Molecular Mechanisms of Aging and Circadian Rhythms

Circadian rhythms have a deep impact on most aspects of physiology. In most organisms, especially mammals, the biological rhythms are maintained by the indigenous circadian clockwork around geophysical time (~24-h). These rhythms originate inside cells. Several core components are interconnected through transcriptional/translational feedback loops to generate molecular oscillations. They are tightly controlled over time. Also, they exert temporal controls over many fundamental physiological activities. This helps in coordinating the body’s internal time with the external environments. The mammalian circadian clockwork is composed of a hierarchy of oscillators, which play roles at molecular, cellular, and higher levels. The master oscillation has been found to be developed at the hypothalamic suprachiasmatic nucleus in the brain. It acts as the core pacemaker and drives the transmission of the oscillation signals. These signals are distributed across different peripheral tissues through humoral and neural connections. The synchronization among the master oscillator and tissue-specific oscillators offer overall temporal stability to mammals. Recent technological advancements help us to study the circadian rhythms at dynamic scale and systems level. Here, we outline the current understanding of circadian clockwork in terms of molecular mechanisms and interdisciplinary concepts. We have also focused on the importance of the integrative approach to decode several crucial intricacies. This review indicates the emergence of such a comprehensive approach. It will essentially accelerate the circadian research with more innovative strategies, such as developing evidence-based chronotherapeutics to restore de-synchronized circadian rhythms.

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Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

The Scientific World JOURNAL ◽

10.1100/tsw.2007.213 ◽

2007 ◽

Vol 7 ◽

pp. 194-202 ◽

Cited By ~ 65

Author(s):

Colleen A. McClung

Keyword(s):

Circadian Rhythms ◽

Drug Addiction ◽

Molecular Mechanisms ◽

Dopaminergic System ◽

Treatment Options ◽

Drug Induced ◽

Circadian Genes ◽

Dopaminergic Transmission ◽

Central Pacemaker

Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

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Modulatory Effects of Circadian Rhythms in the Lung Adenocarcinoma Tumor Microenvironment

10.21203/rs.3.rs-838444/v1 ◽

2021 ◽

Author(s):

Qianzhun Huang ◽

Xiaoyang Su ◽

Ning Fang ◽

Jian Huang

Keyword(s):

Tumor Microenvironment ◽

Circadian Rhythms ◽

Lung Adenocarcinoma ◽

Circadian Clock ◽

Drug Sensitivity ◽

Molecular Mechanisms ◽

Clock Genes ◽

Functional Enrichment ◽

Expression Levels ◽

Circadian Clock Genes

Abstract Background: Dysregulated circadian dynamic balance is strongly associated with cancer development. However, biological functions of circadian rhythms in lung adenocarcinoma (LUAD) have not been elucidated. This study aimed at valuating the modulatory effects of circadian rhythms in the LUAD tumor microenvironment.Methods: Multiple open-source bioinformatics research platforms are used to comprehensively elucidate the expression level, prognosis, potential biological function, drug sensitivity, and immune microenvironment of circadian clock genes in LUAD.Results: Most circadian clock genes in LUAD are dysregulated and are strongly correlated with patient prognosis, and missense mutations at splicing sites of these genes. Besides, these genes are closely associated with some well-known cancer-related marker pathways, which are mainly involved in the inhibition of the Apoptosis, Cell cycle, and DNA Damage Response Pathway. Furthermore, functional enrichment analysis revealedthat circadian clock genes regulate transcription factor activities and circadian rhythms in LUAD tissues. As for drug sensitivity, high expression of CLOCK, CRY1, and NR1D2 as well as suppressedPER2 and CRY2 expression levels are associated with drug resistance. The expression levels of circadian clock genes in LUAD correlate with immune infiltration and are involved in the regulation of immunosuppression.Conclusions: Our multi-omics analysis provides a more comprehensive understanding of the molecular mechanisms of the circadian clock genes in LUAD and provides new insights for a more precise screening of prognostic biomarkers and immunotherapy.

