Редактирование: CLOCK

Circadian locomoter output cycles protein kaput (EC 2.3.1.48) (hCLOCK) (Class E basic helix-loop-helix protein 8) (bHLHe8) [BHLHE8] [KIAA0334]

==Publications==

{{medline-entry
|title=Circadian rhythm disruption and Alzheimer's disease: The dynamics of a vicious cycle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32348224
|abstract=All mammalian cells exhibit circadian rhythm in cellular metabolism and energetics. Autonomous cellular clocks are modulated by various pathways that are essential for robust time keeping. In addition to the canonical transcriptional translational feedback loop, several new pathways of circadian timekeeping - non-transcriptional oscillations, post-translational modifications, epigenetics and cellular signaling in the circadian clock - have been identified. The physiology of circadian rhythm is expansive, and its link to the neurodegeneration is multifactorial. Circadian rhythm disruption is prevelant in contamporary society where light-noise, shift-work, and transmeridian travel are commonplace, and is also reported from the early stages of Alzheimer's disease (AD). Circadian alignment by bright light therapy in conjunction with chronobiotics is beneficial for treating sundowning syndrome and other cognitive symptoms in advanced AD patients. We performed a comprehensive analysis of the clinical and translational reports to review the physiology of the circadian clock, delineate its dysfunction in AD, and unravel the dynamics of the vicious cycle between two pathologies. The review delineates the role of putative targets like clock proteins PER, [[CLOCK]], BMAL1, ROR, and clock-controlled proteins like [[AVP]], [[SIRT1]], FOXO, and PK2 towards future approaches for management of AD. Furthermore, the role of circadian rhythm disruption in aging is delineated.

|keywords=* aging
* circadian rhythm coupling
* post-translational
modifications
* redox
* sleep-wake cycle
* suprachiasmatic nuclei
|full-text-url=https://sci-hub.do/10.2174/1570159X18666200429013041
}}
{{medline-entry
|title=Investigating circadian clock gene expression in human tendon biopsies from acute exercise and immobilization studies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30923873
|abstract=The discovery of musculoskeletal tissues, including muscle, tendons, and cartilage, as peripheral circadian clocks strongly implicates their role in tissue-specific homeostasis. Age-related dampening and misalignment of the tendon circadian rhythm and its outputs may be responsible for the decline in tendon homeostasis. It is unknown which entrainment signals are responsible for the synchronization of the tendon clock to the light-dark cycle. We sought to examine any changes in the expression levels of core clock genes (BMAL1, [[CLOCK]], [[PER2]], [[CRY1]], and NR1D1) in healthy human patellar tendon biopsies obtained from three different intervention studies: increased physical activity (leg kicks for 1 h) in young, reduced activity (2 weeks immobilization of one leg) in young, and in old tendons. The expression level of clock genes in human tendon in vivo was very low and a high variation between individuals was found. We were thus unable to detect any differences in core clock gene expression neither after acute exercise nor immobilization. We are unable to find evidence for an effect of exercise or immobilization on circadian clock gene expression in human tendon samples.
|mesh-terms=* Adult
* Aged
* Circadian Rhythm Signaling Peptides and Proteins
* Exercise
* Humans
* Immobilization
* Male
* Patellar Ligament
|keywords=* Aging
* Circadian clock
* Exercise
* Gene expression
* Immobilization
* Tendon
|full-text-url=https://sci-hub.do/10.1007/s00421-019-04129-2
}}
{{medline-entry
|title=[[CLOCK]] gene polymorphisms and quality of aging in a cohort of nonagenarians - The MUGELLO Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30728411
|abstract=A total of 356 elderly subjects [257F; 88-106 years] were genotyped for three polymorphisms of the [[CLOCK]] gene by TaqMan real-time PCR approach, in order to find associations with quality of aging. Subjects homozygous for the minor allele of rs1801260 were less frequently overweight (p = 0.046), had higher fasting glucose levels (p = 0.037), better scores at the Clock Drawing Test (CDT) (p = 0.047) and worse scores at the Geriatric Depression Scale (p = 0.032). Subjects homozygous for the minor allele of rs11932595 showed higher fasting glucose levels (p = 0.044) and better scores at CDT (p = 0.030). Conversely, subjects homozygous for the minor allele of rs4580704 showed higher triglyceride (p = 0.012), and LDL-cholesterol levels (p = 0.44), and a greater adherence to the Mediterranean diet (MD) (p = 0.044). In addition, AAC, AAG, GGC and AGC (rs1801260-rs11932595-rs4580704) haplotypes were analyzed: AAG was associated with higher risk of overweight (p = 0.008), hypertriglyceridemia (p = 0.040) and hypercholesterolemia (p = 0.036); GGC with lower risk of hyperglycemia (p = 0.022), better sleep pattern (p = 0.001) and with better score at mini-mental state examination (p = 0.010); AGC with lower risk of depression (p = 0.026) and AAC with lower adherence to the MD (p = 0.028). Therefore, [[CLOCK]] gene polymorphisms let us hypothesize an involvement in the quality of aging in a cohort of nonagenarians.
