Epigenomic insights into common human disease pathology.

The epigenome-the chemical modifications and chromatin-related packaging of the genome-enables the same genetic template to be activated or repressed in different cellular settings. This multi-layered mechanism facilitates cell-type specific function by setting the local sequence and 3D interactive activity level. Gene transcription is further modulated through the interplay with transcription factors and co-regulators. The human body requires this epigenomic apparatus to be precisely installed throughout development and then adequately maintained during the lifespan. The causal role of the epigenome in human pathology, beyond imprinting disorders and specific tumour suppressor genes, was further brought into the spotlight by large-scale sequencing projects identifying that mutations in epigenomic machinery genes could be critical drivers in both cancer and developmental disorders. Abrogation of this cellular mechanism is providing new molecular insights into pathogenesis. However, deciphering the full breadth and implications of these epigenomic changes remains challenging. Knowledge is accruing regarding disease mechanisms and clinical biomarkers, through pathogenically relevant and surrogate tissue analyses, respectively. Advances include consortia generated cell-type specific reference epigenomes, high-throughput DNA methylome association studies, as well as insights into ageing-related diseases from biological 'clocks' constructed by machine learning algorithms. Also, 3rd-generation sequencing is beginning to disentangle the complexity of genetic and DNA modification haplotypes. Cell-free DNA methylation as a cancer biomarker has clear clinical utility and further potential to assess organ damage across many disorders. Finally, molecular understanding of disease aetiology brings with it the opportunity for exact therapeutic alteration of the epigenome through CRISPR-activation or inhibition.

Biological Clocks: Why We Need Them, Why We Cannot Trust Them, How They Might Be Improved.

Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)). In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading. Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body's primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.

Organ-specific biological clocks: Ageotyping for personalized anti-aging medicine.

Aging is a complex multidimensional, progressive remodeling process affecting multiple organ systems. While many studies have focused on studying aging across multiple organs, assessment of the contribution of individual organs to overall aging processes is a cutting-edge issue. An organ's biological age might influence the aging of other organs, revealing a multiorgan aging network. Recent data demonstrated a similar yet asynchronous inter-organs and inter-individuals progression of aging, thereby providing a foundation to track sources of declining health in old age. The integration of multiple omics with common clinical parameters through artificial intelligence has allowed the building of organ-specific aging clocks, which can predict the development of specific age-related diseases at high resolution. The peculiar individual aging-trajectory, referred to as ageotype, might provide a novel tool for a personalized anti-aging, preventive medicine. Here, we review data relative to biological aging clocks and omics-based data, suggesting different organ-specific aging rates. Additional research on longitudinal data, including young subjects and analyzing sex-related differences, should be encouraged to apply ageotyping analysis for preventive purposes in clinical practice.

[Insomnia and the biological clock]. / Insomnie et horloge biologique.

INSOMNIA AND THE BIOLOGICAL CLOCK. Multiple physiological and biological rhythms known as «circadian¼ are generated by the biological clock that controls them within the suprachiasmatic nuclei of the hypothalamus. However, the most emblematic circadian rhythm is that of sleep and awakening. It is therefore crucial to check how the clock may be involved in chronic insomnia. What is the influence of the clock on the time and quality of sleep? What are the typical clock disorders that explain insomnia in adolescents, shift and night workers, the elderly and the blind individuals? What are the tools to recommend in general and specialized medicine in the evaluation of the clock in insomnia? What influence finally of the light on the clock and the light therapy to recommend? So many questions and elements of understanding often-poorly known of chronic insomnia.

