Journal of Biological Rhythms最新文献

This review summarizes recent insights into the roles of the circadian clock in regulating cancer hallmarks, with a focus on its impact on the tumor microenvironment, and highlights the translational promise of circadian-informed strategies for cancer therapy. The circadian clock is a 24-hour biological timekeeping system that aligns physiological processes with cyclic environmental cues, such as light-dark cycles. Disruptions of circadian rhythms caused by lifestyle factors, including shift work, irregular sleep patterns, and jet lag, can lead to physiological dysregulation and increased risk of various diseases including cancer, positioning the circadian clock as both a critical driver of tumorigenesis and a potential target for chronotherapies. This review provides a comprehensive overview of circadian regulation in tumorigenesis across diverse cancer types by framing its role according to established cancer hallmarks, with particular emphasis on how the circadian system shapes immune cell dynamics within the tumor microenvironment to modulate tumor progression and immune surveillance. We further discuss recent preclinical and clinical advances in chronotherapy, highlighting how aligning therapeutic interventions with biological rhythms can enhance treatment efficacy, including responses to immunotherapy. By integrating mechanistic insights with translational applications, this review bridges circadian biology and oncology, providing a framework for future chronobiology-based cancer therapies.

Circadian clocks present throughout the brain and body coordinate diverse physiological processes to support daily homeostasis, yet the specific interorgan signaling axes involved are not well defined. We previously demonstrated that the skeletal muscle clock controls transcript oscillations of genes involved in fatty acid metabolism in the liver, yet the impact of the liver clock on the muscle remained unknown. Here, we use male hepatocyte-specific Bmal1 KO mice (Bmal1^hep-/-) to reveal that approximately one-third of transcript rhythms in skeletal muscle are influenced by the liver clock in vivo. Treatment of myotubes with serum harvested from Bmal1^hep-/- mice inhibits expression of genes involved in metabolic pathways, including oxidative phosphorylation. Only small transcriptional changes were induced by liver clock-driven endocrine communication in vitro, leading us to surmise that the liver clock acts to fine-tune metabolic gene expression in muscle. Consistent with functional tuning, treatment of myotubes with serum collected from Bmal1^hep-/- mice during the dark phase lowers mitochondrial ATP production compared with serum from wild-type mice. Overall, our results reveal communication between the liver clock and skeletal muscle, uncovering a bidirectional endocrine communication pathway that may contribute to the metabolic phenotypes of circadian disruption.

Circadian (24 h) rhythmicity is a nearly-ubiquitous property of eukaryotic cells, and the mechanisms that generate this rhythmicity have been studied in a number of organisms for many years. However, there are still gaps in our understanding of the generation and regulation of rhythms. Although transcription/translation feedback loops (TTFLs) are said to be essential to generating rhythmicity in eukaryotes, there are many examples of rhythmicity seen in organisms without functioning TTFLs. Our lab previously found that two genes that function in the TOR (Target of Rapamycin) pathway, vta and gtr2, are essential for non-TTFL rhythmicity in the fungus Neurospora crassa. These two mutants were also shown to dampen the output rhythm of spore-formation (conidiation) and the rhythm of the TTFL component protein FRQ, and dampen the amplitude of the underlying oscillator in strains with functioning TTFLs. Therefore, we are interested in the role of TOR in generating and/or sustaining rhythmicity in both the presence and absence of a functioning TTFL. Here we report the development and validation of an improved assay for TOR activity in Neurospora, and using this assay we demonstrate that TOR activity displays circadian rhythmicity in strains with functioning TTFLs. The period of TOR rhythmicity is affected by a long-period mutation in a TTFL component (frq⁷), and the TOR rhythm is dampened in the vta and gtr2 knockouts. The mean level of TOR activity (mesor) in the vta and gtr2 knockout mutants is within the range of the TOR rhythm in wild type, indicating that it is rhythmicity of TOR, not a constant level of activity, that is required to sustain output rhythmicity. These results establish Neurospora as a valuable model for investigating the role of TOR in circadian rhythmicity and implicate TOR activity as a rhythmic state variable of the circadian system.

The temporal organization of biological activities by circadian clocks is pivotal for the survival of organisms. Significant progress has been made in understanding the molecular foundations of animal circadian clocks through the characterization of key components, such as CLOCK, BMAL1/Cycle (CYC), Period (PER), Timeless, and Cryptochrome (CRY) in several model organisms. To determine the extent of conservation of these elements, we investigated the sequences of these genes and their paralogs across 46 animal species that encompass multiple phyla in the Metazoan kingdom to resolve the relative timing of duplication and loss events that have diversified core clock components. Using analyses of orthology and protein-protein binding predictions, we identified and characterized elements in diverse animal species. Based on these analyses, we propose a circadian molecular mechanism employed by the ancestor of all animals. We also identify derived losses and expansions of circadian elements in smaller animal clades and provide insight into the evolutionary pressures faced by their ancestors to change such an important piece of internal machinery. Our study is the first systematic analysis of the deep phylogeny of nearly all major clades of extant animals.

