Light pollution: time to consider testicular effects.

Technological advances have led to a modern-day lighting and smartphone revolution, with artificial light exposure at night increasing to levels never before seen in the evolutionary history of living systems on Earth. Light as a pollutant, however, remains largely unrecognized, and the reproductive effects of light pollution are mostly if not entirely unconsidered. This is despite the reproductive system being intricately linked to metabolism and the circadian system, both of which can be disturbed even by low levels of light. Here, we aim to change this perspective by reviewing the physiological and pathophysiological mechanisms by which light exposure alters the intricate hormonal, metabolic and reproductive networks that are relevant to reproductive toxicology. Nascent human studies have recently identified the photoreceptors responsible for the light dose relationship with melatonin suppression and circadian re-entrainment, directly shown the association between the alignment of light-dark cycles with activity-rest cycles on metabolic health and provided proof-of-principle that properly timed blue light-enriched and blue light-depleted delivery can accelerate circadian re-entrainment. With these advances, there is now a need to consider testicular effects of light pollution.

Effectiveness of a guided digital self-help intervention to improve sleep and the biological clock in university students - Study protocol for a randomized controlled trial.

Background: Sleep problems occur in many university students which affects their mental health and daily functioning. Cognitive behavioural therapy for insomnia (CBT-I) has been proven effective in adults but research in university students, who struggle to maintain a 24-hour rhythm, is still limited. We hypothesize that a guided digital CBT-I intervention, enriched with components on the biological clock ('i-Sleep & BioClock') will be effective in reducing insomnia severity and improving mental health outcomes for students with sleep problems. Objectives: We aim to evaluate the effectiveness of a guided online sleep and biological clock self-help intervention in improving sleep, depression symptoms, anxiety symptoms, functioning, academic performance, and quality of life in university students at 6 weeks and 18 weeks. Methods: This is a two-arm parallel-group superiority randomized controlled trial, comparing a 5-week guided online 'i-Sleep & BioClock' intervention to online psychoeducation (PE). We aim to include 192 university students (Bachelor, Master, and PhD) with at least subthreshold insomnia (Insomnia Severity Index ≥10), aged ≥16, who can speak Dutch or English. We are excluding students with current risk for suicide or night shifts. The primary outcome is insomnia severity. Secondary outcomes include sleep estimates (sleep and light exposure diary), depression, anxiety, functioning, quality of life, and academic performance. The effectiveness of the intervention compared to online PE will be evaluated using linear mixed models. Discussion: The current study tests the effectiveness of an online self-help intervention for university students who suffer from sleep problems. This trial builds upon an open feasibility study and will provide evidence of an online guided self-help program for students. The findings of this study will determine the potential wider dissemination of the intervention to address the high need for available and accessible help for students experiencing insomnia. Trial registration: ClinicalTrials.Gov (NCT06023693), registered on August 3rd, 2023.

Salivary DNA methylation derived estimates of biological aging, cellular frequency and protein expression as predictors of oral mucositis severity and survival in head and neck cancer patients.

BACKGROUND: Oral mucositis is a painful and debilitating condition that occurs in the majority of head and neck cancer patients receiving radiation and/or chemotherapy. While some patient and treatment related factors are known to contribute to the incidence and severity of disease, reliable biomarkers remain elusive. In the following study, we investigated the association of salivary DNA methylation derived biological aging, cellular frequency and protein concentration measures with the severity of oral mucositis and overall survival in a cohort of head and neck cancer (HNC) patients (n = 103). METHODS: DNA methylation profiling was performed on saliva samples obtained prior to treatment. Biological aging measures included Horvath2, PhenoAge, FitAge and GrimAge, and cellular frequency included epithelial and specific immune cell populations. RESULTS: Severe mucositis (i.e. grade 3 or 4) occurred in nearly half of patients. For malignant HNC patients (n = 84), every 1-SD increase in GrimAge was associated with 2.62-times risk of severe mucositis (95 % CI: 1.38, 5.57), while a 1-SD increase in monocyte frequency was associated with a decreased risk (OR [95 %CI]: 0.40 [0.18, 0.80]). Over a median follow-up of 53 months, 39 of 103 participants died. Six protein scores (TNFSF14, GCSF, MATN3, GDF8, nCDase, TNF-ß) were associated with survival at q < 0.15. CONCLUSION: We provide evidence that the risk-related biological aging measure GrimAge may be a useful predictor of mucositis severity in HNC patients. Salivary monocyte frequency may be protective against mucositis, and this measure could be used as a predictive biomarker while also providing clues into the pathobiology of the disease.