|mesh-terms=* Aged, 80 and over
* Aging
* CLOCK Proteins
* Cohort Studies
* Female
* Gene Frequency
* Geriatric Assessment
* Haplotypes
* Humans
* Male
* Polymorphism, Single Nucleotide
* Quality of Life

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365537
}}
{{medline-entry
|title=Is the aging human ovary still ticking?: Expression of clock-genes in luteinized granulosa cells of young and older women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30463623
|abstract=It has been shown - mostly in animal models - that circadian clock genes are expressed in granulosa cells and in corpora luteum and might be essential for the ovulatory process and steroidogenesis. We sought to investigate which circadian clock genes exist in human granulosa cells and whether their expression and activity decrease during aging of the ovary. Human luteinized granulosa cells were isolated from young (age 18-33) and older (age 39-45) patients who underwent in-vitro fertilization treatment. Levels of clock genes expression were measured in these cells 36 h after human chorionic gonadotropin stimulation. Human luteinized granulosa cells were isolated from follicular fluid during oocyte retrieval. The mRNA expression levels of the circadian genes [[CRY1]], [[CRY2]], [[PER1]], [[PER2]], [[CLOCK]], [[ARNTL]], [[ARNTL]]2, and [[NPAS2]] were analyzed by quantitative polymerase chain reaction. We found that the circadian genes [[CRY1]], [[CRY2]], [[PER1]], [[PER2]], [[CLOCK]], [[ARNTL]], [[ARNTL]]2, and [[NPAS2]], are expressed in cultured human luteinized granulosa cells. Among these genes, there was a general trend of decreased expression in cells from older women but it reached statistical significance only for [[PER1]] and [[CLOCK]] genes (fold change of 0.27 ± 0.14; p = 0.03 and 0.29 ± 0.16; p = 0.05, respectively). This preliminary report indicates that molecular circadian clock genes exist in human luteinized granulosa cells. There is a decreased expression of some of these genes in older women. This decline may partially explain the decreased fertility and steroidogenesis of reproductive aging.
|mesh-terms=* Adolescent
* Adult
* Aging
* Circadian Rhythm Signaling Peptides and Proteins
* Female
* Gene Expression
* Granulosa Cells
* Humans
* Luteinization
* Middle Aged
* RNA, Messenger
* Young Adult
|keywords=* Circadian clock genes
* Granulosa cells
* Reproductive aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247686
}}
{{medline-entry
|title=Aging and chromatoid body assembly: Are these two physiological events linked?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29958504
|abstract=The chromatoid body is a cytoplasmic male germ cell structure that plays a role in the regulation of mRNA transcription during spermatogenesis. A proteomic analysis of this structure has identified the presence of its classic molecular markers (MVH and MIWI), as well as a significant number of transient proteins. Circadian locomotor output cycles protein kaput ([[CLOCK]]) and brain and muscle [[ARNT]]-like 1 (BMAL1), which are molecular components of the circadian clock, are likely located in the chromatoid body in a transient fashion. This study sought to determine whether aging produces morphological changes in the chromatoid bodies of round spermatids similar to those previously observed in BMAL1 knockout mice. A sample of 30 male mice was divided into three groups: juvenile mice (45 days old), adult mice (120 days old), and old mice ( 180 days old). Aging was confirmed by viability and sperm count analyses and testosterone dosage. Squash slides prepared with fragments of seminiferous tubules were immunostained for MVH, MIWI, BMAL1, and [[CLOCK]] detection. In juvenile and adult specimens, single round chromatoid bodies were observed using MVH/BMAL1 and MIWI/[[CLOCK]] immunostaining. In old specimens, many chromatoid bodies displayed changes in number and morphology, as well as an increase in the interactions between MVH and BMAL1; MIWI and [[CLOCK]]. Changes in chromatoid body morphology increased interactions between the proteins analyzed herein, and decreased amounts of these proteins in seminiferous tubules of older mice may indicate that aging influences the assembly and physiology of chromatoid bodies, which may, in turn, affect fertility. Impact statement The results discussed in this paper indicate that aging compromises the structure and physiology of chromatoid bodies (CBs) in post-meiotic male cells. Since CB is a fundamental structure for the differentiation of the mature male germ cell it is possible that this imbalance in CB physiology may play a role in the reduction of fertility in older men. It is important to note that not only the classic CB markers (such as the MIWI and MVH proteins) were used to showcase the structural changes in the CBs but also the main components of circadian cycle control (the [[CLOCK]] and BMAL1 proteins), indicating that the reduction of circadian control in aged males may contribute to these changes in CBs as well. Therefore, it is intriguing to evaluate the hypothesis that controlling these physiological/structural changes in CBs may be a way of delaying the effects of aging in males.