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The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4044606 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Yanan Jiang ◽

Xiuyun Shen ◽

Moyondafoluwa Blessing Fasae ◽

Fengnan Zhi ◽

Lu Chai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Circadian Rhythm ◽

Circadian Rhythms ◽

Molecular Mechanisms ◽

Therapeutic Targets ◽

Pathogenic Mechanism ◽

Research Progress ◽

Biological Processes ◽

And Function ◽

Novel Therapeutic

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

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Circadian Mechanisms: Cardiac Ion Channel Remodeling and Arrhythmias

Frontiers in Physiology ◽

10.3389/fphys.2020.611860 ◽

2021 ◽

Vol 11 ◽

Author(s):

Joyce Bernardi ◽

Kelly A. Aromolaran ◽

Hua Zhu ◽

Ademuyiwa S. Aromolaran

Keyword(s):

Heart Failure ◽

Circadian Rhythms ◽

Molecular Mechanisms ◽

Normal Sinus Rhythm ◽

Critical Role ◽

The United States ◽

Therapeutic Interventions ◽

Cellular Mechanisms ◽

Normal Sinus ◽

Obesity And Diabetes

Circadian rhythms are involved in many physiological and pathological processes in different tissues, including the heart. Circadian rhythms play a critical role in adverse cardiac function with implications for heart failure and sudden cardiac death, highlighting a significant contribution of circadian mechanisms to normal sinus rhythm in health and disease. Cardiac arrhythmias are a leading cause of morbidity and mortality in patients with heart failure and likely cause ∼250,000 deaths annually in the United States alone; however, the molecular mechanisms are poorly understood. This suggests the need to improve our current understanding of the underlying molecular mechanisms that increase vulnerability to arrhythmias. Obesity and its associated pathologies, including diabetes, have emerged as dangerous disease conditions that predispose to adverse cardiac electrical remodeling leading to fatal arrhythmias. The increasing epidemic of obesity and diabetes suggests vulnerability to arrhythmias will remain high in patients. An important objective would be to identify novel and unappreciated cellular mechanisms or signaling pathways that modulate obesity and/or diabetes. In this review we discuss circadian rhythms control of metabolic and environmental cues, cardiac ion channels, and mechanisms that predispose to supraventricular and ventricular arrhythmias including hormonal signaling and the autonomic nervous system, and how understanding their functional interplay may help to inform the development and optimization of effective clinical and therapeutic interventions with implications for chronotherapy.

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Molecular mechanisms and physiological importance of circadian rhythms

Nature Reviews Molecular Cell Biology ◽

10.1038/s41580-019-0179-2 ◽

2019 ◽

Vol 21 (2) ◽

pp. 67-84 ◽

Cited By ~ 50

Author(s):

Alina Patke ◽

Michael W. Young ◽

Sofia Axelrod

Keyword(s):

Circadian Rhythms ◽

Molecular Mechanisms ◽

Physiological Importance

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Aging and circadian rhythms: general trends

Principles and Practice of Geriatric Sleep Medicine ◽

10.1017/cbo9780511770661.004 ◽

2010 ◽

pp. 3-21 ◽

Cited By ~ 1

Author(s):

S. R. Pandi-Perumal ◽

D. Warren Spence ◽

Vijay Kumar Sharma

Keyword(s):

Circadian Rhythms ◽

Aging And Circadian Rhythms

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The lysine demethylase dKDM2 is non-essential for viability, but regulates circadian rhythms in Drosophila

10.1101/291070 ◽

2018 ◽

Author(s):

Yani Zheng ◽

Yongbo Xue ◽

Xingjie Ren ◽

Xiao-Jun Xie ◽

Mengmeng Liu ◽

...