Identification of circadian clock-related immunological prognostic index and molecular subtypes in prostate cancer.

BACKGROUND: Evidence suggests that the circadian clock (CIC) is among the important factors for tumorigenesis. We aimed to provide new insights into CIC-mediated molecular subtypes and gene prognostic indexes for prostate cancer (PCa) patients undergoing radical prostatectomy (RP) or radical radiotherapy (RT). METHODS: PCa data from TCGA was analyzed to identify differentially expressed genes (DEGs) with significant fold changes and p-values. A prognostic index called CIC-related gene prognostic index (CICGPI) was developed through clustering methods and survival analysis and validated on multiple data sets. The diagnostic accuracy of CICGPI for resistance to chemotherapy and radiotherapy was confirmed. Additionally, the interaction between tumor immune environment and CICGPI score was explored, along with their correlation with prognosis. RESULTS: TOP2A, APOE, and ALDH2 were used to classify the PCa patients into two subtypes. Cluster 2 had a higher risk of biochemical recurrence (BCR) than cluster 1 for PCa patients undergoing RP or RT. A CIC-related gene prognostic index (CICGPI) was constructed using the above three genes for PCa patents in the TCGA database. The CICGPI score showed good prognostic value in the TCGA database and was externally confirmed by PCa patients in GSE116918, MSKCC2010 and GSE46602. In addition, the CICGPI score had a certain and high diagnostic accuracy for tumor chemoresistance (AUC: 0.781) and radioresistance (AUC: 0.988). For gene set variation analysis, we observed that both beta alanine metabolism and limonene and pinene degradation were upregulated in cluster 1 for PCa patients undergoing RP or RT. For PCa patients undergoing RP, cell cycle, homologous recombination, mismatch repair, and DNA replication were upregulated in cluster 2. A strongly positive relationship between cancer-related fibroblasts and CICGPI score was observed in PCa patients undergoing RP or RT. Moreover, a high density of CAFs was highly closely associated with poorer BCR-free survival of PCa patients. CONCLUSIONS: In this study, we established CIC-related immunological prognostic index and molecular subtypes, which might be useful for the clinical practice.

Digital Clock and Recall: a digital, process-driven evolution of the Mini-Cog.

Introduction: Alzheimer's disease and related dementias (ADRD) represent a substantial global public health challenge with multifaceted impacts on individuals, families, and healthcare systems. Brief cognitive screening tools such as the Mini-Cog© can help improve recognition of ADRD in clinical practice, but widespread adoption continues to lag. We compared the Digital Clock and Recall (DCR), a next-generation process-driven adaptation of the Mini-Cog, with the original paper-and-pencil version in a well-characterized clinical trial sample. Methods: DCR was administered to 828 participants in the Bio-Hermes-001 clinical trial (age median ± SD = 72 ± 6.7, IQR = 11; 58% female) independently classified as cognitively unimpaired (n = 364) or as having mild cognitive impairment (MCI, n = 274) or dementia likely due to AD (DLAD, n = 190). MCI and DLAD cohorts were combined into a single impaired group for analysis. Two experienced neuropsychologists rated verbal recall accuracy and digitally drawn clocks using the original Mini-Cog scoring rules. Inter-rater reliability of Mini-Cog scores was computed for a subset of the data (n = 508) and concordance between Mini-Cog rule-based and DCR scoring was calculated. Results: Inter-rater reliability of Mini-Cog scoring was good to excellent, but Rater 2's scores were significantly higher than Rater 1's due to variation in clock scores (p < 0.0001). Mini-Cog and DCR scores were significantly correlated (τ B = 0.71, p < 0.0001). However, using a Mini-Cog cut score of 4, the DCR identified more cases of cognitive impairment (n = 47; χ 2 = 13.26, p < 0.0005) and Mini-Cog missed significantly more cases of cognitive impairment (n = 87). In addition, the DCR correctly classified significantly more cognitively impaired cases missed by the Mini-Cog (n = 44) than vice versa (n = 4; χ 2 = 21.69, p < 0.0001). Discussion: Our findings demonstrate higher sensitivity of the DCR, an automated, process-driven, and process-based digital adaptation of the Mini-Cog. Digital metrics capture clock drawing dynamics and increase detection of diagnosed cognitive impairment in a clinical trial cohort of older individuals.