|mesh-terms=* ARNTL Transcription Factors
* Age Factors
* Aging
* Animals
* Argonaute Proteins
* CLOCK Proteins
* Cytoplasmic Granules
* DEAD-box RNA Helicases
* Male
* Mice
* Microscopy, Fluorescence
* Nucleoproteins
* Spermatids
|keywords=* Aging
* chromatoid body
* fertility
* spermatogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108056
}}
{{medline-entry
|title=CIRCADIAN [[CLOCK]]-ASSOCIATED 1 Inhibits Leaf Senescence in [i]Arabidopsis[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29559987
|abstract=Leaf senescence is an integral part of plant development, and the timing and progressing rate of senescence could substantially affect the yield and quality of crops. It has been known that a circadian rhythm synchronized with external environmental cues is critical for the optimal coordination of various physiological and metabolic processes. However, the reciprocal interactions between the circadian clock and leaf senescence in plants remain unknown. Here, through measuring the physiological and molecular senescence related markers of several circadian components mutants, we found that CIRCADIAN [[CLOCK]]-ASSOCIATED 1 inhibits leaf senescence. Further molecular and genetic studies revealed that CCA1 directly activates [i]GLK2[/i] and suppresses [i]ORE1[/i] expression to counteract leaf senescence. As plants age, the expression and periodic amplitude of [i]CCA1[/i] declines and thus weakens the inhibition of senescence. Our findings reveal an age-dependent circadian clock component of the process of leaf senescence.

|keywords=* CCA1
* GLK2
* ORE1
* aging
* circadian clock
* leaf senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845730
}}
{{medline-entry
|title=Circadian clocks: from stem cells to tissue homeostasis and regeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29258993
|abstract=The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep-to-wake transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock machinery comprises a pathway that is driven by rhythmic docking of the transcription factors BMAL1 and [[CLOCK]] on clock-controlled output genes, which results in tissue-specific oscillatory gene expression programs. Genetic as well as environmental perturbation of the circadian clock has been implicated in various diseases ranging from sleep to metabolic disorders and cancer development. Here, we review the origination of circadian rhythms in stem cells and their function in differentiated cells and organs. We describe how clocks influence stem cell maintenance and organ physiology, as well as how rhythmicity affects lineage commitment, tissue regeneration, and aging.
