Circadian Dysfunction Research Articles

The Use of an Amyloid beta Intracerebroventricular Model to Investigate the Interaction between Alzheimer‘s Disease and Circadian Dysfunction

The Use of an Amyloid beta Intracerebroventricular Model to Investigate the Interaction between Alzheimer‘s Disease and Circadian Dysfunction

Memory and learning for sleep and circadian treatment in serious mental illness treated in a community mental health setting

ObjectiveExisting research has demonstrated that patient memory and learning of treatment contents are poor and poorer learning is associated with worse treatment outcome. Most prior studies have included individuals from only a single diagnostic group, offer limited data on possible contributors to poor memory and learning, and have included small samples recruited in university settings. This study sought to describe patient recall of treatment contents, describe patient learning of treatment contents, examine contributors to patient recall and learning of treatment contents, and examine the association of patient recall and learning of treatment contents with treatment outcome. MethodsAdults with serious mental illness and sleep and circadian dysfunction (N = 99) received the Transdiagnostic Intervention for Sleep and Circadian Dysfunction in a community mental health setting. Measures of recall, learning, age, years of education, symptom severity, and treatment outcome were collected at post-treatment and 6-month follow-up. ResultsRecall and learning were poor, fewer years of education was associated with worse recall and learning, and recall and learning were not associated with treatment outcome. ConclusionsThe findings offer evidence that poor patient memory for, and learning of, treatment contents extends to community settings and are transdiagnostic concerns.

Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer’s disease and longevity in an Italian population

Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

Association of Night Shift Work With Chronic Spontaneous Urticaria and Effect Modification by Circadian Dysfunction Among Workers.

Purpose: Night shift work is common in the current working environment and is a risk factor for many diseases. The study aimed to explore the relationship between night shift work with chronic spontaneous urticaria (CSU), and the modification effect of circadian dysfunction on it.Methods: A cross-sectional survey was conducted among Chinese workers. Exposure was measured by night work history and duration. Circadian dysfunction was characterized by excessive daytime sleepiness (EDS). The diagnosis of CSU was made by dermatologists who were investigating on the spot. The effect size was expressed as odds ratios (ORs).Results: A total of 8,057 participants were recruited, and 7,411 (92%) with complete information were included in the final analyses. The prevalence rates of CSU for workers without night shift and those with night shift history were 0.73 and 1.28%, respectively. Compared with workers who never worked night shifts, the risk of CSU increased with the length of night shift work: OR = 1.55 (95% confidence interval [CI]: 0.78–3.06) for duration <5 years and OR = 1.91 (95% CI: 1.12–3.26) for duration ≥5 years. EDS s EDS has been shown to modify this combination. Among workers without EDS, there was no association between night shift and CSU (OR = 0.94; 95% CI: 0.49–1.79). Whereas, in participants with EDS, the correlation was significant (OR = 3.58; 95% CI: 1.14–11.20). However, the effect modification by sleep disturbance was not observed.Conclusions: Night shift work is a risk factor for CSU, and there is a dose-response relationship between night shift work hours and the risk of CSU. This connection may be modified by circadian dysfunction.

Identifying pathways to early-onset metabolic dysfunction, insulin resistance and inflammation in young adult inpatients with emerging affective and major mood disorders.

Young people with common mood disorders face the prospect of shortened life expectancy largely due to premature cardiovascular disease. Metabolic dysfunction is a risk factor for premature cardiovascular disease. There is an ongoing debate whether metabolic dysfunction can be simply explained by weight gain secondary to psychotropic medications or whether shared genetic vulnerability, intrinsic immune-metabolic disturbances or other system perturbations (e.g. dysregulated sympathetic nervous system, circadian dysfunction) are more relevant determinants of premature cardiovascular disease. Thus, we aimed to investigate underlying drivers of metabolic dysfunction and premature cardiovascular disease in young people in the early phases of common mood disorders. We evaluated the relationships between insulin resistance (assessed by HOMA2-IR) and body mass index (BMI), sex, diagnosis, medication, inflammatory markers and hormonal factors in 327 inpatients with emerging affective and major mood disorders admitted to the Young Adult Mental Health Unit, St Vincent's Private Hospital, Sydney. While HOMA2-IR scores were positively associated with BMI (rs =0.465, p < .001), they were also higher in those prescribed mood stabilizers (p=.044) but were not associated with specific diagnoses, other medication types or the number of prescribed medications. Further, high-sensitivity C-reactive protein levels (but not thyroid-stimulating hormone and ferritin levels) were positively associated with HOMA2-IR (rs =0. 272, p < .001) and BMI (rs =. 409, p < .001). In addition to BMI, other non-specific markers of inflammation are associated with early metabolic dysfunction in young people with emerging affective and major mood disorders.

