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Effects of caffeine on the human circadian clock in vivo and in vitro
Abstract
Caffeine’s wakefulness-promoting and sleep-disrupting effects are well established, yet whether caffeine affects human circadian timing is unknown. We show that evening caffeine consumption delays the human circadian melatonin rhythm in vivo and that chronic application of caffeine lengthens the circadian period of molecular oscillations in vitro, primarily with an adenosine receptor/cyclic adenosine monophosphate (AMP)–dependent mechanism. In a double-blind, placebo-controlled, ~49-day long, within-subject study, we found that consumption of a caffeine dose equivalent to that in a double espresso 3 hours before habitual bedtime induced a ~40-min phase delay of the circadian melatonin rhythm in humans. This magnitude of delay was nearly half of the magnitude of the phase-delaying response induced by exposure to 3 hours of evening bright light (~3000 lux, ~7 W/m2) that began at habitual bedtime. Furthermore, using human osteosarcoma U2OS cells expressing clock gene luciferase reporters, we found a dose-dependent lengthening of the circadian period by caffeine. By pharmacological dissection and small interfering RNA knockdown, we established that perturbation of adenosine receptor signaling, but not ryanodine receptor or phosphodiesterase activity, was sufficient to account for caffeine’s effects on cellular timekeeping. We also used a cyclic AMP biosensor to show that caffeine increased cyclic AMP levels, indicating that caffeine influenced a core component of the cellular circadian clock. Together, our findings demonstrate that caffeine influences human circadian timing, showing one way that the world’s most widely consumed psychoactive drug affects human physiology.
... In humans, several clinical observational studies with small sample size have witnessed the alterations of circadian sleepwake (Landolt et al., 1995a;Landolt et al., 1995b;McHill et al., 2014;Weibel et al., 2021), body temperature (Wright et al., 1997;Wright et al., 2000;McHill et al., 2014), blood pressure (Green and Suls, 1996;Guessous et al., 2014), heart rates (Green and Suls, 1996;Kohler et al., 2006;Crooks et al., 2019), melatonin (Wright et al., 1997;Wright et al., 2000;Burke et al., 2015), and cortisol rhythms (Lovallo et al., 2005;Rieth et al., 2016) in adults who consumed caffeine by comparison with placebo controls. ...
... Caffeine also potentiated the light-induced phase shift, which responded to the rest-activity circadian rhythms, indicating that caffeine enhanced the clock sensitivity to light (Antle et al., 2001;Vivanco et al., 2013;van Diepen et al., 2014;Jha et al., 2017;Ruby et al., 2018). In addition, caffeine lengthened the period and amplitude of circadian clocks in mammalian cells in vitro and in mice ex vivo and in vivo (Oike et al., 2011;Narishige et al., 2014;Burke et al., 2015). At the cellular level, caffeine also altered the expression of circadian clock genes, such as Clock, Bmal1, and Per1 in the liver and jejunum of mice under ad libitum feeding conditions (Sherman et al., 2011). ...
... Caffeine influences the circadian rhythms by modulating the endogenous cAMP/Ca 2+ signaling pathway, the core components of the mammalian circadian pacemaker (Harvey et al., 2020;O'Neill et al., 2008), through a variety of complex mechanisms (Aguilar-Roblero et al., 2007;Narishige et al., 2014;Burke et al., 2015;Landolt, 2015;Jagannath et al., 2021) (Figure 3). Basically, caffeine antagonizes all types of adenosine receptors (A 1 , A 2A , A 2B , and A 3 receptors) and mainly functions by non-specifically antagonizing the A 1 and A 2A receptors (Nehlig et al., 1992;Cappelletti et al., 2015;Rodak et al., 2021;Yang et al., 2021). ...
Caffeine is the globally consumed psychoactive substance and the drug of choice for the treatment of apnea of prematurity (AOP), but its therapeutic effects are highly variable among preterm infants. Many of the molecular underpinnings of the marked individual response have remained elusive yet. Interestingly, the significant association between Clock gene polymorphisms and the response to caffeine therapy offers an opportunity to advance our understanding of potential mechanistic pathways. In this review, we delineate the functions and mechanisms of human circadian rhythms. An up-to-date advance of the formation and ontogeny of human circadian rhythms during the perinatal period are concisely discussed. Specially, we summarize and discuss the characteristics of circadian rhythms in preterm infants. Second, we discuss the role of caffeine consumption on the circadian rhythms in animal models and human, especially in neonates and preterm infants. Finally, we postulate how circadian-based therapeutic initiatives could open new possibilities to promote precision caffeine therapy for the AOP management in preterm infants.