INSOMNIE ET HORLOGE BIOLOGIQUE. De multiples rythmes physiologiques et biologiques dits « circadiens ¼ sont influencés par l'horloge biologique qui les contrôle au sein des noyaux suprachiasmatiques de l'hypothalamus. Mais le rythme circadien le plus emblématique est celui du sommeil et de l'éveil. Il est donc indispensable de vérifier comment l'horloge biologique peut être impliquée dans une insomnie chronique : quelle est son influence sur les horaires et la qualité du sommeil ? Quels sont les troubles caractéristiques de l'horloge biologique expliquant l'insomnie des adolescents, des travailleurs postés et de nuit, des personnes âgées et des non-voyants ? Quels outils conseiller en médecine générale et spécialisée pour évaluer l'horloge biologique face à une insomnie ? Quelle influence, enfin, de la lumière sur l'horloge biologique et quels conseils donner vis-à-vis de la lumière ? Autant de questions et d'éléments de compréhension sur l'insomnie chronique éclaircis.

A novel small-animal locomotor activity recording device for biological clock research.

The rodent running-wheel recording apparatus is a reliable approach for studying circadian rhythm. This study demonstrated how to construct a simple and intelligent running-wheel recording system. The running wheel was attached to the cage's base, whereas the Hall sensor was attached to the cage's cover. Then, the RJ25 adaptor relayed the running signal to the main control board. Finally, the main control board was connected to the USB port of the computer with the USB connection. Data were collected using the online-accessible, self-created software Magturning. Through Magturning, generated data were saved and exported in real time. Afterward, the device was validated by collecting data on the locomotor activities of mice under different light conditions. In conclusion, this new device can record circadian activity of rodents. Our device is appropriate for interdisciplinary investigations related to biological clock research.

Endocrine-circadian interactions in birds: implications when nights are no longer dark.

Biological clocks are evolved time-keeping systems by which organisms rhythmically coordinate physiology within the body, and align it with rhythms in their environment. Clocks are highly sensitive to light and are at the interface of several major endocrine pathways. Worryingly, exposure to artificial-light-at-night (ALAN) is rapidly increasing in ever more extensive parts of the world, with likely impact on wild organisms mediated by endocrine-circadian pathways. In this overview, we first give a broad-brush introduction to biological rhythms. Then, we outline interactions between the avian clock, endocrine pathways, and environmental and internal modifiers. The main focus of this review is on the circadian hormone, melatonin. We summarize information from avian field and laboratory studies on melatonin and its relationships with behaviour and physiology, including often neglected developmental aspects. When exposed to ALAN, birds are highly vulnerable to disruption of behavioural rhythms and of physiological systems under rhythmic control. Several studies suggest that melatonin is likely a key mediator for a broad range of effects. We encourage further observational and experimental studies of ALAN impact on melatonin, across the full functional range of this versatile signalling molecule, as well as on other candidate compounds at the endocrine-circadian interface. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'.

Prostaglandin F2α Affects the Cycle of Clock Gene Expression and Mouse Behavior.

Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor (Ptgfr) has no known relationship with biological rhythms. Here, we first measured the locomotor period lengths of Ptgfr-KO (B6.129-Ptgfrtm1Sna) mice and found that they were longer under constant dark conditions (DD) than those of wild-type (C57BL/6J) mice. We then investigated the clock gene patterns within the suprachiasmatic nucleus in Ptgfr-KO mice under DD and observed a decrease in the expression of the clock gene cryptochrome 1 (Cry1), which is related to the circadian cycle. Moreover, the expression of Cry1, Cry2, and Period2 (Per2) mRNA were significantly altered in the mouse liver in Ptgfr-KO mice under DD. In the wild-type mouse, the plasma prostaglandin F2α (PGF2α) levels showed a circadian rhythm under a 12 h cycle of light-dark conditions. In addition, in vitro experiments showed that the addition of PTGFR agonists altered the amplitude of Per2::luc activity, and this alteration differed with the timing of the agonist addition. These results lead us to hypothesize that the plasma rhythm of PGF2α is important for driving clock genes, thus suggesting the involvement of PGF2α- and Ptgfr-targeting drugs in the biological clock cycle.

Timing and duration of dog walking and dog owner's chronotype in relation to incident depression risk among middle to older-aged female nurses.