Multimodal evaluation of the melanopsin retinal ganglion cells system in relation to circadian rhythms in Alzheimer’s disease and aging

AbstractBackgroundMelanopsin retinal ganglion cells (mRGCs) are deputed to circadian photoentrainment and pupillary light reflex (PLR) regulations. Circadian dysfunction is reported in Alzheimer’s disease (AD) and contributes to dementia. Single‐Nucleotide‐Polymorphisms (SNPs) in clock genes have been associated to AD.MethodWe included 29 mild‐moderate AD and 26 matched controls performing neuroophthalmological evaluation including optical coherence tomography (OCT), actigraphic recordings of rest‐activity rhythms, chromatic pupillometry and brain functional MRI (fMRI) with light stimulation. 84 clock genes were analyzed by NGS and relevant SNPs validated in a larger cohort of AD (n=449) and controls (n=326).ResultIn AD disease duration was 3.9±2.8 years and MMSEc score 20.2±4.2. OCT showed a significant reduction of the infero‐temporal GCL thickness (p=0.036) in AD. Actigraphy did not disclose significant differences for circadian parameters (IS, IV, RA). However, a subgroup of “circadian‐impaired” AD was evident, and most of circadian parameters declined with aging. Pupillometry revealed a significant reduction of PLR peak amplitude in the rod protocol (p=0.006) significantly correlating with aging in AD. Brain fMRI documented the absence of significant responses in AD with sustained blue light stimulation at difference with controls. Genetic analysis in extended AD and control cohorts showed a significant association of the rs30127178 SNP in PER1 gene with AD.ConclusionThese results demonstrate, by innovative multi‐modal approach, that mRGC system in AD is affected by neurodegeneration. This can be envisaged as a possible biomarker also for conversion from MCI to AD with potential implication for light therapy as a counteracting measure for dementia.

A time-restricted feeding intervention reduces alterations in circadian behaviors and pathology in a mouse model of Alzheimer's disease.

Circadian rhythm disruptions impact nearly all Alzheimer's disease (AD) patients, with daytime sleepiness, sundowning, sleep fragmentation, and night-time insomnia being common disturbances. These early and progressive declines support the role of circadian dysfunction as a driver of AD pathology, hence the therapeutic potential of circadian-modulating interventions needs to be investigated. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. We have recently shown that early, presymptomatic time-restricted feeding (TRF) can ameliorate a range of symptoms related to neurodegenerative conditions, including improving sleep/wake timing and circadian rhythmicity. At 12 months of age, the APP23 mouse model of AD (expressing the human APP gene containing the Swedish mutation) exhibits disrupted behavior resembling sundowning. We hypothesized that imposing early-age TRF in APP23 mice would improve circadian rhythmicity and deter the disruptions observed to emerge and progress with advancing neuropathology. Adult male and female APP23 transgenic (AD) and littermate non-transgenic (control) mice were housed individually and subjected to ab libitum (ALF) feeding or a TRF protocol consisting of 6-hours feeding in the middle of the active phase followed by 18-hours fasting for 3 months. Behavioral sleep (48 hours) and ongoing cage locomotor activity were recorded from an early age. Our analysis shows that AD mice exhibit disruptions in total sleep (P < 0.001) and the emergence of excessive wakefulness (P < 0.001). AD mice also show significant active-phase agitation (P < 0.05) accompanied by excessive sleep-phase fragmentation (P < 0.05). TRF induced nutritional ketosis (β-Hydroxybutyrate > 0.5 mM) accompanied by reduced blood glucose when compared to ALF mice, although mice consumed equivalent volumes of food in both experimental groups. Importantly, TRF improved total and sleep-phase sleep in AD mice (P < 0.05) and significantly reduced agitation and fragmentation (P < 0.05). Early application of TRF can forestall circadian disruptions in AD mice. TRF has been reported to modulate expression of clock and clock-controlled genes, transcriptional regulators, metabolism related genes, BDNF, and other neurotrophic factors. Our results suggest that these changes may also impact sleep, circadian behaviors, and agitation associated with AD.

Multimodal evaluation of the melanopsin retinal ganglion cells system in relation to circadian rhythms in Alzheimer's disease and aging

Melanopsin retinal ganglion cells (mRGCs) are deputed to circadian photoentrainment and pupillary light reflex (PLR) regulations. Circadian dysfunction is reported in Alzheimer's disease (AD) and contributes to dementia. Single-Nucleotide-Polymorphisms (SNPs) in clock genes have been associated to AD.

