Temporal Decoupling via Circadian Clock Reset

A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential

The circadian clock coordinates daily rhythmicity of biochemical, physiologic, and behavioral functions in humans. Gene expression, cell division, and DNA repair are modulated by the clock, which gives rise to the hypothesis that clock dysfunction may predispose individuals to cancer. Although the results of many epidemiologic and animal studies are consistent with there being a role for the clock in the genesis and progression of tumors, available data are insufficient to conclude that clock disruption is generally carcinogenic. Similarly, studies have suggested a circadian time-dependent efficacy of chemotherapy, but clinical trials of chronochemotherapy have not demonstrated improved outcomes compared with conventional regimens. Future hypothesis-driven and discovery-oriented research should focus on specific interactions between clock components and carcinogenic mechanisms to realize the full clinical potential of the relationship between clocks and cancer.

Chronic gastrointestinal (GI) diseases, including functional, inflammatory, and neoplastic conditions, are increasing globally, partly due to modern lifestyles. The circadian rhythm, regulated by the central clock in the hypothalamus and synchronized with peripheral clocks in the GI organs, orchestrates GI functions in response to environmental cycles. This clock is influenced by cues such as light, sleep, and eating times. The circadian machinery prepares the host to cope with environmental conditions to adjust cellular and organ function accordingly. Modern behaviors-like night-time light exposure, travel across time zones, shift work, mistimed eating, and social jet lag-disrupt the circadian clock, affecting GI processes such as digestion, absorption, motility, intestinal barrier function, immune function, and the microbiome, promoting not only GI pathology, but also systemic inflammatory and metabolic disorders. This review summarizes the circadian rhythm's role in normal GI functi

The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the core clock gene period (Per) and cryptochrome (Cry) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein-1 (Bmal1). By binding to E-box sequences in the promoters of Per1/2 and Cry1/2 genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and st

IMPORTANCE: Liver transplants are performed around the clock, often associated with substantial disutility for patients and clinicians. While short-duration dual hypothermic oxygenated machine perfusion (short-DHOPE) mitigates ischemia-reperfusion injury and related complications, prolonged DHOPE (DHOPE-PRO) may further extend preservation time and facilitate daytime liver transplant. OBJECTIVE: To assess whether the use of DHOPE-PRO is associated with an increased proportion of daytime liver transplants without compromising graft or patient outcomes. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study conducted at a large academic liver transplant center in the Netherlands included adult and pediatric recipients of liver grafts received from donation after brain death (DBD), donation after circulatory death (DCD), or living donors. The study compared all liver transplants performed between January 1, 2023, and December 31, 2024, following routine DHOPE-PRO implementation,

BACKGROUND: Immune system is regulated by circadian rhythms, which promote inflammation and facilitate pathogen elimination. Antimicrobial peptides secreted by milk somatic cells and mammary gland epithelial cells play a crucial role in protecting the mammary gland from pathogenic invasion and mastitis. In this study, we aimed to investigate the circadian rhythms of clock gene and antimicrobial peptide gene expression in goat milk somatic cells, as well as the circadian variation in antimicrobial peptide concentrations in milk. RESULTS: Milk and blood samples were collected from eight goats every 4 h for three days, with light exposure from 6:30 to 19:00. Notably, plasma prolactin level, milk Na+ concentration, and somatic cell count exhibited circadian rhythms (cosinor: P < 0.05; time: P < 0.01). Expression levels of some clock genes (Clock, cryptochrome circadian regulator 2, period circadian regulator 2, and nuclear receptor subfamily 1 group D member 1) exhibited circadian rhythms

Noxious temperature changes and high levels of reactive oxygen species (ROS) have traditionally been regarded as harmful stimuli. However, there is now substantial evidence for the importance of small-to-moderate changes in temperature and ROS levels-well below the thresholds that induce cell death or physiological dysfunction-as fundamental signaling cues that regulate a wide range of physiological functions in mammals. In this review, I summarize our recent findings on the regulatory roles of slight fluctuations in temperature and intracellular ROS in biological processes. In particular, this review focuses on two key examples: (A) the effects of subtle changes in physiological circadian body temperature fluctuations on the translational efficiency of the core clock gene Period2 and (B) the role of non-toxic levels of ROS as essential intracellular signals that modulate transient receptor potential ion channel activity and cold sensitivity. Our findings challenge longstanding assumpt

With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.