BACKGROUND: We examined associations between dog ownership, morning dog walking and its timing and duration, and depression risk in female nurses, exploring effect modification by chronotype. We hypothesized that dog ownership and morning walking with the dog are associated with lower odds of depression, and that the latter is particularly beneficial for evening chronotypes by helping them to synchronize their biological clock with the solar system. METHODS: 26,169 depression-free US women aged 53-72 from the Nurses' Health Study 2 (NHS2) were prospectively followed from 2017-2019. We used age- and multivariable-adjusted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for depression according to dog ownership, and morning dog walking, duration, and timing. RESULTS: Overall, there was no association between owning a dog (ORvs_no_pets = 1.12, 95%CI = 0.91-1.37), morning dog walking (ORvs_not = 0.87, 95%CI = 0.64-1.18), or the duration (OR>30min vs. ≤15mins = 0.68, 95%CI = 0.35-1.29) or timing of morning dog walks (ORafter9am vs. before7am = 1.06, 95%CI = 0.54-2.05) and depression. Chronotype of dog owners appeared to modify these associations. Compared to women of the same chronotype but without pets, dog owners with evening chronotypes had a significantly increased odds of depression (OR = 1.60, 95%CI = 1.12-2.29), whereas morning chronotypes did not (OR = 0.94, 95%CI = 0.71-1.23). Further, our data suggested that evening chronotypes benefited more from walking their dog themselves in the morning (OR = 0.75, 95%CI = 0.46-1.23, Pintx = 0.064;) than morning chronotypes. CONCLUSIONS: Overall, dog ownership was not associated with depression risk though it was increased among evening chronotypes. Walking their dog in the morning might help evening chronotypes to lower their odds of depression, though more data are needed to confirm this finding.

Permanent standard time is the optimal choice for health and safety: an American Academy of Sleep Medicine position statement.

The period of the year from spring to fall, when clocks in most parts of the United States are set one hour ahead of standard time, is called daylight saving time, and its beginning and ending dates and times are set by federal law. The human biological clock is regulated by the timing of light and darkness, which then dictates sleep and wake rhythms. In daily life, the timing of exposure to light is generally linked to the social clock. When the solar clock is misaligned with the social clock, desynchronization occurs between the internal circadian rhythm and the social clock. The yearly change between standard time and daylight saving time introduces this misalignment, which has been associated with risks to physical and mental health and safety, as well as risks to public health. In 2020, the American Academy of Sleep Medicine (AASM) published a position statement advocating for the elimination of seasonal time changes, suggesting that evidence best supports the adoption of year-round standard time. This updated statement cites new evidence and support for permanent standard time. It is the position of the AASM that the United States should eliminate seasonal time changes in favor of permanent standard time, which aligns best with human circadian biology. Evidence supports the distinct benefits of standard time for health and safety, while also underscoring the potential harms that result from seasonal time changes to and from daylight saving time. CITATION: Rishi MA, Cheng JY, Strang AR, et al. Permanent standard time is the optimal choice for health and safety: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2024;20(1):121-125.

Mitochondria as a sensor, a central hub and a biological clock in psychological stress-accelerated aging.

The theory that oxidative damage caused by mitochondrial free radicals leads to aging has brought mitochondria into the forefront of aging research. Psychological stress that encompasses many different experiences and exposures across the lifespan has been identified as a catalyst for accelerated aging. Mitochondria, known for their dynamic nature and adaptability, function as a highly sensitive stress sensor and central hub in the process of accelerated aging. In this review, we explore how mitochondria as sensors respond to psychological stress and contribute to the molecular processes in accelerated aging by viewing mitochondria as hormonal, mechanosensitive and immune suborganelles. This understanding of the key role played by mitochondria and their close association with accelerated aging helps us to distinguish normal aging from accelerated aging, correct misconceptions in aging studies, and develop strategies such as exercise and mitochondria-targeted nutrients and drugs for slowing down accelerated aging, and also hold promise for prevention and treatment of age-related diseases.

