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Trends in Cancer Aug 2019Circadian clocks constitute the evolutionary molecular machinery that dictates the temporal regulation of physiology to maintain homeostasis. Disruption of the circadian... (Review)
Review
Circadian clocks constitute the evolutionary molecular machinery that dictates the temporal regulation of physiology to maintain homeostasis. Disruption of the circadian rhythm plays a key role in tumorigenesis and facilitates the establishment of cancer hallmarks. Conversely, oncogenic processes directly weaken circadian rhythms. Pharmacological modulation of core clock genes is a new approach in cancer therapy. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, encompassing the prevention, diagnosis, and treatment of this devastating disease. This review highlights the role of the circadian clock in tumorigenesis and cancer hallmarks, and discusses how pharmacological modulation of circadian clock genes can lead to new therapeutic options.
Topics: Antineoplastic Agents; Carcinogenesis; Circadian Clocks; Circadian Rhythm; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Neoplasms
PubMed: 31421905
DOI: 10.1016/j.trecan.2019.07.002 -
EMBO Reports May 2022Food intake profoundly affects systemic physiology. A large body of evidence has indicated a link between food intake and circadian rhythms, and ~24-h cycles are deemed... (Review)
Review
Food intake profoundly affects systemic physiology. A large body of evidence has indicated a link between food intake and circadian rhythms, and ~24-h cycles are deemed essential for adapting internal homeostasis to the external environment. Circadian rhythms are controlled by the biological clock, a molecular system remarkably conserved throughout evolution. The circadian clock controls the cyclic expression of numerous genes, a regulatory program common to all mammalian cells, which may lead to various metabolic and physiological disturbances if hindered. Although the circadian clock regulates multiple metabolic pathways, metabolic states also provide feedback on the molecular clock. Therefore, a remarkable feature is reprogramming by nutritional challenges, such as a high-fat diet, fasting, ketogenic diet, and caloric restriction. In addition, various factors such as energy balance, histone modifications, and nuclear receptor activity are involved in the remodeling of the clock. Herein, we review the interaction of dietary components with the circadian system and illustrate the relationships linking the molecular clock to metabolism and critical roles in the remodeling process.
Topics: Animals; Circadian Clocks; Circadian Rhythm; Diet; Energy Metabolism; Fasting; Mammals
PubMed: 35412705
DOI: 10.15252/embr.202152412 -
Annual Review of Physiology Feb 2020A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness,... (Review)
Review
A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness, and lifestyle, affecting in equal measure women and men, athletes and couch potatoes, spinach eaters and fast food enthusiasts. Importantly, the decline in mHR is the major determinant of the age-dependent decline in aerobic capacity that ultimately limits functional independence for many older individuals. The gradual reduction in mHR with age reflects a slowing of the intrinsic pacemaker activity of the sinoatrial node of the heart, which results from electrical remodeling of individual pacemaker cells along with structural remodeling and a blunted β-adrenergic response. In this review, we summarize current evidence about the tissue, cellular, and molecular mechanisms that underlie the reduction in pacemaker activity with age and highlight key areas for future work.
Topics: Aging; Animals; Biological Clocks; Female; Heart; Heart Rate; Humans; Male; Sinoatrial Node
PubMed: 31756134
DOI: 10.1146/annurev-physiol-021119-034453 -
Circulation Research Jan 2023Driven by autonomous molecular clocks that are synchronized by a master pacemaker in the suprachiasmatic nucleus, cardiac physiology fluctuates in diurnal rhythms that... (Review)
Review
Driven by autonomous molecular clocks that are synchronized by a master pacemaker in the suprachiasmatic nucleus, cardiac physiology fluctuates in diurnal rhythms that can be partly or entirely circadian. Cardiac contractility, metabolism, and electrophysiology, all have diurnal rhythms, as does the neurohumoral control of cardiac and kidney function. In this review, we discuss the evidence that circadian biology regulates cardiac function, how molecular clocks may relate to the pathogenesis of heart failure, and how chronotherapeutics might be applied in heart failure. Disrupting molecular clocks can lead to heart failure in animal models, and the myocardial response to injury seems to be conditioned by the time of day. Human studies are consistent with these findings, and they implicate the clock and circadian rhythms in the pathogenesis of heart failure. Certain circadian rhythms are maintained in patients with heart failure, a factor that can guide optimal timing of therapy. Pharmacologic and nonpharmacologic manipulation of circadian rhythms and molecular clocks show promise in the prevention and treatment of heart failure.