Knockdown of the Clock gene in the liver aggravates MASLD in mice via inhibiting lipophagy.

The increased global prevalence of metabolic dysfunction-associated steatohepatitis (MASLD) has been closely associated with chronic disorders of the circadian clock. Herein, we investigate the role of Clock, a core circadian gene, in the pathogenesis of MASLD. Wild-type (WT) and liver-specific Clock knockdown (Clock-KD) mice were fed a Western diet for 20 weeks to induce MASLD. A cellular MASLD model was established by treating AML12 cells with free fatty acids and the effects of Clock knockdown were examined following transfection with Clock siRNA. Increased lipid deposition and more severe steatohepatitis and fibrosis were observed in the livers of Western diet-fed but not normal chow diet-fed Clock-KD mice after 20 weeks compared to WT mice. Moreover, the Clock gene was found to be significantly downregulated in WT MASLD mice. The Clock gene was shown to regulate the expression of lipophagy-related proteins (LC3B, P62, RAB7, and PLIN2) in vivo and in vitro. Knockdown of Clock was found to inhibit lipophagy resulting in increased accumulation of lipid droplets in the mouse liver and AML12 cells. Interestingly, the CLOCK protein was shown to interact with P62. However, knockdown of the Clock gene did not promote transcription of the P62 gene but suppressed degradation of the P62 protein during lipophagy in AML12 cells. The hepatic Clock gene regulates lipophagy and affects lipid droplet deposition in liver cells, and thus plays a critical role in the development of MASLD induced by a Western diet.

Uncertainty quantification in epigenetic clocks via conformalized quantile regression.

DNA methylation (DNAm) is a chemical modification of DNA that can be influenced by various factors, including age, environment, and lifestyle. An epigenetic clock is a predictive tool that measures biological age based on DNAm levels. It can provide insights into an individual's biological age, which may differ from their chronological age. This difference, known as the epigenetic age acceleration, may indicate the state of one's health and risk for age-related diseases. Moreover, epigenetic clocks are used in studies of aging to assess the effectiveness of anti-aging interventions and to understand the underlying mechanisms of aging and disease. Various epigenetic clocks have been developed using samples from different populations, tissues, and cell types, typically by training high-dimensional linear regression models with an elastic net penalty. While these models can predict mean biological age with high precision, there is a lack of uncertainty quantification which is important for interpreting the precision of age estimations and for clinical decision-making. To understand the distribution of a biological age clock beyond its mean, we propose a general pipeline for training epigenetic clocks, based on an integration of high-dimensional quantile regression and conformal prediction, to effectively reveal population heterogeneity and construct prediction intervals. Our approach produces adaptive prediction intervals not only achieving nominal coverage but also accounting for the inherent variability across individuals. By using the data collected from 728 blood samples in 11 DNAm datasets from children, we find that our quantile regression-based prediction intervals are narrower than those derived from conventional mean regression-based epigenetic clocks. This observation demonstrates an improved statistical efficiency over the existing pipeline for training epigenetic clocks. In addition, the resulting intervals have a synchronized varying pattern to age acceleration, effectively revealing cellular evolutionary heterogeneity in age patterns in different developmental stages during individual childhoods and adolescent cohort. Our findings suggest that conformalized high-dimensional quantile regression can produce valid prediction intervals and uncover underlying population heterogeneity. Although our methodology focuses on the distribution of aging in children, it is applicable to a broader range of populations to improve understanding of epigenetic age beyond the mean. This inference-based toolbox could provide valuable insights for future applications of epigenetic interventions for age-related diseases.

Quantifying the Transition from Unconscious to Conscious Detection of Temporal Patterns in Vigilance Tasks: A Unique Adaptation of Mackworth's Clock Test.