... It increases the light-entraining activity rhythm and lengthens the period of hPer2 and mBmal1 [97,99]. In human-cultured cells, caffeine produced its effect on the circadian clock through adenosine receptor-cAMP signaling [100]. ...
... cAMP Signaling Pathway cAMP is also a classical downstream signaling pathway of both A 1 R and A 2A R and plays a key role in the mammalian circadian clock [100,105,115]. The A 1 R can suppress the cAMP pathway through inhibiting adenylate cyclase (AC) via its G i ; contrarily, the adenosine A 2A receptor can stimulate cAMP pathway through activating AC via its G s (Fig. 1) [3]. ...
... The A 1 R can suppress the cAMP pathway through inhibiting adenylate cyclase (AC) via its G i ; contrarily, the adenosine A 2A receptor can stimulate cAMP pathway through activating AC via its G s (Fig. 1) [3]. Burke et al. found that the intracellular mechanism of caffeine-induced regulation of the circadian rhythm is via the adenosine A 1 receptor-cAMP signaling pathway in human cells in vitro [100]. In addition, it was revealed that the cAMP-protein kinase A (PKA)-CREB pathway in rat hippocampal neurons was involved in the antidepressant-like effect of serum [116]. ...
Several studies have reported separate roles of adenosine receptors and circadian clockwork in major depressive disorder. While less evidence exists for regulation of the circadian clock by adenosine signaling, a small number of studies have linked the adenosinergic system, the molecular circadian clock, and mood regulation. In this article, we review relevant advances and propose that adenosine receptor signaling, including canonical and other alternative downstream cellular pathways, regulates circadian gene expression, which in turn may underlie the pathogenesis of mood disorders. Moreover, we summarize the convergent point of these signaling pathways and put forward a pattern by which Homer1a expression, regulated by both cAMP-response element binding protein (CREB) and circadian clock genes, may be the final common pathogenetic mechanism in depression.
... More recent experiments indicated that adenosine may also affect the circadian clock and the interaction between the circadian clock and sleep homeostatic mechanisms. In humans,~200 mg caffeine ingested in the early evening delayed the endogenous melatonin rhythm by roughly 40 min, nearly half of the delay caused by bright light exposure at bedtime (Burke et al., 2015). Convergent pharmacological, genetic, and immunochemical data in vitro suggested that these effects were mediated by an A 1 receptor-, cAMP-dependent mechanism (Burke et al., 2015). ...
... In humans,~200 mg caffeine ingested in the early evening delayed the endogenous melatonin rhythm by roughly 40 min, nearly half of the delay caused by bright light exposure at bedtime (Burke et al., 2015). Convergent pharmacological, genetic, and immunochemical data in vitro suggested that these effects were mediated by an A 1 receptor-, cAMP-dependent mechanism (Burke et al., 2015). In mice, the period of rest-activity in constant conditions became longer, suggesting that the clock slows FIGURE 1 Timeline of sleep and circadian research discoveries demonstrating a role for adenosine in sleep-wake regulation (see text). ...
... In animals, timing of rest-activity after caffeine treatment did not differ from placebo during constant darkness (Jha et al., 2017). In humans, acute caffeine administration under dim-light delayed the dim-light melatonin onset (DLMO) (Burke et al., 2015). Melatonin levels (Wright et al., 2000;Wright, Badia, Myers, Plenzler, & Hakel, 1997) or the course of core body temperature (Wright, Badia, Myers, Plenzler, & Hakel, 1997) during 1 night of sleep deprivation were not significantly affected by acute evening caffeine treatment under dim-light conditions. ...
For hundreds of years, mankind has been influencing its sleep and waking state through the adenosinergic system. For ~100 years now, systematic research has been performed, first started by testing the effects of different dosages of caffeine on sleep and waking behaviour. About 70 years ago, adenosine itself entered the picture as a possible ligand of the receptors where caffeine hooks on as an antagonist to reduce sleepiness. Since the scientific demonstration that this is indeed the case, progress has been fast. Today, adenosine is widely accepted as an endogenous sleep‐regulatory substance. In this review, we discuss the current state of the science in model organisms and humans on the working mechanisms of adenosine and caffeine on sleep. We critically investigate the evidence for a direct involvement in sleep homeostatic mechanisms and whether the effects of caffeine on sleep differ between acute intake and chronic consumption. In addition, we review the more recent evidence that adenosine levels may also influence the functioning of the circadian clock and address the question of whether sleep homeostasis and the circadian clock may interact through adenosinergic signalling. In the final section, we discuss the perspectives of possible clinical applications of the accumulated knowledge over the last century that may improve sleep‐related disorders. We conclude our review by highlighting some open questions that need to be answered, to better understand how adenosine and caffeine exactly regulate and influence sleep.