Disruptions in sleep and circadian rhythms have been consistently linked to higher mortality rates in the general population. Among cancer patients, these disruptions are not only prevalent but may significantly influence prognosis. Despite this, sleep and circadian trajectories remain unexplored in the context of cancer, particularly related to prognostic outcomes in modern therapies such as immune checkpoint inhibitors (ICIs), which are rapidly transforming oncological care. In this pioneering report, we examined how trajectories of sleep and circadian rhythms relate to prognostic outcomes in patients with non-small cell lung cancer (NSCLC), offering novel insights into their potential role as modifiable biomarkers of clinical outcomes. Forty-nine treatment-naïve NSCLC patients were enrolled in this prospective longitudinal study. Continuous 24-h recordings of circadian function (Circadian Function Index [CFI]) were collected over the first 5 months of treatment, alongside weekly assessments of insomnia severity (Insomnia Severity Index [ISI]) and estimations of total sleep time (TST) derived from sleep diaries every 3 weeks. Follow-up data, time to treatment discontinuation, disease progression, and cancer-related death were obtained from medical records. We estimated hazard ratios (HRs) for these outcomes based on ISI, TST, and CFI, analyzed as continuous variables and median-split. Cox regression analyses indicated that patients with trajectories portraying circadian robustness below the median had a higher risk of earlier progression (HR = 3.75, 95% confidence interval [CI] = [1.475-9.536], p = 0.005) and death (HR = 3.07, 95% CI = [1.128-8.360], p = 0.028). No significant associations were found between insomnia severity, TST, and the prognostic outcomes. Patients with more pronounced declines in circadian robustness demonstrated significantly elevated risks of disease progression and mortality. As the circadian rhythm is modifiable, these findings, if replicated, underscore the need for interventional studies aimed at stabilizing circadian rhythms to further explore potential improvements in patient outcomes and efficacy of cancer therapies.

Obesity is a major public health concern, with disparities across racial and sex groups. While sleep duration has been extensively studied in relation to obesity, the role of sleep regularity remains less explored. In 2 nationally representative samples of US adults in the National Health and Nutrition Examination Survey (NHANES 2011/2012 & 2013/2014, n = 7085), we investigated the cross-sectional association between a sleep regularity index (SRI) derived from accelerometer data and obesity measures. Body mass index (BMI), waist circumference (WC), body roundness index (BRI), total fat mass, sagittal abdominal diameter (SAD), sagittal abdominal diameter to height ratio (SADHtR), fat mass index (FMI), lipid accumulation product (LAP), and visceral adiposity index (VAI) were derived from NHANES body measures. Multivariable-adjusted regression models were used to estimate multiplication factors (MF) and 95% confidence intervals (CIs) comparing mean BMI across quintiles of SRI and to test for effect modification by sex and ethnicity. Higher SRI was associated with significantly lower BMI (MF SRI_Q5vs.Q1: 0.92; 95% CI, 0.91-0.94; P_trend < 0.001), translating into 8% lower BMI among those with most versus least regular sleep. This association was more pronounced among women than men (MF SRI_Q5vs.Q1 women: 0.92; 95% CI, 0.90-0.95; men: 0.98; 95% CI, 0.96-1.00), with strongest effects in non-Hispanic White and other/multi-racial women (P_interaction < 0.001). Similar inverse associations were observed for all other obesity measures. In conclusion, sleep regularity, measured by the SRI, was inversely associated with BMI and any other obesity measures. The observed disparities suggest sleep regularity may contribute differentially to obesity risk by sex and race/ethnicity.

