Causes of chronodisruption may be environmental or internal to the patient. In particular, inadequate daytime illumination and nocturnal light pollution disrupt healthy circadian periodicity. Internal causes of circadian arrhythmia include critical illness itself and subjective experience of distress and pain. Observational studies of windowed rooms and real-time ambient lighting have found that physiologic light-dark patterns may support recovery from critical illness. Studies of early morning bright light or evening melatonin agonists have found improved rates of delirium, enhanced sleep, and lower arrhythmia prevalence. The current evidence base emphasizes that lighting and melatoninergic interventions deserve to be tested in full-scale trials.

The ticking clock of Cayo Santiago macaques and its implications for understanding human circadian rhythm disorders.

The circadian clock disorders in humans remain poorly understood. However, their impact on the development and progression of major human conditions, from cancer to insomnia, metabolic or mental illness becomes increasingly apparent. Addressing human circadian disorders in animal models is, in part, complicated by inverse temporal relationship between the core clock and specific physiological or behavioral processes in diurnal and nocturnal animals. Major advantages of a macaque model for translational circadian research, as a diurnal vertebrate phylogenetically close to humans, are further emphasized by the discovery of the first familial circadian disorder in non-human primates among the rhesus monkeys originating from Cayo Santiago. The remarkable similarity of their pathological phenotypes to human Delayed Sleep Phase Disorder (DSPD), high penetrance of the disorder within one branch of the colony and the large number of animals available provide outstanding opportunities for studying the mechanisms of circadian disorders, their impact on other pathological conditions, and for the development of novel and effective treatment strategies.

[Temporal order deterioration and circadian disruption with age. 2. Systemic mechanisms and correction].

Part 2 of the present review highlights the impact of aging on mechanisms involved in response of the circadian system to different photic and non-photic factors, especially zeitgebers. Promising strategies to prevent age-dependent circadian disruption using internal and external factors that may entrain circadian rhythms are presented. In particular, benefits of bright light, melatonin and other chronobiotics, the circadian body temperature rhythm, physical activity and regular feeding schedules to preserve the temporal order of aged organisms are discussed, emphasizing especially a personalized approach based on the assessment of individual overt rhythms parameters.