|mesh-terms=* ARNTL Transcription Factors
* Aging
* Animals
* CLOCK Proteins
* Cell Differentiation
* Circadian Clocks
* Circadian Rhythm
* Feedback, Physiological
* Gene Expression Regulation
* Homeostasis
* Humans
* Neoplasms
* Organ Specificity
* Regeneration
* Signal Transduction
* Sleep
* Stem Cells
|keywords=* aging
* circadian rhythms
* clock
* regeneration
* stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757216
}}
{{medline-entry
|title=Female ClockΔ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28927226
|abstract=Circadian rhythms are important for healthy cardiovascular physiology and they are regulated by the molecular circadian mechanism. Previously, we showed that disruption of the circadian mechanism factor [[CLOCK]] in male ClockΔ19/Δ19 mice led to development of age-dependent cardiomyopathy. Here, we investigate the role of biological sex in protecting against heart disease in aging female ClockΔ19/Δ19 mice. Female ClockΔ19/Δ19 mice are protected from the development of cardiomyopathy with age, as heart structure and function are similar to 18 months of age vs. female WT mice. We show that female ClockΔ19/Δ19 mice maintain normal glucose tolerance as compared with female WT. Tissue metabolic profiling revealed that aging female ClockΔ19/Δ19 mice maintain normal cardiac glucose uptake, whereas the male ClockΔ19/Δ19 mice have increased cardiac glucose uptake consistent with pathological remodelling. Shotgun lipidomics revealed differences in phospholipids that were sex and genotype specific, including cardiolipin CL76:11 that was increased and CL72:8 that was decreased in male ClockΔ19/Δ19 mice. Additionally, female ClockΔ19/Δ19 mice show increased activation of AKT signalling and preserved cytochrome c oxidase activity compared with male ClockΔ19/Δ19 mice, which can help to explain why they are protected from heart disease. To determine how this protection occurs in females even with the Clock mutation, we examined the effects of ovarian hormones. We show that ovarian hormones protect female ClockΔ19/Δ19 mice from heart disease as ovariectomized female ClockΔ19/Δ19 mice develop cardiac dilation, glucose intolerance and reduced cardiac cytochrome c oxidase; this phenotype is consistent with the age-dependent decline observed in male ClockΔ19/Δ19 mice. These data demonstrate that ovarian hormones protect female ClockΔ19/Δ19 mice from the development of age-dependent cardiomyopathy even though Clock function is disturbed. Understanding the interaction of biological sex and the circadian mechanism in cardiac growth, renewal and remodelling opens new doors for understanding and treating heart disease.
|mesh-terms=* Age Factors
* Aging
* Animals
* Blood Glucose
* CLOCK Proteins
* Cardiolipins
* Cardiomyopathies
* Circadian Rhythm
* Electron Transport Complex IV
* Female
* Genetic Predisposition to Disease
* Hemodynamics
* Mice, Inbred C57BL
* Mice, Transgenic
* Myocardium
* Ovariectomy
* Ovary
* Phenotype
* Proto-Oncogene Proteins c-akt
* Sex Factors
* Signal Transduction
* Ventricular Function, Left
|keywords=* Aging
* Cardiovascular
* Circadian
* Female
* Hypertrophy
* Lipidomics
|full-text-url=https://sci-hub.do/10.1093/cvr/cvx185
}}
{{medline-entry
|title=Effects of circadian clock genes and environmental factors on cognitive aging in old adults in a Taiwanese population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28412756
|abstract=Previous animal studies have indicated associations between circadian clock genes and cognitive impairment . In this study, we assessed whether 11 circadian clockgenes are associated with cognitive aging independently and/or through complex interactions in an old Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examinations (MMSE) were administered to all subjects, and MMSE scores were used to evaluate cognitive function. Our data showed associations between cognitive aging and single nucleotide polymorphisms (SNPs) in 4 key circadian clock genes, [[CLOCK]] rs3749473 (p = 0.0017), [[NPAS2]] rs17655330 (p = 0.0013), [[RORA]] rs13329238 (p = 0.0009), and [[RORB]] rs10781247 (p = 7.9 x 10-5). We also found that interactions between [[CLOCK]] rs3749473, [[NPAS2]] rs17655330, [[RORA]] rs13329238, and [[RORB]] rs10781247 affected cognitive aging (p = 0.007). Finally, we investigated the influence of interactions between [[CLOCK]] rs3749473, [[RORA]] rs13329238, and [[RORB]] rs10781247 with environmental factors such as alcohol consumption, smoking status, physical activity, and social support on cognitive aging (p = 0.002 ~ 0.01). Our study indicates that circadian clock genes such as the [[CLOCK]], [[NPAS2]], [[RORA]], and [[RORB]] genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-environment interactions.