The purpose of this study was twofold: (a) to determine whether, and the extent to which, the challenge of a single night of total sleep deprivation (TSD) unmasks lingering brain health-related deficits in individuals who within the past 3 to 12 months had been diagnosed (yet medically cleared) with a mild traumatic brain injury (mTBI+), and (b) to determine whether mTBI+ results in any neurophysiobehavioral deficits in the ability to recover from TSD. Seven previously concussed (mTBI+) adults (24.5 ± 5.3 years old) and six non-concussed control (mTBI-) adults underwent 24 h TSD preceded by 8 h baseline sleep (BSL) and followed by 8 h recovery sleep (REC). Study measures included the psychomotor vigilance test (PVT) across the entire study and polysomnography during nighttime sleep and daytime nap tests. mTBI+ (vs mTBI-) subjects exhibited more minor lapses on the PVT across all study phases. NREM (N3) sleep and total sleep time (TST) amounts were lower and wake after sleep onset (WASO) was higher in mTBI+ subjects (vs mTBI) at baseline and REC. mTBI+ (vs mTBI-) subjects showed no main effects in maintenance of wakefulness across TSD. Although there is some evidence that TSD may unmask latent performance deficits in mTBI+ subjects, a definitive conclusion was precluded by differences in baseline sleep in mTBI+ (vs mTBI-) subjects, suggesting that they may habitually carry a relatively elevated sleep debt (vs mTBI- controls). Reversal of TSD-induced neurophysiobehavioral deficits following recovery sleep were comparable for both groups, revealing no significant abnormalities in the responsivity of the sleep homeostat in the mTBI+ subjects.

Light is the primary circadian time cue, but there are large interindividual differences in how sensitive the circadian system is to light. Currently, it is not well understood how individual differences in light sensitivity interact with real-world light environments to determine sleep and circadian timing. We used a validated computational model to simulate sleep and circadian timing (predicted dim light melatonin onset) under realistic assumptions about light and work schedules. Simulations were repeated varying light sensitivity (translated to equivalent ED50 values for interpretability), as well as evening, morning, and daytime illuminances. Brighter evening light led to later predicted circadian and sleep timing, with this effect being amplified by high light sensitivity. Reducing evening light was particularly beneficial for those with high light sensitivity or a long circadian period. Brighter morning light was beneficial for individuals with a long circadian period, or those with both high light sensitivity and high evening light. However, bright morning light could be maladaptive in individuals with a short circadian period or those with low light sensitivity and low evening light. Brighter daytime light attenuated the delaying effects of evening artificial light across conditions, indicating that increasing daytime light was the most universally beneficial lighting intervention. Our results demonstrate how circadian light sensitivity can be used to tailor individual-level solutions that support optimal sleep and circadian timing.

In animals, the brain contains circadian clock neurons that regulate activity rhythms. The fruit fly Drosophila melanogaster exhibits a bimodal activity pattern characterized by two peaks, in the morning (M) and evening (E), known as the M and E peaks. These activity peaks are orchestrated by a network of approximately 240 clock neurons. The neuropeptide pigment-dispersing factor (PDF) is expressed in two sets of clock neurons, the large ventrolateral neurons (l-LN_v) and the small ventrolateral neurons (s-LN_v). Mutants of Pdf, as well as flies lacking PDF neurons, exhibit a characteristic E activity that is commonly simplified to a phase-advanced pattern under 12 h:12 h light-dark cycles. Previous studies have demonstrated that l-LN_v neurons regulate the phase of the E peak; however, this effect is evident only under long photoperiod conditions. Therefore, the E peak phenotype observed in Pdf mutants remains incompletely explained. In this study, we employed genetic cell ablation and Pdf RNA interference using Gal4 lines specific to l-LN_v neurons in a well-controlled genetic background. Under long photoperiod conditions, flies lacking l-LN_v, s-LN_v, or both neuronal groups exhibited an early termination of E activity prior to lights-off, resulting in a phase-advanced E peak. Similar results were obtained in Pdf knockdown flies. Notably, l-LN_v neurons had a stronger effect on the timing of E activity termination than s-LN_v neurons. These findings demonstrate that LN_v neurons control the phase of E activity by modulating the timing of its offset, providing new insights into the neuronal mechanisms that shape daily activity patterns.

Circadian clocks regulate the immune system, rendering humans more susceptible to infections at certain times of the day. Circadian modulation of SARS-CoV-2 infection has not yet been clearly established, nonetheless the circadian control of other respiratory viruses such as influenza A makes apparent the need to study the interaction between circadian rhythms and COVID-19 disease progression. We incorporated circadian oscillations into a mechanistic model of SARS-CoV-2 dynamics and immune response fit to viral load data from COVID-19 patients. The model predicts that circadian variation of parameters associated with the innate immune response and viral death rate lead to faster clearance of the virus, whereas circadian variation of parameters representing the susceptible cell infection rate, the viral production rate, and the adaptive immune response lead to slower clearance of the virus. We then used a model of remdesivir to simulate antiviral therapy. Our model simulations predict that the effectiveness of the treatment depends on the time of day the drug is administered. This prediction is conditional on the plausible, but entirely hypothetical, circadian interactions added to the model. Based on our proof-of-concept modeling results, we advocate for experimental and clinical studies to assess the impact that dosing time of day may have on the efficacy and toxicity of current COVID-19 antiviral drugs.