Taking biological rhythms into account: From study design to results reporting.

Numerous physiological and behavioral processes in living organisms exhibit strong rhythmicity and are regulated within a 24-hour cycle. These include locomotor activity and sleep patterns, feeding-fasting cycles, hormone synthesis, body temperature, and even mood and cognitive abilities, all of which are segregated into different phases throughout the day. These processes are governed by the internal timing system, a hierarchical multi-oscillator structure conserved across all organisms, from bacteria to humans. Circadian rhythms have been seen across multiple taxonomic kingdoms. In mammals, a hierarchical internal timing system is comprised of so-called central and periphereal clocks. Although these rhythms are intrinsic, they are under environmental influences, such as seasonal temperature changes, photoperiod variations, and day-night cycles. Recognizing the existence of biological rhythms and their primary external influences is crucial when designing and reporting experiments. Neglecting these physiological variations may result in inconsistent findings and misinterpretations. Thus, here we propose to incorporate biological rhythms into all stages of human and animal research, including experiment design, analysis, and reporting of findings. We also provide a flowchart to support decision-making during the design process, considering biological rhythmicity, along with a checklist outlining key factors that should be considered and documented throughout the study. This comprehensive approach not only benefits the field of chronobiology but also holds value for various other research disciplines. The insights gained from this study have the potential to enhance the validity, reproducibility, and overall quality of scientific investigations, providing valuable guidance for planning, developing, and communicating scientific studies.

Biological clocks: Hungry on time.

Remembering when it was last able to eat helps an animal optimise its foraging strategy for future meals. But where is that time memory located? A new study now shows that it is embedded in an enigmatic, light-entrainable circadian (daily) clock.

Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.

Implications of biological clocks in pharmacology and pharmacokinetics of antitumor drugs.

Mammalians' circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). SCN control biological rhythms such as the sleep-wake rhythm and homeostatic functions of steroid hormones and their receptors. Alterations in these biological rhythms are implicated in the outcomes of pathogenic conditions such as depression, diabetes, and cancer. Chronotherapy is about optimizing treatment to combat risks and intensity of the disease symptoms that vary depending on the time of day. Thus, conditions/diseases such as allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease, prone to manifest severe symptoms depending on the time of day, would be benefited from chronotherapy. Monitoring rhythm, overcoming rhythm disruption, and manipulating the rhythms from the viewpoints of underlying molecular clocks are essential to enhanced chronopharmacotherapy. New drugs focused on molecular clocks are being developed to improve therapeutics. In this review, we provide a critical summary of literature reports concerning (a) the rationale/mechanisms for time-dependent dosing differences in therapeutic outcomes and safety of antitumor drugs, (b) the molecular pathways underlying biological rhythms, and (c) the possibility of pharmacotherapy based on the intra- and inter-individual variabilities from the viewpoints of the clock genes.

A dual-clock-driven model of lymphatic muscle cell pacemaking to emulate knock-out of Ano1 or IP3R.

Lymphatic system defects are involved in a wide range of diseases, including obesity, cardiovascular disease, and neurological disorders, such as Alzheimer's disease. Fluid return through the lymphatic vascular system is primarily provided by contractions of muscle cells in the walls of lymphatic vessels, which are in turn driven by electrochemical oscillations that cause rhythmic action potentials and associated surges in intracellular calcium ion concentration. There is an incomplete understanding of the mechanisms involved in these repeated events, restricting the development of pharmacological treatments for dysfunction. Previously, we proposed a model where autonomous oscillations in the membrane potential (M-clock) drove passive oscillations in the calcium concentration (C-clock). In this paper, to model more accurately what is known about the underlying physiology, we extend this model to the case where the M-clock and the C-clock oscillators are both active but coupled together, thus both driving the action potentials. This extension results from modifications to the model's description of the IP3 receptor, a key C-clock mechanism. The synchronised dual-driving clock behaviour enables the model to match IP3 receptor knock-out data, thus resolving an issue with previous models. We also use phase-plane analysis to explain the mechanisms of coupling of the dual clocks. The model has the potential to help determine mechanisms and find targets for pharmacological treatment of some causes of lymphoedema.

