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CLOCK deficiency does not affect body weight of mice. Age-dependent changes in body weight of wild type and Clock-/-mice. (a) Males, (b) females.
Source publication
Circadian clock is implicated in the regulation of aging. The transcription factor CLOCK, a core component of the circadian system, operates in complex with another circadian clock protein BMAL1. Recently it was demonstrated that BMAL1 deficiency results in premature aging in mice. Here we investigate the aging of mice deficient for CLOCK protein....
Contexts in source publication
Context 1
... previously reported [9], Bmal1 -/-mice demonstrate growth retardation at 3-4 months of age, reach maximum weight at around 4-6 months of age and then start losing weight. In sharp contrast to Bmal1 -/-mice, there was no statistically significant difference between weight accumulation of Clock -/-and wild type mice (Figure 1a and 1b). It was reported that the weight of Clock/Clock mutant mice was significantly higher than the weight of wild type mice, most likely as a consequence of hyperphagia [23]. ...
Context 2
... deficiency also affects lifespan; the average lifespan of Clock -/-mice is reduced by 15% compared with wild type mice. CLOCK deficiency does not result in early mortality, and no significant differences in the death rate between genotypes at the beginning of survival curves was observed (Figure 1), which indicates that CLOCK deficiency does not result in the development of life-threatening specific pathologies at early or middle age. Nevertheless, the difference in the maximum lifespan between wild type and Clock -/-was dramatic, which suggests that CLOCK plays a more important role at advanced age. ...
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Citations
... 12,13 Robust circadian rhythms have a positive effect on health while disturbance of the rhythms causes metabolic disorders and may lead to premature aging. [14][15][16][17][18] In mammals, the central clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and is entrained by the periodic light/dark cycle. 19 Peripheral clocks which orchestrate the rhythms in other tissues receive the signals from both the central clock and external cues such as feeding. ...
Sexual dimorphism affects various aspects of physiology, metabolism and longevity. Circadian clock is a master regulator of metabolism. Anti-aging dietary interventions reprogram circadian transcriptome in the liver and other tissues, but little is known about sexual dimorphism of circadian transcriptome. We compared circadian transcriptomes in the liver of male and female mice on ad libitum (AL) and 30% caloric restriction (CR) diets. We found that AL female mice had a larger number of oscillating genes than male mice, and the portion of the transcriptome with sex-specific rhythms displayed phase difference. We found that CR increased the number of oscillating genes in both sexes and strongly synchronized the transcriptome without complete elimination of sex dimorphism in rhythms. Sex also had an effect on the response of the rhythms to CR. Gene ontology analysis revealed sex-specific signatures in metabolic pathways, which suggests a complex interaction of sex, circadian rhythms, and diet.
... The breakdown of circadian rhythm is linked with tumorigenesis by a large number of studies (1). Interestingly, circadian rhythm has also been found to impact the aging process (2)(3)(4)(5). Jet-lag in aged mice increases the mortality rate (2), and genetic deficiency in either Bmal1 (3) or Clock (4) leads to the development of agingassociated phenotypes in mice. Moreover, a recent study reported that BMAL1 antagonizes cellular senescence through repressing LINE1 retrotransposon in primates (5). ...
... On the other hand, Clock knockout mice (Clock −/− ) had minimal muscle alterations and only a slight reduction in the duration of the circadian locomotor activity cycle. However, they experienced a decrease in lifespan and suffered from other conditions such as cataracts and a higher risk of dermatitis [98][99][100]. These differences are possibly due to the distinct mutations in the Clock gene between the two types of mice, with potential compensation by the NPAS2 protein in Clock −/− mice in the absence of CLOCK. ...
Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria and organelle, where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.
... On the other hand, Clock knockout mice (Clock -/-) had minimal muscle alterations and only a slight reduction in the duration of the circadian locomotor activity cycle. However, they experienced a decrease in lifespan and suffered from other conditions such as cataracts and a higher risk of dermatitis [91][92][93]. These differences are possibly due to the distinct mutations in the Clock gene between the two types of mice, with potential compensation by the NPAS2 protein in Clock -/mice in the absence of CLOCK. ...
Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risks of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria, organelle where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.
... One third of the world population is affected by insomnia [48], while we are still learning about the negative impact(s) of chronic insomnia and CRSD on body's homeostasis. It is intriguing to think that CLOCK mutants in mice, where compensatory mechanisms still act to support the circadian rhythm, impaired quality of life and decreased total lifespan by 15% [77]. Accumulating clinical and pre-clinical evidence indicates the potential of medicinal mushrooms, rich in serotonin, as a therapeutic intervention, in depressive disorders [66]. ...
Circadian rhythm consists of complicated molecular mechanisms to orchestrate environmental stimuli to intrinsic molecular clocks. However, circadian rhythm is frequently deregulated in modern society by both extrinsic and biological factors leading to Circadian Rhythm Sleep Disorders (CRSD).
... There is solid evidence from animal studies showing that circadian disruption can accelerate cellular aging and aggravate many age-related diseases and chronic disorders. [35][36][37][38] System-wide knockdown of core circadian genes accelerates aging phenotypes and mortality in mice models. [35][36][37] The circadian clock also affects longevity and health span through the regulation of clock-controlled genes, ie, the genes that are under the control of the clock mechanism, are responsible for the integration between the clock mechanism and other physiological pathways, and ultimately orchestrate the biological output of the circadian pathway. ...
... [35][36][37][38] System-wide knockdown of core circadian genes accelerates aging phenotypes and mortality in mice models. [35][36][37] The circadian clock also affects longevity and health span through the regulation of clock-controlled genes, ie, the genes that are under the control of the clock mechanism, are responsible for the integration between the clock mechanism and other physiological pathways, and ultimately orchestrate the biological output of the circadian pathway. Dysregulation of clock-controlled genes may affect immune system function shortening life span. ...
Objectives:
The majority of the previous research has focused on the impact of average sleep parameters on longevity. In this study, we aimed to investigate the associations of day-to-day deviations in sleep parameters with biological ages among 6052 adults participating in the 2011-2014 waves of the US National Health and Nutrition Examination Survey.
Methods:
Sleep parameters, including sleep duration, efficiency, midpoint, and day-to-day deviations in sleep parameters, including standard deviation of sleep duration (sleep variability), standard deviation of sleep midpoint (sleep irregularity), catch-up sleep, and social jetlag, were obtained from 4 to 7 days of 24-h accelerometer recording. We used physiological data to compute measurements of biological aging according to 3 published algorithms: PhenoAge, Klemera-Doubal method Biological Age, and homeostatic dysregulation.
Results:
After adjustment of multiple covariates, we observed that all parameters of day-to-day deviations in sleep were significantly associated with biological aging with larger sleep variability, larger sleep irregularity, more catch-up sleep, and more social jetlag linked with more advanced biological aging. The significant associations of sleep irregularity, catch-up sleep, and social jetlag with biological aging indices remained even after adjustment for sleep duration, efficiency, and midpoint.
Conclusion:
In this study, we found that day-to-day deviations in sleep parameters are independently associated with biological aging in US general population. Since day-to-day deviation in sleep is a modifiable behavioral factor, our finding suggests that intervention aiming at increasing regularity in sleep patterns may be a novel approach for extending a healthy life span.
... Disruption of the circadian clock gene Bmal1 in mouse leads to pronounced early senescence and dysregulation of blood neutrophil/monocyte/lymphocyte profiles (Kondratov et al., 2006). Similar but less-pronounced progeria effects are seen in Clock gene mutants (Antoch et al., 2008;Dubrovsky, Samsa & Kondratov, 2010). Programmed changes in the human circadian rhythm are seen with ageing (reviewed in Hood & Amir, 2017). ...
The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial - specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.