|mesh-terms=* Aged
* Asian Continental Ancestry Group
* Circadian Clocks
* Cognitive Aging
* Environment
* Female
* Gene-Environment Interaction
* Humans
* Life Style
* Male
* Middle Aged
* Polymorphism, Single Nucleotide
* Public Health Surveillance
* Taiwan
|keywords=* Gerotarget
* circadian clock genes
* circadian rhythms
* cognitive aging
* gene-gene and gene-environment interactions
* single nucleotide polymorphisms
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421829
}}
{{medline-entry
|title=Disrupting the key circadian regulator [[CLOCK]] leads to age-dependent cardiovascular disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28223222
|abstract=The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease and worse outcomes. However, the role of circadian rhythms is generally clinically unappreciated. Clock is a core component of the circadian mechanism and here we examine the role of Clock as a vital determinant of cardiac physiology and pathophysiology in aging. Clock  mice develop age-dependent increases in heart weight, hypertrophy, dilation, impaired contractility, and reduced myogenic responsiveness. Young Clock  hearts express dysregulated mRNAs and miRNAs in the [[PTEN]]-AKT signal pathways important for cardiac hypertrophy. We found a rhythm in the Pten gene and [[PTEN]] protein in WT hearts; rhythmic oscillations are lost in Clock  hearts. Changes in [[PTEN]] are associated with reduced AKT activation and changes in downstream mediators GSK-3β, PRAS40, and S6K1. Cardiomyocyte cultures confirm that Clock regulates the AKT signalling pathways crucial for cardiac hypertrophy. In old Clock  mice cardiac AKT, GSK3β, S6K1 phosphorylation are increased, consistent with the development of age-dependent cardiac hypertrophy. Lastly, we show that pharmacological modulation of the circadian mechanism with the REV-ERB agonist SR9009 reduces AKT activation and heart weight in old WT mice. Furthermore, SR9009 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction (TAC), supporting that the circadian mechanism plays an important role in regulating cardiac growth. These findings demonstrate a crucial role for Clock in growth and renewal; disrupting Clock leads to age-dependent cardiomyopathy. Pharmacological targeting of the circadian mechanism provides a new opportunity for treating heart disease.
|mesh-terms=* Aging
* Animals
* CLOCK Proteins
* Cardiovascular Diseases
* Circadian Clocks
* Disease Models, Animal
* Echocardiography
* Gene Expression Regulation
* Hemodynamics
* Mice
* Mice, Knockout
* Myocytes, Cardiac
* Proto-Oncogene Proteins c-akt
* RNA, Small Interfering
* Signal Transduction
|keywords=* Aging
* Cardiac hypertrophy
* Cardiovascular
* Circadian
* MicroRNA
|full-text-url=https://sci-hub.do/10.1016/j.yjmcc.2017.01.008
}}
{{medline-entry
|title=Circadian deep sequencing reveals stress-response genes that adopt robust rhythmic expression during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28221375
|abstract=Disruption of the circadian clock, which directs rhythmic expression of numerous output genes, accelerates aging. To enquire how the circadian system protects aging organisms, here we compare circadian transcriptomes in heads of young and old Drosophila melanogaster. The core clock and most output genes remained robustly rhythmic in old flies, while others lost rhythmicity with age, resulting in constitutive over- or under-expression. Unexpectedly, we identify a subset of genes that adopted increased or de novo rhythmicity during aging, enriched for stress-response functions. These genes, termed late-life cyclers, were also rhythmically induced in young flies by constant exposure to exogenous oxidative stress, and this upregulation is [[CLOCK]]-dependent. We also identify age-onset rhythmicity in several putative primary piRNA transcripts overlapping antisense transposons. Our results suggest that, as organisms age, the circadian system shifts greater regulatory priority to the mitigation of accumulating cellular stress.
|mesh-terms=* Adaptation, Physiological
* Aging
* Animals
* Circadian Clocks
* Circadian Rhythm
* Drosophila Proteins
* Drosophila melanogaster
* Gene Ontology
* Genes, Insect
* High-Throughput Nucleotide Sequencing
* Oxidative Stress
* Transcriptome

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321795
}}
{{medline-entry
|title=The circadian rhythm controls telomeres and telomerase activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25109806
|abstract=Circadian clocks are fundamental machinery in organisms ranging from archaea to humans. Disruption of the circadian system is associated with premature aging in mice, but the molecular basis underlying this phenomenon is still unclear. In this study, we found that telomerase activity exhibits endogenous circadian rhythmicity in humans and mice. Human and mouse TERT mRNA expression oscillates with circadian rhythms and are under the control of [[CLOCK]]-BMAL1 heterodimers. [[CLOCK]] deficiency in mice causes loss of rhythmic telomerase activities, TERT mRNA oscillation, and shortened telomere length. Physicians with regular work schedules have circadian oscillation of telomerase activity while emergency physicians working in shifts lose the circadian rhythms of telomerase activity. These findings identify the circadian rhythm as a mechanism underlying telomere and telomerase activity control that serve as interconnections between circadian systems and aging. 