A single photoreceptor splits perception and entrainment by cotransmission.

Vision enables both image-forming perception, driven by a contrast-based pathway, and unconscious non-image-forming circadian photoentrainment, driven by an irradiance-based pathway1,2. Although two distinct photoreceptor populations are specialized for each visual task3-6, image-forming photoreceptors can additionally contribute to photoentrainment of the circadian clock in different species7-15. However, it is unknown how the image-forming photoreceptor pathway can functionally implement the segregation of irradiance signals required for circadian photoentrainment from contrast signals required for image perception. Here we report that the Drosophila R8 photoreceptor separates image-forming and irradiance signals by co-transmitting two neurotransmitters, histamine and acetylcholine. This segregation is further established postsynaptically by histamine-receptor-expressing unicolumnar retinotopic neurons and acetylcholine-receptor-expressing multicolumnar integration neurons. The acetylcholine transmission from R8 photoreceptors is sustained by an autocrine negative feedback of the cotransmitted histamine during the light phase of light-dark cycles. At the behavioural level, elimination of histamine and acetylcholine transmission impairs R8-driven motion detection and circadian photoentrainment, respectively. Thus, a single type of photoreceptor can achieve the dichotomy of visual perception and circadian photoentrainment as early as the first visual synapses, revealing a simple yet robust mechanism to segregate and translate distinct sensory features into different animal behaviours.

Macroscopic waves, biological clocks and morphogenesis driven by light in a giant unicellular green alga.

A hallmark of self-organisation in living systems is their capacity to stabilise their own dynamics, often appearing to anticipate and act upon potential outcomes. Caulerpa brachypus is a marine green alga consisting of differentiated organs resembling leaves, stems and roots. While an individual can exceed a metre in size, it is a single multinucleated giant cell. Thus Caulerpa presents the mystery of morphogenesis on macroscopic scales in the absence of cellularization. The experiments reported here reveal self-organised waves of greenness - chloroplasts - that propagate throughout the alga in anticipation of the day-night light cycle. Using dynamical systems analysis we show that these waves are coupled to a self-sustained oscillator, and demonstrate their entrainment to light. Under constant conditions light intensity affects the natural period and drives transition to temporal disorder. Moreover, we find distinct morphologies depending on light temporal patterns, suggesting waves of chlorophyll could link biological oscillators to metabolism and morphogenesis in this giant single-celled organism.

A minimal model of peripheral clocks reveals differential circadian re-entrainment in aging.

The mammalian circadian system comprises a network of endogenous oscillators, spanning from the central clock in the brain to peripheral clocks in other organs. These clocks are tightly coordinated to orchestrate rhythmic physiological and behavioral functions. Dysregulation of these rhythms is a hallmark of aging, yet it remains unclear how age-related changes lead to more easily disrupted circadian rhythms. Using a two-population model of coupled oscillators that integrates the central clock and the peripheral clocks, we derive simple mean-field equations that can capture many aspects of the rich behavior found in the mammalian circadian system. We focus on three age-associated effects that have been posited to contribute to circadian misalignment: attenuated input from the sympathetic pathway, reduced responsiveness to light, and a decline in the expression of neurotransmitters. We find that the first two factors can significantly impede re-entrainment of the clocks following perturbation, while a weaker coupling within the central clock does not affect the recovery rate. Moreover, using our minimal model, we demonstrate the potential of using the feed-fast cycle as an effective intervention to accelerate circadian re-entrainment. These results highlight the importance of peripheral clocks in regulating the circadian rhythm and provide fresh insights into the complex interplay between aging and the resilience of the circadian system.