Major progress has been made in elucidating the molecular, cellular, and supracellular mechanisms underlying aging. This has spurred the birth of geroscience, which aims to identify actionable hallmarks of aging. Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors. Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans. Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation. New molecular profiling technologies enable the characterization of ge

Solid tumors are commonly treated with cisplatin, which can cause off-target side effects in cancer patients. Chronotherapy is a potential strategy to reduce drug toxicity. To determine the effectiveness of timed-cisplatin treatment in mammals, we compared two conditions: clock disrupted jet-lag and control conditions. Under normal and disrupted clock conditions, triple-negative mammary carcinoma cells were injected subcutaneously into eight-week-old NOD.Cg-Prkdcscid/J female mice. Tumor volumes and body weights were measured in these mice before and after treatment with cisplatin. We observed an increase in tumor volumes in mice housed under disrupted clock compared to the normal clock conditions. After treatment with cisplatin, we observed a reduced tumor growth rate in mice treated at ZT10 compared to ZT22 and untreated cohorts under normal clock conditions. However, these changes were not seen with the jet-lag protocol. We also observed greater body weight loss in mice treated with

Disruptions of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly affect health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this Review, we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer's disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.

Endogenous biological clocks, orchestrated by the suprachiasmatic nucleus, time the circadian rhythms that synchronize physiological and behavioural functions in humans. The circadian system influences most physiological processes, including sleep, alertness and cognitive performance. Disruption of circadian homeostasis has deleterious effects on human health. Neurodegenerative disorders involve a wide range of symptoms, many of which exhibit diurnal variations in frequency and intensity. These disorders also disrupt circadian homeostasis, which in turn has negative effects on symptoms and quality of life. Emerging evidence points to a bidirectional relationship between circadian homeostasis and neurodegeneration, suggesting that circadian function might have an important role in the progression of neurodegenerative disorders. Therefore, the circadian system has become an attractive target for research and clinical care innovations. Studying circadian disruption in neurodegenerative di

Alzheimer disease (AD) and aging have similar molecular mechanisms that are affected by genetic as well as environmental variables. Based on current research, gut microbiomes contribute to age-specific biological processes and play an essential role in maintaining host homeostasis. Several molecular processes, including the host DNA methylation mechanism, are affected by microbially derived metabolites such as short-chain fatty acids, folate, and choline. This interaction establishes a mechanistic causal relationship that further shapes gene expression, inflammatory balance, and neuronal function in aging and related diseases. In this review, we looked at recent research showing how gut dysbiosis and its associated metabolites impact DNA methylation, which consequently contributes to disease progression in AD and aging. We also talked about how the DNA clock and age-associated methylation drifts can be used for forecasting biological aging. In addition, we discussed recent findings on

Glaucoma, a leading cause of irreversible blindness, is a complex polygenic disease where significant clinical and genetic heterogeneity do not explain all glaucoma cases, highlighting the need for a deeper understanding of molecular mechanisms like epigenetics. This review examines the emerging role of key epigenetic mechanisms, specifically DNA methylation, histone modifications, and non-coding RNAs in glaucoma pathogenesis and their potential as biomarkers and therapeutic targets. We discuss how aberrant DNA methylation (e.g., GDF7 hypomethylation/CDKN2B hypermethylation) promotes trabecular meshwork fibrosis and increases optic nerve vulnerability, contributing to disease development and/or progression. The METTL23 histone methylation linked to retinal ganglion cell death at normal eye pressure, and disease-specific microRNA profiles further support the role of epigenetic involvement in glaucoma. The proof-of-concept studies of GDF7 neutralization in primate models and the OSK-fact