|mesh-terms=* ARNTL Transcription Factors
* Aging
* Animals
* CLOCK Proteins
* Circadian Clocks
* Circadian Rhythm
* Emergency Medical Services
* Humans
* Mice
* Physicians
* RNA, Messenger
* Telomerase
* Telomere
* Work Schedule Tolerance
* Workforce
|keywords=* Aging
* Circadian rhythm
* Telomerase activity
* Telomere
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2014.07.138
}}
{{medline-entry
|title=Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24270424
|abstract=Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with [[CLOCK]] or [[NPAS2]] regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration. 
|mesh-terms=* ARNTL Transcription Factors
* Aging
* Animals
* Basic Helix-Loop-Helix Transcription Factors
* Brain
* CLOCK Proteins
* Cerebral Cortex
* Circadian Rhythm
* Corpus Striatum
* Gene Expression Regulation
* Gliosis
* Hippocampus
* Homeostasis
* Locomotion
* Mice, Inbred C57BL
* Mice, Knockout
* Mice, Neurologic Mutants
* Nerve Degeneration
* Nerve Tissue Proteins
* Neuroglia
* Neurons
* Oxidation-Reduction
* Oxidative Stress
* Period Circadian Proteins
* RNA Interference
* Sleep Disorders, Circadian Rhythm

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859381
}}
{{medline-entry
|title=[[SIRT1]] mediates central circadian control in the SCN by a mechanism that decays with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23791176
|abstract=[[SIRT1]] is a NAD( )-dependent protein deacetylase that governs many physiological pathways, including circadian rhythm in peripheral tissues. Here, we show that [[SIRT1]] in the brain governs central circadian control by activating the transcription of the two major circadian regulators, BMAL1 and [[CLOCK]]. This activation comprises an amplifying circadian loop involving [[SIRT1]], [[PGC]]-1α, and Nampt. In aged wild-type mice, [[SIRT1]] levels in the suprachiasmatic nucleus are decreased, as are those of BMAL1 and [[PER2]], giving rise to a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain [[SIRT1]] phenocopy these aging-dependent circadian changes, whereas mice that overexpress [[SIRT1]] in the brain are protected from the effects of aging. Our findings indicate that [[SIRT1]] activates the central pacemaker to maintain robust circadian control in young animals, and a decay in this activity may play an important role in aging. 
|mesh-terms=* ARNTL Transcription Factors
* Aging
* Animals
* Brain
* Circadian Clocks
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Neurons
* Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
* Promoter Regions, Genetic
* Sirtuin 1
* Suprachiasmatic Nucleus
* Trans-Activators
* Transcription Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748806
}}
{{medline-entry
|title=Long-lasting effect of perinatal exposure to L-tryptophan on circadian clock of primary cell lines established from male offspring born from mothers fed on dietary protein restriction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23460795
|abstract=Maternal undernutrition programs metabolic adaptations which are ultimately detrimental to adult. L-tryptophan supplementation was given to manipulate the long-term sequelae of early-life programming by undernutrition and explore whether cultured cells retain circadian clock dysregulation. Male rat pups from mothers fed on low protein (8%, LP) or control (18%, CP) diet were given, one hour before light off, an oral bolus of L-tryptophan (125 mg/kg) between Day-12 and Day-21 of age. Body weight, food intake, blood glucose along with the capacity of colonization of primary cells from biopsies were measured during the young (45-55 days) and adult (110-130 days) phases. Circadian clock oscillations were re-induced by a serum shock over 30 hours on near-confluent cell monolayers to follow PERIOD1 and [[CLOCK]] proteins by Fluorescent Linked ImmunoSorbent Assay (FLISA) and period1 and bmal1 mRNA by RT-PCR. Cell survival in amino acid-free conditions were used to measure circadian expression of MAP-LC3B, MAP-LC3B-FP and Survivin. Tryptophan supplementation did not alter body weight gain nor feeding pattern. By three-way ANOVA of blood glucose, sampling time was found significant during all phases. A significant interaction between daily bolus (Tryptophan, saline) and diets (LP, CP) were found during young (p = 0.0291) and adult (p = 0.0285) phases. In adult phase, the capacity of colonization at seeding of primary cells was twice lower for LP rats. By three-way ANOVA of PERIOD1 perinuclear/nuclear immunoreactivity during young phase, we found a significant effect of diets (p = 0.049), daily bolus (p<0.0001) and synchronizer hours (p = 0.0002). All factors were significantly interacting (p = 0.0148). MAP-LC3B, MAP-LC3B-FP and Survivin were altered according to diets in young phase. Sequelae of early-life undernutrition and the effects of L-tryptophan supplementation can be monitored non-invasively by circadian sampling of blood D-glucose and on the expression of PERIOD1 protein in established primary cell lines.