Keyword(s):

Circadian Rhythms ◽

Histone Methylation ◽

Molecular Mechanisms ◽

Abnormal Development ◽

Null Alleles ◽

Constant Darkness ◽

Post Translational Modification ◽

Developmental Defects ◽

Chromatin Dynamics

AbstractPost-translational modification of histones, such as histone methylation controlled by specific methyltransferases and demethylases, play critical roles in modulating chromatin dynamics and transcription in eukaryotes. Misregulation of histone methylation can lead to aberrant gene expression, thereby contributing to abnormal development and diseases such as cancer. As such, the mammalian lysine-specific demethylase 2 (KDM2) homologs, KDM2A and KDM2B, are either oncogenic or tumor suppressive, depending on specific pathological contexts. However, the role of KDM2 proteins during development in the whole organisms remains poorly understood. Unlike vertebrates, Drosophila has only one KDM2 homolog (dKDM2), but its functions in vivo remain elusive due to the complexities of the existing mutant alleles. To address this problem, we have generated two dKdm2 null alleles using the CRISPR/Cas9 technique. These dKdm2 homozygous mutants are fully viable and fertile, with no developmental defects observed under laboratory conditions. However, the dKdm2 null mutant adults display defects in circadian rhythms. Most of the dKdm2 mutants become arrhythmic under constant darkness, while the circadian period of the rhythmic mutant flies is approximately one hour shorter than the control. Interestingly, opposite defects are observed when dKDM2 is overexpressed in circadian pacemaker neurons. Taken together, these results demonstrate that dKdm2 is not essential for viability; instead, dKDM2 protein plays important roles in regulating circadian rhythms in Drosophila. Further analyses of the molecular mechanisms of how dKDM2 and its orthologs in vertebrates regulate circadian rhythms will advance our understanding of the epigenetic regulations of circadian clocks.

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Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2019756118 ◽

2021 ◽

Vol 118 (28) ◽

pp. e2019756118

Author(s):

Yangbo Xiao ◽

Ye Yuan ◽

Mariana Jimenez ◽

Neeraj Soni ◽

Swathi Yadlapalli

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Nuclear Envelope ◽

Molecular Mechanisms ◽

Clock Genes ◽

Nuclear Periphery ◽

Spatiotemporal Organization ◽

Subnuclear Localization ◽

Clock Proteins ◽

Spatial Reorganization

Circadian clocks regulate ∼24-h oscillations in gene expression, behavior, and physiology. While the genetic and molecular mechanisms of circadian rhythms are well characterized, what remains poorly understood are the intracellular dynamics of circadian clock components and how they affect circadian rhythms. Here, we elucidate how spatiotemporal organization and dynamics of core clock proteins and genes affect circadian rhythms in Drosophila clock neurons. Using high-resolution imaging and DNA-fluorescence in situ hybridization techniques, we demonstrate that Drosophila clock proteins (PERIOD and CLOCK) are organized into a few discrete foci at the nuclear envelope during the circadian repression phase and play an important role in the subnuclear localization of core clock genes to control circadian rhythms. Specifically, we show that core clock genes, period and timeless, are positioned close to the nuclear periphery by the PERIOD protein specifically during the repression phase, suggesting that subnuclear localization of core clock genes might play a key role in their rhythmic gene expression. Finally, we show that loss of Lamin B receptor, a nuclear envelope protein, leads to disruption of PER foci and per gene peripheral localization and results in circadian rhythm defects. These results demonstrate that clock proteins play a hitherto unexpected role in the subnuclear reorganization of core clock genes to control circadian rhythms, revealing how clocks function at the subcellular level. Our results further suggest that clock protein foci might regulate dynamic clustering and spatial reorganization of clock-regulated genes over the repression phase to control circadian rhythms in behavior and physiology.

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Aging and circadian rhythms

Current Opinion in Insect Science ◽

10.1016/j.cois.2015.03.001 ◽

2015 ◽

Vol 7 ◽

pp. 82-86 ◽

Cited By ~ 11

Author(s):

Jadwiga M Giebultowicz ◽

Dani M Long

Keyword(s):

Circadian Rhythms ◽

Aging And Circadian Rhythms

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