This study investigates the cognitive mechanisms underlying vigilance and pattern recognition using a novel adaptation of Mackworth's Clock Test. We aimed to quantify the time it takes for temporal patterns detected unconsciously through implicit learning to surface in the conscious mind within a dynamic vigilance task environment. Forty-eight participants detected random and non-disclosed rhythmic anomalous clock hand movements in this setting. Our results indicate significant variability in detection accuracy, reaction times, and the ability to recognize the hidden pattern among participants. Notably, 23% of all participants and 56% of those who consciously reported the pattern exhibited statistically lower reaction times indicative of knowledge of the pattern 40 s before conscious identification. These findings provide valuable insights into the transition from unconscious to conscious detection, highlighting the complexity of sustained attention and pattern recognition. The study's implications extend to designing training programs and tasks for high-stakes professions requiring prolonged vigilance. Future research should further explore the cognitive and neural correlates of these processes and the impact of task complexity on performance.

Analysis of Circadian Clock Gene Expression in Human Skin Explants.

Many aspects of skin biochemistry and physiology are known to vary over the course of the 24-hour day. Traditional approaches to study circadian rhythms in the skin have employed rodents or human subjects, which limit the experimental variables that can be studied. Although explants derived from discarded surgical skin are a commonly used model in the skin biology field, circadian rhythms have yet to be examined ex vivo. In this study, using human panniculectomy skin, we used RT-qPCR to monitor the epidermal expression of 4 core circadian clock genes over the course of 1 day ex vivo. Although significant interindividual variability in overall gene expression profiles was observed, robust circadian oscillations were observed in many of the genes and individual explants. Comparison of our gene expression data with microarray data from 2 previous human-subject studies involving primarily young adult White males revealed both similarities and differences, including greater distribution in the time of day of peak expression in the skin explants. This increased variability appears to be due in part to the increased age and altered sex distribution of the donated skin. Nonetheless, our results indicate that skin explants offer an additional experimental system for studying circadian skin biology.

Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity.

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.

Newborn DNA methylation age differentiates long-term weight trajectories: the Boston Birth Cohort.

BACKGROUND: Gestational age (GEAA) estimated by newborn DNA methylation (GAmAge) is associated with maternal prenatal exposures and immediate birth outcomes. However, the association of GAmAge with long-term overweight or obesity (OWO) trajectories is yet to be determined. METHODS: GAmAge was calculated for 831 children from a US predominantly urban, low-income, multi-ethnic birth cohort based on cord blood DNA methylation profile using Illumina EPIC array. Repeated anthropometric measurements aligned with pediatric primary care schedule allowed us to calculate body-mass-index percentiles (BMIPCT) at specific age and to define long-term weight trajectories from birth to 18 years. RESULTS: GAmAge was associated with BMIPCT trajectories, defined by 4 groups: stable (consistent OWO: "early OWO"; constant normal weight: "NW") or non-stable (OWO by year 1 of follow-up: "late OWO"; OWO by year 6 of follow-up: "NW to very late OWO"). GAmAge differentiated between the group with consistently normal BMIPCT pattern and the non-stable groups with late and very late OWO development. Such differentiation was observed in the age periods of birth to 1year, 3years, 6years, 10years, and 14years (p < 0.05 for all). The findings persisted after adjusting for GEAA, maternal smoking, delivery method, and child's sex in multivariate models. Birth weight was a mediator for the GAmAge effect on OWO status for specific groups at multiple age periods. CONCLUSIONS: GAmAge is associated with BMIPCT trajectories from birth to age 18 years, independent of GEAA and birth weight. If further confirmed, GAmAge may serve as an early biomarker for predicting BMI trajectory to inform early risk assessment and prevention of OWO. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03228875).

[Mechanism of berberine in improving adipocytic IR by mediating BMAL1:CLOCK complex and regulating glucose and lipid metabolism].