The systolic to diastolic pressure ratio in non-dipping essential hypertension patients

Nocturnal blood-pressure (BP) decline or dipping is a physiological response in healthy BP-regulation; the lack of this adaptation is frequently observed in patients with essential hypertension (EH) [Chesebro,2020]. Involvement of autonomic dysregulation in EH may result in adrenergic overdrive [Mancia and Grassi,2014; Carthy, 2014]. Heart morphology [Henein, 2011] and systolic to diastolic pressure ratio (SDPR) were previously related to the harmony of the so-called golden ratio (GR = 1.618) [Yetkin, 2015]. We aimed here to identify patterns of circadian dysfunction in newly diagnosed patients with EH compared to individuals with normotensive individuals (NIs) by monitoring them with a non-invasive ambulatory blood pressure monitoring (ABPM) system and evaluating their SDPR.

Barriers and Facilitators to Behavior Change for Individuals with Severe Mental Illness who Received the Transdiagnostic Intervention for Sleep and Circadian Dysfunction in a Community Mental Health Setting.

The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) was implemented in a community mental health center (CMHC) setting. The goal of TranS-C is to improve sleep and circadian dysfunction among people with severe mental illness. The present study uses the Theoretical Domains Framework (TDF) to uncover barriers and facilitators to changing behaviors learned in TranS-C. Adults with severe mental illness who completed TranS-C (n = 14) were given a semi-structured interview based on the TDF. Interview transcripts were independently coded using inductive and deductive coding. The most commonly coded TDF domains were Behavior Regulation, Beliefs about Consequences, Knowledge and Beliefs about Capabilities. Action planning was the most discussed facilitator and compromising sleep health in favor of time spent with loved ones was the most discussed barrier. These findings suggest that TranS-C has promising strengths and raise important barriers that can be addressed in TranS-C to improve its fit within CMHCs.

Predictive value of early amplitude integrated electroencephalogram (aEEG) in sleep related problems in children with perinatal hypoxic-ischemia (HIE)

BackgroundWhile great attention has been paid to motor and cognitive impairments in children with neonatal Hypoxic-Ischemic Encephalopathy (HIE), sleep related circadian rhythm problems, although commonly present, are often neglected. Subsequently, no early clinical indicators have been reported to correlate with sleep-related circadian dysfunction during development.MethodsIn this study, we first analyzed patterns of the amplitude integrated electroencephalogram (aEEG) in a cohort of newborns with various degrees of HIE. Next, during follow-ups, we collected information of sleep and circadian related problems in these patients and performed correlation analysis between aEEG parameters and different sleep/circadian disorders.ResultsA total of 101 neonates were included. Our results demonstrated that abnormal aEEG background pattern is significantly correlated with circadian rhythmic (r = 0.289, P = 0.01) and breathing issues during sleep (r = 0.237, P = 0.037). In contrast, the establishment of sleep–wake cycle (SWC) showed no correlation with sleep/circadian problems. Detailed analysis showed that summation of aEEG score, along with low base voltage (r = 0.272, P = 0.017 and r = -0.228, P = 0.048, respectively), correlates with sleep circadian problems. In contrast, background pattern (BP) score highly correlates with sleep breathing problem (r = 0.319, P = 0.004).ConclusionAbnormal neonatal aEEG pattern is correlated with circadian related sleep problems. Our study thus provides novel insights into predictive values of aEEG in sleep-related circadian problems in children with HIE.

The promising oncostatic effects of melatonin against ovarian cancer

Melatonin is a pineal hormone, secreted at the subjective night. It is involved in the regulation of many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. Melatonin acts through cell surface receptors (MT1 and MT2) as well as nuclear receptors. Circadian dysfunction can alter the secretion of melatonin. Inappropriate melatonin level promotes the initiation of many pathologies including cancer. Ovarian cancer is a common form of gynecological disease. Several studies indicate the profound link between impaired melatonin secretion and the progression of ovarian cancer. Melatonin exerts oncostatic effects in multiple ways; it acts as a potent antioxidant, induces apoptosis, and regulates metabolism, and chronic inflammatory response in ovarian cancer cells. Moreover, melatonin improves the efficacy of the current treatment regimen of ovarian cancer and can be used as an adjuvant.

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.