Topics: Animals; Humans; Circadian Rhythm; Heart; Heart Failure; Biology; Circadian Clocks
PubMed: 36656971
DOI: 10.1161/CIRCRESAHA.122.321369 -
Molecular Cell Sep 2018Age-associated changes to the mammalian DNA methylome are well documented and thought to promote diseases of aging, such as cancer. Recent studies have identified... (Review)
Review
Age-associated changes to the mammalian DNA methylome are well documented and thought to promote diseases of aging, such as cancer. Recent studies have identified collections of individual methylation sites whose aggregate methylation status measures chronological age, referred to as the DNA methylation clock. DNA methylation may also have value as a biomarker of healthy versus unhealthy aging and disease risk; in other words, a biological clock. Here we consider the relationship between the chronological and biological clocks, their underlying mechanisms, potential consequences, and their utility as biomarkers and as targets for intervention to promote healthy aging and longevity.
Topics: Aging; Animals; Biological Clocks; Cellular Senescence; CpG Islands; DNA Methylation; Epigenesis, Genetic; Humans; Longevity
PubMed: 30241605
DOI: 10.1016/j.molcel.2018.08.008 -
Signal Transduction and Targeted Therapy Feb 2022The term "circadian rhythms" describes endogenous oscillations with ca. 24-h period associated with the earth's daily rotation and light/dark cycle. Such rhythms reflect... (Review)
Review
The term "circadian rhythms" describes endogenous oscillations with ca. 24-h period associated with the earth's daily rotation and light/dark cycle. Such rhythms reflect the existence of an intrinsic circadian clock that temporally orchestrates physiological processes to adapt the internal environment with the external cues. At the molecular level, the circadian clock consists of multiple sets of transcription factors resulting in autoregulatory transcription-translation feedback loops. Notably, in addition to their primary role as generator of circadian rhythm, the biological clock plays a key role in controlling physiological functions of almost all tissues and organs. It regulates several intracellular signaling pathways, ranging from cell proliferation, DNA damage repair and response, angiogenesis, metabolic and redox homeostasis, to inflammatory and immune response. In this review, we summarize findings showing the crosstalk between the circadian molecular clock and some key intracellular pathways, describing a scenario wherein their reciprocal regulation impinges upon several aspects of mammalian physiology. Moreover, based on evidence indicating that circadian rhythms can be challenged by environmental factors, social behaviors, as well as pre-existing pathological conditions, we discuss implications of circadian misalignment in human pathologies, such as cancer and inflammatory diseases. Accordingly, disruption of circadian rhythm has been reported to affect several physiological processes that are relevant to human diseases. Expanding our understanding of this field represents an intriguing and transversal medicine challenge in order to establish a circadian precision medicine.
Topics: Circadian Clocks; Circadian Rhythm; Humans; Inflammation; Neoplasms; Precision Medicine
PubMed: 35136018
DOI: 10.1038/s41392-022-00899-y -
Current Biology : CB Jun 2017Circadian rhythms, metabolism, and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We...
Circadian rhythms, metabolism, and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hr delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hr intervals, beginning either 0.5 (early) or 5.5 (late) hr after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hr constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hr (p < 0.001), and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hr (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronizing peripheral circadian rhythms in humans and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travelers.