To explore the action mechanism of berberine in improving adipocytic insulin resistance(IR) by mediating brain and muscle arnt-like 1(BMAL1): circadian locomotor output cycles kaput(CLOCK) complex and regulating glucose and lipid metabolism. After the IR-3T3-L1 adipocyte model was established by dexamethasone induction for 96 h, 0.5, 1, 5, 10, and 20 µmol·L~(-1) berberine was administered for 24 h. The glucose oxidase method and cell counting kit-8(CCK-8) were used to detect extracellular glucose content and cell viability, respectively. The triglyceride(TG) and glycerol contents were detected by enzyme colorimetry. Oil red O staining was used to detect lipid droplets, and fluorescence staining was used to detect Ca~(2+), mitochondrial structure, and reactive oxygen species(ROS). Adiponectin(ADPN), BMAL1, CLOCK, hormone-sensitive triglyceride lipase(HSL), carbohydrate-response element-binding protein(ChREBP), sterol regulatory element-binding protein 1C(SREBP-1C), peroxisome proliferator-activated receptor γ coactivator 1α(PGC1α), carnitine palmitoyl transferase 1α(CPT1α), and peroxisome proliferator-activated receptor α(PPARα) were detected by Western blot(WB). Moreover, the nuclear localization of BMAL1 was detected by immunofluorescence. In addition, 20 µmol·L~(-1) CLK8 inhibitor was added to detect glucose consumption and BMAL1/ChREBP/PPARα protein. The results showed that berberine increased glucose consumption in IR-3T3-L1 adipocytes without affecting cell viability and reduced TG content. In addition, 5 µmol·L~(-1) berberine increased glycerol content and reduced lipid droplet accumulation due to enhanced lipolysis, while 10 µmol·L~(-1) berberine did not affect glycerol content, and fewer lipid droplets were observed due to enhanced lipolysis and glycerol utilization. Berberine improved mitochondrial function by reducing intracellular Ca~(2+) and ROS in IR-3T3-L1 adipocytes and upregulated PGC1α to improve the mitochondrial structure. The results also showed that berberine elevated ADPN to increase the insulin sensitivity of IR-3T3-L1 adipocytes, upregulated peripheral rhythm-related proteins BMAL1 and CLOCK, and strengthened the nuclear localization of BMAL1. In addition, berberine increased key lipolysis protein and lipid oxidation rate-limiting enzyme CPT1α and downregulated the key protein of TG synthesis, SREBP-1C. Moreover, ChREBP and PPARα in IR-3T3-L1 adipocytes were upregula-ted. All the above results suggested that berberine may transform glucose into lipids to enhance the hypoglycemic effect. By considering that CLK8 specifically inhibited the CLOCK acylation to modify BMAL1 and form complex, the results showed that the addition of CLK8 to the berberine group reduced glucose consumption, which suggested that berberine upregulated the formation of BMAL1:CLOCK complex to improve glucose metabolism. The addition of CLK8 to the berberine group upregulated BMAL1 but downregulated ChREBP and PPARα, which suggested that berberine mediated BMAL1:CLOCK complex for the regulation of glucose and lipid metabo-lism to improve adipocytic IR.

Phylogeny and evolution of dissimilatory sulfite reduction in prokaryotes.

Sulfate is the second most common nonmetallic ion in modern oceans, as its concentration dramatically increased alongside tectonic activity and atmospheric oxidation in the Proterozoic. Microbial sulfate/sulfite metabolism, involving organic carbon or hydrogen oxidation, is linked to sulfur and carbon biogeochemical cycles. However, the coevolution of microbial sulfate/sulfite metabolism and Earth's history remains unclear. Here, we conducted a comprehensive phylogenetic analysis to explore the evolutionary history of the dissimilatory sulfite reduction (Dsr) pathway. The phylogenies of the Dsr-related genes presented similar branching patterns but also some incongruencies, indicating the complex origin and evolution of Dsr. Among these genes, dsrAB is the hallmark of sulfur-metabolizing prokaryotes. Our detailed analyses suggested that the evolution of dsrAB was shaped by vertical inheritance and multiple horizontal gene transfer events and that selection pressure varied across distinct lineages. Dated phylogenetic trees indicated that key evolutionary events of dissimilatory sulfur-metabolizing prokaryotes were related to the Great Oxygenation Event (2.4-2.0 Ga) and several geological events in the "Boring Billion" (1.8-0.8 Ga), including the fragmentation of the Columbia supercontinent (approximately 1.6 Ga), the rapid increase in marine sulfate (1.3-1.2 Ga), and the Neoproterozoic glaciation event (approximately 1.0 Ga). We also proposed that the voluminous iron formations (approximately 1.88 Ga) might have induced the metabolic innovation of iron reduction. In summary, our study provides new insights into Dsr evolution and a systematic view of the coevolution of dissimilatory sulfur-metabolizing prokaryotes and the Earth's environment.

