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Nature Reviews. Drug Discovery Apr 2021The circadian clock evolved in diverse organisms to integrate external environmental changes and internal physiology. The clock endows the host with temporal precision... (Review)
Review
The circadian clock evolved in diverse organisms to integrate external environmental changes and internal physiology. The clock endows the host with temporal precision and robust adaptation to the surrounding environment. When circadian rhythms are perturbed or misaligned, as a result of jet lag, shiftwork or other lifestyle factors, adverse health consequences arise, and the risks of diseases such as cancer, cardiovascular diseases or metabolic disorders increase. Although the negative impact of circadian rhythm disruption is now well established, it remains underappreciated how to take advantage of biological timing, or correct it, for health benefits. In this Review, we provide an updated account of the circadian system and highlight several key disease areas with altered circadian signalling. We discuss environmental and lifestyle modifications of circadian rhythm and clock-based therapeutic strategies, including chronotherapy, in which dosing time is deliberately optimized for maximum therapeutic index, and pharmacological agents that target core clock components and proximal regulators. Promising progress in research, disease models and clinical applications should encourage a concerted effort towards a new era of circadian medicine.
Topics: Animals; Cardiovascular Diseases; Circadian Clocks; Circadian Rhythm; Drug Administration Schedule; Drug Chronotherapy; Humans; Metabolic Diseases; Neoplasms; Time Factors
PubMed: 33589815
DOI: 10.1038/s41573-020-00109-w -
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 -
Genome Biology Nov 2019Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of... (Review)
Review
Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.
Topics: Aging; Animals; Biological Clocks; DNA Methylation; Epigenesis, Genetic; Genome, Human; Genome-Wide Association Study; Humans
PubMed: 31767039
DOI: 10.1186/s13059-019-1824-y -
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 -
Journal of Biological Rhythms Dec 2021Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and... (Review)
Review
Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and metabolism. The adaptive value of clocks is evident when internal body clocks and daily environmental cycles are mismatched, such as in the case of shift work and jet lag or even mistimed eating, all of which are associated with physiological disruption and disease. Studies with animal and human models have also unraveled an important role of functional circadian clocks in modulating cellular and organismal responses to physiological cues (ex., food intake, exercise), pathological insults (e.g. virus and parasite infections), and medical interventions (e.g. medication). With growing knowledge of the molecular and cellular mechanisms underlying circadian physiology and pathophysiology, it is becoming possible to target circadian rhythms for disease prevention and treatment. In this review, we discuss recent advances in circadian research and the potential for therapeutic applications that take patient circadian rhythms into account in treating disease.
Topics: Animals; Chronotherapy; Circadian Clocks; Circadian Rhythm; Humans; Sleep
PubMed: 34547953
DOI: 10.1177/07487304211044301 -
Progress in Lipid Research Jul 2023Lipids play important roles in energy metabolism along with diverse aspects of biological membrane structure, signaling and other functions. Perturbations of lipid... (Review)
Review
Lipids play important roles in energy metabolism along with diverse aspects of biological membrane structure, signaling and other functions. Perturbations of lipid metabolism are responsible for the development of various pathologies comprising metabolic syndrome, obesity, and type 2 diabetes. Accumulating evidence suggests that circadian oscillators, operative in most cells of our body, coordinate temporal aspects of lipid homeostasis. In this review we summarize current knowledge on the circadian regulation of lipid digestion, absorption, transportation, biosynthesis, catabolism, and storage. Specifically, we focus on the molecular interactions between functional clockwork and biosynthetic pathways of major lipid classes comprising cholesterol, fatty acids, triacylglycerols, glycerophospholipids, glycosphingolipids, and sphingomyelins. A growing body of epidemiological studies associate a socially imposed circadian misalignment common in modern society with growing incidence of metabolic disorders, however the disruption of lipid metabolism rhythms in this connection has only been recently revealed. Here, we highlight recent studies that unravel the mechanistic link between intracellular molecular clocks, lipid homeostasis and development of metabolic diseases based on animal models of clock disruption and on innovative translational studies in humans. We also discuss the perspectives of manipulating circadian oscillators as a potentially powerful approach for preventing and managing metabolic disorders in human patients.
Topics: Animals; Humans; Lipid Metabolism; Circadian Rhythm; Circadian Clocks; Diabetes Mellitus, Type 2; Energy Metabolism; Metabolic Diseases; Lipids
PubMed: 37187314
DOI: 10.1016/j.plipres.2023.101235 -
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 -
Cell Stem Cell Oct 2019Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for...
Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we developed human cortical organoids that dynamically change cellular populations during maturation and exhibited consistent increases in electrical activity over the span of several months. The spontaneous network formation displayed periodic and regular oscillatory events that were dependent on glutamatergic and GABAergic signaling. The oscillatory activity transitioned to more spatiotemporally irregular patterns, and synchronous network events resembled features similar to those observed in preterm human electroencephalography. These results show that the development of structured network activity in a human neocortex model may follow stable genetic programming. Our approach provides opportunities for investigating and manipulating the role of network activity in the developing human cortex.
Topics: Biological Clocks; Cells, Cultured; Cerebellar Cortex; Electromagnetic Radiation; Gene Expression Profiling; Humans; Induced Pluripotent Stem Cells; Neocortex; Nerve Net; Neurogenesis; Organoids; Signal Transduction; Single-Cell Analysis; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 31474560
DOI: 10.1016/j.stem.2019.08.002 -
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