... During the aging process, the circadian control declines, resulting in dampened and occasionally shifted oscillations of sleep-week cycle, body temperature, suprachiasmatic nucleus (SCN) activity, hormone release, and plasma glucose levels (41)(42)(43). Mice deficient in BMAL1, CLOCK, or PER show reduced life span and premature aging phenotypes, including sarcopenia, osteoporosis, loss of soft tissues, and cataracts (44)(45)(46)(47). ...
The circadian clock governs activity of many physiological processes, thereby playing a pivotal role in human health. Circadian disruption is closely associated with cancer development; in particular, recent discoveries have provided strong evidence supporting specific functions of different molecular clock components in either promoting or inhibiting tumorigenesis. This narrative review aims to summarize the existing data on molecular connections between the clock and cancer. These results along with future efforts pave the road to targeting the circadian clock as a novel pathway for therapeutic intervention. Given the implications of chrono-nutrition interventions such as time-restricted feeding in extending lifespan, chrono-nutrition may have preventive and therapeutic applications for individuals with and at-risk of age-related diseases including cancer.
... Another core protein of the circadian machinery is CLOCK, and this basic helix-loophelix PAS domain transcription factor functions together with ARNTL (BMAL1) in the control of circadian-regulated genes, such as CRY1, PER1/2/3, REV-Erb, ROR, etc. Interestingly, CLOCK null mice display a normal phenotype, presumably due to the fact that CLOCK can be substituted by the PAS domain protein NPAS2 [50]. Indeed, we found NPAS2 nearly three-fold induced upon diclofenac treatment. ...
... Additionally, CLOCK stimulated Histone 3 and 4 acetylation, thereby enabling gene transcription and, through physical interactions with the glucocorticoid receptor (GR), reduced its transcriptional responses, while its interaction with the Rel protein p65 augmented expression of pro-inflammatory molecules [44]. CLOCK is a positive regulator of NFκB-mediated transcription [51], and, given that CLOCK and BMAL1 function together, the dysfunction of these proteins resulted in distinct physiological phenotypes [50]. This included an impaired detoxification of drugs [52]. ...
Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an inflammatory response but returned to normal after 4 weeks of treatment. Notwithstanding, histopathology revealed drug-induced hepatitis, marked glycogen depletion, necrosis and steatosis. Strikingly, the genomic study revealed diclofenac to desynchronize the liver clock with manifest inductions of its components CLOCK, NPAS2 and BMAL1. The > 4-fold induced
CRY1 expression underscored an activated core-loop, and the dose dependent > 60% reduction in PER2mRNA repressed the negative feedback loop; however, it exacerbated hepatotoxicity. Bioinformatics enabled the construction of gene-regulatory networks, and we linked the disruption of the liver-clock to impaired glycogenesis, lipid metabolism and the control of immune responses, as shown by the 3-, 6- and 8-fold induced expression of pro-inflammatory CXCL2, lysozyme and ßdefensin.
Additionally, diclofenac treatment caused adrenocortical hypertrophy and thymic atrophy, and we evidenced induced glucocorticoid receptor (GR) activity by immunohistochemistry. Given that REV-ERB connects the circadian clock with hepatic GR, its > 80% repression alleviated immune responses as manifested by repressed expressions of CXCL9(90%), CCL8(60%) and RSAD2(70%). Together, we propose a circuitry, whereby diclofenac desynchronizes the liver clock in the control of the hepatic metabolism and immune response.
... Compared to other tissues, the ocular lens contains a potent antioxidant system to combat oxidative stress-induced damage. However, with advancing age, deterioration of the antioxidant system results in higher oxidative loaddriven failure of the lens' homeostasis and onset of lens opacity [3,[51][52][53][54][55][56][57][58][59]. Herein, it is worth mentioning that the eye lens has been suggested as one of the best model systems to delineate the molecular mechanism(s) of oxidative-and age-associated pathological signaling as well as therapeutic interventions [3,[60][61][62]. ...
A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2’s activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders.