Hypothyroidism alters the rhythmicity of the central clock, body temperature and metabolism: evidence of Bmal1 transcriptional regulation by T3.

In mammals, the central circadian oscillator is located in the suprachiasmatic nucleus (SCN). Hypothalamus-pituitary-thyroid axis components exhibit circadian oscillation, regulated by both central clock innervation and intrinsic circadian clocks in the anterior pituitary and thyroid glands. Thyroid disorders alter the rhythmicity of peripheral clocks in a tissue-dependent response; however, whether these effects are influenced by alterations in the master clock remains unknown. This study aimed to characterize the effects of hypothyroidism on the rhythmicity of SCN, body temperature (BT) and metabolism, and the possible mechanisms involved in this signalling. C57BL/6J adult male mice were divided into Control and Hypothyroid groups. Profiles of spontaneous locomotor activity (SLA), BT, oxygen consumption ( V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) and respiratory quotient (RQ) were determined under free-running conditions. Clock gene expression, and neuronal activity of the SCN and medial preoptic nucleus (MPOM) area were investigated in light-dark (LD) conditions. Triiodothyronine (T3) transcriptional regulation of Bmal1 promoter activity was evaluated in GH3-transfected cells. Hypothyroidism delayed the rhythmicity of SLA and BT, and altered the expression of core clock components in the SCN. The activity of SCN neurons and their outputs were also affected, as evidenced by the loss of circadian rhythmicity in V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ and RQ and alterations in the neuronal activity pattern of MPOM. In GH3 cells, T3 increased Bmal1 promoter activity in a time-dependent manner. Thyroid hormone may act as a temporal cue for the central circadian clock, and the uncoupling of central and peripheral clocks might contribute to a wide range of metabolic and thermoregulatory impairments observed in hypothyroidism. KEY POINTS: Hypothyroidism alters clock gene expression in the suprachiasmatic nucleus (SCN). Thyroid hypofunction alters the phase of spontaneous locomotor activity and body temperature rhythms. Thyroid hormone deficiency alters the daily pattern of SCN and medial preoptic nucleus neuronal activities. Hypothyroidism alterations are extended to daily oscillations of oxygen consumption and metabolism, which might contribute to the development of metabolic syndrome. Triiodothyronine increases Bmal1 promoter activity acting as temporal cue for the central circadian clock.

Circadian Clock and Body Temperature.

The circadian fluctuation of body temperature is one of the most prominent and stable outputs of the circadian clock and plays an important role in maintaining optimal day-night energy homeostasis. The body temperature of homothermic animals is not strictly constant, but it shows daily oscillation within a range of 1-3 °C, which is sufficient to synchronize the clocks of peripheral tissues throughout the body. The thermal entrainment mechanisms of the clock are partly mediated by the action of the heat shock transcription factor and cold-inducible RNA-binding protein-both have the ability to affect clock gene expression. Body temperature in the poikilotherms is not completely passive to the ambient temperature change; they can travel to the place of preferred temperature in a manner depending on the time of their endogenous clock. Based on this behavior-level thermoregulation, flies exhibit a clear body temperature cycle. Noticeably, flies and mice share the same molecular circuit for the controlled body temperature; in both species, the calcitonin receptors participate in the formation of body temperature rhythms during the active phase and exhibit rather specific expression in subsets of clock neurons in the brain. We summarize knowledge on mutual relationships between body temperature regulation and the circadian clock.

A mathematical model of melatonin synthesis and interactions with the circadian clock.

A new mathematical model of melatonin synthesis in pineal cells is created and connected to a slightly modified previously created model of the circadian clock in the suprachiasmatic nucleus (SCN). The SCN influences the production of melatonin by upregulating two key enzymes in the pineal. The melatonin produced enters the blood and the cerebrospinal fluid and thus the SCN, influencing the circadian clock. We show that the model of melatonin synthesis corresponds well with extant experimental data and responds similarly to clinical experiments on bright light in the middle of the night. Melatonin is widely used to treat jet lag and sleep disorders. We show how the feedback from the pineal to the SCN causes phase resetting of the circadian clock. Melatonin doses early in the evening advance the clock and doses late at night delay the clock with a dead zone in between where the phase of the clock does not change.