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* Autophagy
* Biomarkers
* Blood Glucose
* CLOCK Proteins
* Cell Adhesion
* Cell Line
* Circadian Clocks
* Colony-Forming Units Assay
* Diet, Protein-Restricted
* Energy Metabolism
* Feeding Behavior
* Female
* Intra-Abdominal Fat
* Lactation
* Male
* Maternal Exposure
* Phenotype
* Pregnancy
* Rats
* Serum
* Tryptophan
* Tryptophan Hydroxylase
* Weight Gain

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584092
}}
{{medline-entry
|title=Common genetic variants in [[ARNTL]] and [[NPAS2]] and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23449886
|abstract=To determine the association between common genetic variation in the clock gene pathway and objectively measured acti-graphic sleep and activity rhythm traits. Genetic association study in two population-based cohorts of elderly participants: the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men (MrOS) study. Population-based. SOF participants (n = 1,407, 100% female, mean age 84 years) and MrOS participants (n = 2,527, 100% male, mean age 77 years) with actigraphy and genotype data. N/A. Common genetic variation in 30 candidate genes was captured using 529 single nucleotide polymorphisms (SNPs). Sleep and activity rhythm traits were objectively measured using wrist actigraphy. In a region of high linkage disequilibrium on chromosome 12p13 containing the candidate gene [[GNB3]], the rs1047776 A allele and the rs2238114 C allele were significantly associated with higher wake after sleep onset (meta-analysis: rs1047776 PADD = 2 × 10(-5), rs2238114 PADD = 5 × 10(-5)) and lower [[LRRC23]] gene expression (rs1047776: ρ = -0.22, P = 0.02; rs2238114: ρ = -0.50, P = 5 × 10(-8)). In MrOS participants, SNPs in [[ARNTL]] and [[NPAS2]], genes coding for binding partners, were associated with later sleep and wake onset time (sleep onset time: [[ARNTL]] rs3816358 P2DF = 1 × 10(-4), [[NPAS2]] rs3768984 P2DF = 5 × 10(-5); wake onset time: rs3816358 P2DF = 3 × 10(-3), rs3768984 P2DF = 2 × 10(-4)) and the SNP interaction was significant (sleep onset time PINT = 0.003, wake onset time PINT = 0.001). A SNP association in the [[CLOCK]] gene replicated in the MrOS cohort, and rs3768984 was associated with sleep duration in a previously reported study. Cluster analysis identified four clusters of genetic associations. These findings support a role for common genetic variation in clock genes in the regulation of inter-related sleep traits in the elderly. Evans DS; Parimi N; Nievergelt CM; Blackwell T; Redline S; Ancoli-Israel S; Orwoll ES; Cummings SR; Stone KL; Tranah GJ. Common genetic variants in [[ARNTL]] and [[NPAS2]] and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. SLEEP 2013;36(3):431-446.
|mesh-terms=* ARNTL Transcription Factors
* Actigraphy
* Aged
* Aged, 80 and over
* Basic Helix-Loop-Helix Transcription Factors
* Chromosomes, Human, Pair 12
* Circadian Rhythm
* Cohort Studies
* Female
* Genetic Variation
* Geriatric Assessment
* Humans
* Linkage Disequilibrium
* Male
* Nerve Tissue Proteins
* Polymorphism, Single Nucleotide
* Polysomnography
* Sleep
* Sleep Wake Disorders
|keywords=* Genetic
* SNP
* actigraphy
* aging
* circadian
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3571755
}}