Topics: Biological Clocks; Circadian Rhythm; Eating; Humans; Male; Time Factors
PubMed: 28578930
DOI: 10.1016/j.cub.2017.04.059 -
Nutrients Aug 2020Breastfeeding is considered the most optimal mode of feeding for neonates and mothers. Human milk changes over the course of lactation in order to perfectly suit the...
BACKGROUND
Breastfeeding is considered the most optimal mode of feeding for neonates and mothers. Human milk changes over the course of lactation in order to perfectly suit the infant's nutritional and immunological needs. Its composition also varies throughout the day. Circadian fluctuations in some bioactive components are suggested to transfer chronobiological information from mother to child to assist the development of the biological clock. This review aims to give a complete overview of studies examining human milk components found to exhibit circadian variation in their concentration.
METHODS
We included studies assessing the concentration of a specific human milk component more than once in 24 h. Study characteristics, including gestational age, lactational stage, sampling strategy, analytical method, and outcome were extracted. Methodological quality was graded using a modified Newcastle-Ottawa Scale (NOS).
RESULTS
A total of 83 reports assessing the circadian variation in the concentration of 71 human milk components were included. Heterogeneity among studies was high. The methodological quality varied widely. Significant circadian variation is found in tryptophan, fats, triacylglycerol, cholesterol, iron, melatonin, cortisol, and cortisone. This may play a role in the child's growth and development in terms of the biological clock.
Topics: Adult; Biological Clocks; Breast Feeding; Circadian Rhythm; Female; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Lactation; Male; Milk, Human
PubMed: 32759654
DOI: 10.3390/nu12082328 -
Nature Reviews. Gastroenterology &... Oct 2021Certain members of the gut microbiota exhibit diurnal variations in relative abundance and function to serve as non-canonical drivers of host circadian rhythms and... (Review)
Review
Certain members of the gut microbiota exhibit diurnal variations in relative abundance and function to serve as non-canonical drivers of host circadian rhythms and metabolism. Also known as microbial oscillators, these microorganisms entrain upon non-photic cues, primarily dietary, to modulate host metabolism by providing input to both circadian clock-dependent and clock-independent host networks. Microbial oscillators are generally promoted by plant-based, low-fat (lean) diets, and most are abolished by low-fibre, high-sugar, high-fat (Western) diets. The changes in microbial oscillators under different diets then affect host metabolism by altering central and peripheral host circadian clock functions and/or by directly affecting other metabolic targets. Here, we review the unique role of the gut microbiota as a non-photic regulator of host circadian rhythms and metabolism. We describe genetic, environmental, dietary and other host factors such as sex and gut immunity that determine the composition and behaviour of microbial oscillators. The mechanisms by which these oscillators regulate host circadian gene expression and metabolic state are further discussed. Because of the gut microbiota's unique role as a non-photic driver of host metabolism and circadian rhythms, the development and clinical application of novel gut microbiota-related diagnostics and therapeutics hold great promise for achieving and maintaining metabolic health.
Topics: Biological Clocks; Circadian Rhythm; Diet; Diet, High-Fat; Diet, Vegetarian; Diet, Western; Dietary Fiber; Dietary Sugars; Energy Metabolism; Gastrointestinal Microbiome; Host Microbial Interactions; Humans; Obesity
PubMed: 34002082
DOI: 10.1038/s41575-021-00452-2 -
Nature Oct 2019Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism. ILC3s and neuronal cells have been shown to...
Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism. ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence. Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut 'postcode receptors' of ILC3s. Strikingly, light-dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis.
Topics: ARNTL Transcription Factors; Animals; Biological Clocks; Brain; Circadian Rhythm; Cues; Feeding Behavior; Female; Gastrointestinal Microbiome; Homeostasis; Immunity, Innate; Intestines; Light; Lipid Metabolism; Lymphocytes; Male; Mice; Photoperiod
PubMed: 31534216
DOI: 10.1038/s41586-019-1579-3