Outcomes of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) in a community setting: Unpacking comorbidity

ObjectiveComorbidity and subdiagnostic symptoms are understudied for sleep and circadian problems. We evaluated 1) impairment associated with (a) number of sleep and circadian problems and (b) diagnostic threshold (full diagnosis vs. subdiagnostic symptoms), and 2) Transdiagnostic Sleep and Circadian Intervention (TranS-C) outcomes for participants with specific sleep and circadian problems. MethodCommunity participants (N = 121) with serious mental illness and sleep and circadian problem(s) were randomized to receive TranS-C plus usual care (TranS-C + UC) or usual care plus delayed TranS-C (UC-DT). Overall impairment, psychiatric symptoms, and sleep and circadian dysfunction were assessed at pre-treatment, post-treatment, and 6-month follow-up. ResultsHigher numbers of sleep and circadian problems, versus one problem, were associated with worse overall impairment, psychiatric symptoms, and sleep and circadian dysfunction (ps < 0.05, ω2 = 0.06–0.15). Diagnostic threshold was not associated with baseline functioning (ps > 0.05). TranS-C + UC versus UC-DT was associated with psychosocial and sleep and circadian improvements for specific sleep and circadian problems (insomnia, hypersomnia, parasomnias, periodic limb movement/restless leg syndrome, circadian rhythm disorders), though improvements varied by problem. TranS-C + UC outcomes were not moderated by number of sleep and circadian problems (ps > 0.05). ConclusionHigher numbers of sleep and circadian problems, not diagnostic threshold, were associated with greater impairment. Transdiagnostic utility of TranS-C + UC was supported.

Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients.

To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. Emens JS, St Hilaire MA, Klerman EB, etal. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.

Analyzing potential correlations between light exposure and skin temperature in a climate chamber

Interactions between occupants and buildings are mediated by physiological and psychological stimuli, which may interfere in the perception of environmental variables. Among these variables, recent studies have shown that daylight may play a relevant role both in terms of light and thermal perception of the built environment, as well as in complex physiological mechanisms not directly related to vision. These include secretion of hormones linked to the regulation of sleep-wake cycles and body thermal homeostasis. The study aimed to explore relationships between light-related variables as colour and intensity and changes in skin temperature (Tsk) of male subjects (n = 16) in a thermally controlled environment with varying light exposure conditions (dynamic light versus static electric light). Tsk during the morning hours was found to be significantly related to daylight availability. Results suggest that the suppression of the variability of brightness and correlated colour temperature (CCT) encountered in natural light can affect the rate of Tsk variation and lead to possible circadian dysfunctions.

Expression of autophagy related genes in peripheral blood cells in Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and affects dopaminergic neurons. Autophagy often shows a circadian rhythm pattern under physiological conditions across 24 h. Abnormal autophagy and circadian dysfunction are two characteristics of PD. Whether the rhythm of autophagy is altered in PD has not yet been reported. Therefore, in this study, we collected peripheral blood samples at 6:00 h and 18:00 h from PD patients and age-matched controls, and analyzed the mRNA expressions of ULK1, BECN1, LAMP2, AMPK, and SNCA using real-time quantitative PCR. Blood samples analysis found that BECN1 and LAMP2 levels were decreased in patients with PD. Simultaneously, the rhythm of autophagy in PD is not consistent with that in the Control group, which may be a manifestation of the abnormal biological rhythm of PD.

Abstract 644: Tumor circadian dysfunction is associated with improved survival in breast cancer patients on neoadjuvant chemotherapy (NAC)