Exploring the potential of epigenetic clocks in aging research.

The process of aging is a notable risk factor for numerous age-related illnesses. Hence, a reliable technique for evaluating biological age or the pace of aging is crucial for understanding the aging process and its influence on the progression of disease. Epigenetic alterations are recognized as a prominent biomarker of aging, and epigenetic clocks formulated on this basis have been shown to provide precise estimations of chronological age. Extensive research has validated the effectiveness of epigenetic clocks in determining aging rates, identifying risk factors for aging, evaluating the impact of anti-aging interventions, and predicting the emergence of age-related diseases. This review provides a detailed overview of the theoretical principles underlying the development of epigenetic clocks and their utility in aging research. Furthermore, it explores the existing obstacles and possibilities linked to epigenetic clocks and proposes potential avenues for future studies in this field.

The Nutritional Status of Elderly Chinese Patients With Parkinson's Disease.

Introduction: To investigate the nutritional status of elderly Chinese patients with Parkinson's disease (PD) and analyze possible factors related to nutritional problems. Methods: Patients with PD aged 65 years or older were enrolled. Anthropometric assessment and Mini Nutritional Assessment were used to determine nutritional status. Various scales were completed to identify potentially related factors, such as Hoehn and Yahr stage (H&Y stage), 30 mL water swallow test, Clock Drawing Test (CDT), and Charlson Comorbidity Index (CCI). Results: 785 patients were enrolled. The prevalence of malnutrition and risk of malnutrition was 3.1% (24/785) and 25.7% (202/785), respectively. Regression analyses indicated that H&Y stage ≥ 3 (OR: 2.151; 95%CI: 1.174-3.941; p = .013), abnormal water swallow test (OR: 4.559; 95%CI: 2.130-9.759; p < .001), CDT score < 6 (OR: 2.810; 95%CI: 1.534-5.148; p = .001), and CCI (OR: 1.621; 95%CI: 1.238-2.124; p < .001) were considered to be potential factors associated with low BMI. Conclusion: 28.8% of elderly PD patients were in abnormal nutritional status. Disease severity, dysphagia, cognitive function, and comorbidities might be related factors.

The Biological Clock of Liver Metabolism in Metabolic Dysfunction-Associated Steatohepatitis Progression to Hepatocellular Carcinoma.

Circadian rhythms are endogenous behavioral or physiological cycles that are driven by a daily biological clock that persists in the absence of geophysical or environmental temporal cues. Circadian rhythm-related genes code for clock proteins that rise and fall in rhythmic patterns driving biochemical signals of biological processes from metabolism to physiology and behavior. Clock proteins have a pivotal role in liver metabolism and homeostasis, and their disturbances are implicated in various liver disease processes. Encoded genes play critical roles in the initiation and progression of metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) and their proteins may become diagnostic markers as well as therapeutic targets. Understanding molecular and metabolic mechanisms underlying circadian rhythms will aid in therapeutic interventions and may have broader clinical applications. The present review provides an overview of the role of the liver's circadian rhythm in metabolic processes in health and disease, emphasizing MASH progression and the oncogenic associations that lead to HCC.

Exploring the Relationships between Lifestyle Patterns and Epigenetic Biological Age Measures in Men.

DNA methylation, validated as a surrogate for biological age, is a potential tool for predicting future morbidity and mortality outcomes. This study aims to explore how lifestyle patterns are associated with epigenetic changes in British men. Five biological age clocks were utilised to investigate the relationship between these epigenetic markers and lifestyle-related factors in a prospective study involving 221 participants. Spearman's correlation test, Pearson's correlation test, and univariate linear regression were employed for analysis. The results indicate that higher consumption of saturated fat and total daily calories, and a higher body mass index (BMI) are associated with accelerated biological aging. Conversely, higher vitamin D intake and a higher healthy lifestyle index (HLI) are linked to decelerated biological aging. These findings highlight the potential impact of specific lifestyle-related factors on biological aging and can serve as a reference for applying healthy lifestyle improvements in future disease prevention studies.