Abstract Introduction Previous studies highlighted the relevance of circadian rhythms for carcinogenesis and therapy in breast cancer. These rhythms are generated in each cell by a molecular clock. We have developed a machine-learning approach (TimeTeller) and constructed an algorithm to measuring circadian clock functionality from the expression levels of clock genes in a single tissue sample (Vlachou et al. Rxiv 2020). Methods TimeTeller was used to analyse tumor molecular clock dysfunction in biopsies from 226 breast cancer patients prior to NAC. Tumour transcriptome was determined using the Affymetrix U133A (Giacchetti et al. EJC 2017). A measure Θ of the level of dysfunction of the cellular clock was computed using TimeTeller, based on the relative mRNA expressions of 16 clock genes, which displayed largest circadian expressions in healthy mouse and human tissues sampled at &amp;gt; 6 circadian times. Thus Θ &amp;lt; 0.1 was indicative of a functional clock in humans irrespective of sampling time. To determine the prognostic value of continuous Θ for breast cancer patients'survival at ten years, we calculated the hazard ratios (HRs) associated with overall survival (OS) and disease-free survival (DFS) of the 226 patients receiving NAC, using the Cox proportional hazards model. HR1/10 corresponded to the risk of an earlier death or relapse for a change of 0.1 in Θ. Results: The breast cancer Θ values ranged from 0.02 to 0.29, with a median of 0.058 [IQR, 0.09]. As compared to patients whose tumor Θ was &amp;lt; median, patients with tumor Θ&amp;gt;median had higher survival rate (71% vs 81%, p = 0.01) and DFS rate, 65% vs 74%, p = 0.02) at 10-years. Multivariate analyses identified continuous Θ as an independent prognostic factor for both OS (HR1/10, 0.38 [0.17-0.84] (p = 0.016) and DFS (HR1/10, 0.46 [0.27-0.80] (p = 0.005), jointly with tumor size for OS (HR1/10, 1.73 [1.12-2.70], p =0.014) and HER2 for DFS (HR1/10, 0.43 [0.23-0.79], p = 0.007). The relevance of Θ was further explored in the three main breast cancer categories. In the HER2+ subset, the HR associated with Θ was 0.19 for OS (p=0.058) and 0.22 for DFS (p=0.048, single significant prognostic factor). The HR1/10 increased to 0.45 for OS and 0.57 for DFS in the HER2-/hormonal receptors + subset, and to 0.45 and 0.46 respectively for the TN group (p&amp;gt;0.10), suggesting a lesser independent prognostic effect of Θ in these subsets. The patients who achieved pCR had a higher median Θ as compared to those who did not (p = 0.035), supporting increased chemosensitivity of those tumors with clock dysfunction to conventional NAC Conclusion: In this population of women on NAC for primary breast cancer, tumor circadian clock dysfunction, as computed by the TimeTeller algorithm, was the strongest independent predictor of survival. Thus, conventional chemotherapy efficacy may be enhanced in tumors with deregulated metabolism and proliferation, as a result of circadian clock dysfunction. Citation Format: Sylvie Giacchetti, Denise Vlachou, Georg A. Bjarnason, David A. Rand, Francis A. Levi. Tumor circadian dysfunction is associated with improved survival in breast cancer patients on neoadjuvant chemotherapy (NAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 644.

Molecular clock REV-ERBα regulates cigarette smoke-induced pulmonary inflammation and epithelial-mesenchymal transition.

Cigarette smoke (CS) is the main etiological factor in the pathogenesis of emphysema/chronic obstructive pulmonary disease (COPD), which is associated with abnormal epithelial-mesenchymal transition (EMT). Previously, we have shown an association among circadian rhythms, CS-induced lung inflammation, and nuclear heme receptor α (REV-ERBα), acting as an antiinflammatory target in both pulmonary epithelial cells and fibroblasts. We hypothesized that molecular clock REV-ERBα plays an important role in CS-induced circadian dysfunction and EMT alteration. C57BL/6J WT and REV-ERBα heterozygous (Het) and –KO mice were exposed to CS for 30 days (subchronic) and 4 months (chronic), and WT mice were exposed to CS for 10 days with or without REV-ERBα agonist (SR9009) administration. Subchronic/chronic CS exposure caused circadian disruption and dysregulated EMT in the lungs of WT and REV-ERBα–KO mice; both circadian and EMT dysregulation were exaggerated in the REV-ERBα–KO condition. REV-ERBα agonist, SR9009 treatment reduced acute CS-induced inflammatory response and abnormal EMT in the lungs. Moreover, REV-ERBα agonist (GSK4112) inhibited TGF-β/CS–induced fibroblast differentiation in human fetal lung fibroblast 1 (HFL-1). Thus, CS-induced circadian gene alterations and EMT activation are mediated through a Rev-erbα–dependent mechanism, which suggests activation of REV-ERBα as a novel therapeutic approach for smoking-induced chronic inflammatory lung diseases.

The regulatory mechanisms of behavioral and cognitive aging.

With the increase of life expectancy, the world's population is aging rapidly. Previous work in the field of aging greatly increases our understanding of biological mechanisms underlying longevity. Researchers have unraveled a number of longevity pathways conserved from yeast to mammals. However, recent evidence shows that mechanisms regulating the life span and those regulating age-related behavioral decline could be dissociated. The regulatory mechanisms underlying behavioral and cognitive aging is largely unknown. Previous work has described a significant age-related decline in cognitive behaviors including episodic memory, working memory, processing speed, as well as motor function deterioration and circadian dysfunction. With the advance of neuroscience and technology, more and more studies have focused on the age-related changes in structure and function of the brain. In this review, we briefly describe the deterioration of cognitive function and other behaviors in the aging process, and survey the role of age-related changes in brain structure and network, neuron morphology and function, transcriptome in brain and some conserved biological pathways on age-related cognitive and behavioral decline. Further studies on the mechanisms underpinning age-related cognitive and behavioral decline may provide clues not only for improving the quality of life for the ageing population, but also for developing intervention approaches for neurodegenerative diseases.