... Participants who did not maintain the required at-home sleep schedule were rescheduled. On the day of entry, participants were asked not to take any non-steroidal anti-inflammatory medications [35] to ingest caffeine [36] to drink alcohol (Alco-Screen 02, Chematics, North Webster IN), or use any non-approved medications (IDTC-II 6 Panel, Cliawaived, Carlsbad CA). ...
... In response to the four different 12-hour exposures to different daytime lighting, there were no differential responses in subjective sleepiness (SSS) during the daytime (F (1, 108) =0.78, p=0.83, Figure 4E). Figure 5A), 10% fastest reaction times (F (3,36) =0.14, p=0.93; Figure 5B), median reaction times (F (3,36) =0.88, p=0.47; Figure 5C), reciprocal reaction time (F (3,36) =0.46, p=0.71; Figure 5D), number of anticipation errors (F (3,36) =1.15, p=0.36; Figure 5E) and lapses (F (3,36) =0.27, p=0.85; Figure 5F). Similarly, in response to evening light exposure, the pattern of EEG activity did not systematically vary based on daytime light exposure, as measured in the theta band during eyes open (F (3,28) =1.14, p=0.35, Figure 6A) and eyes closed (F (3,28) =0.33, p=0.79, Figure 6B), alpha band with eyes open (F (3,28) =1.06, p=0.39, Figure 6C) and closed (F (3,28) =0.67, p=0.58, Figure 6D). ...
... In response to the four different 12-hour exposures to different daytime lighting, there were no differential responses in subjective sleepiness (SSS) during the daytime (F (1, 108) =0.78, p=0.83, Figure 4E). Figure 5A), 10% fastest reaction times (F (3,36) =0.14, p=0.93; Figure 5B), median reaction times (F (3,36) =0.88, p=0.47; Figure 5C), reciprocal reaction time (F (3,36) =0.46, p=0.71; Figure 5D), number of anticipation errors (F (3,36) =1.15, p=0.36; Figure 5E) and lapses (F (3,36) =0.27, p=0.85; Figure 5F). Similarly, in response to evening light exposure, the pattern of EEG activity did not systematically vary based on daytime light exposure, as measured in the theta band during eyes open (F (3,28) =1.14, p=0.35, Figure 6A) and eyes closed (F (3,28) =0.33, p=0.79, Figure 6B), alpha band with eyes open (F (3,28) =1.06, p=0.39, Figure 6C) and closed (F (3,28) =0.67, p=0.58, Figure 6D). ...
Light at night can improve alertness and cognition. Exposure to daytime light, however, has yielded less conclusive results. In addition to direct effects, daytime light may also mitigate the impact of nocturnal light exposure on alertness. To examine the impact of daytime lighting on daytime cognitive performance, and evening alertness, we studied nine healthy individuals using a within subject crossover design. On four visits, participants were exposed to one of four lighting conditions for 10 h (dim fluorescent, room fluorescent, broad-spectrum LED, standard white LED; the latter three conditions were matched for 100 lx) followed by an exposure to bright evening light. Cognitive performance, subjective and objective measures of alertness were regularly obtained. While daytime alertness was not impacted by light exposure, the broad-spectrum LED light improved several aspects of daytime cognition. The impact of evening light on alertness was not mitigated by the pre-exposure to different daytime lighting conditions. Results suggest that daytime exposure to white light with high melanopic efficacy has the potential to improve daytime cognitive function and that such improvements are likely to be direct rather than a consequence of light-induced changes in alertness.
... A 2A -ARs, but not A 1 -ARs, mediate the arousal effect of caffeine (Huang et al., 2005). Intriguingly, caffeine has been shown to influence circadian timing in humans by an A 1 -AR/cAMP-dependent mechanism (Burke et al., 2015). The basic mechanism of the clock is a cell-autonomous interlocked transcription-translation feedback loop sustained by transcriptional activators brain and muscle ARNT-Like 1 (BMAL1), also known as aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL1), Circadian Locomotor Output Cycles Kaput (CLOCK) or neuronal PAS domain protein (NPAS2), as well as period (PER) and cryptochrome (CRY) (Hardin and Panda, 2013). ...
... Caffeine has been reported to affect the phase of the human circadian clock and primarily affect human cellular circadian clocks via an A 1 -R/cAMP-dependent mechanism (Burke et al., 2015). Recent studies have revealed that caffeine and adenosine alter clock gene expression and circadian rhythms in vitro and in vivo via the Ca 2+ -ERK-AP-1 pathway (Jagannath et al., 2021). ...
... These findings suggest that the circadian rhythm may play critical roles in the response to caffeine citrate therapy in babies experiencing AOP episodes. Interestingly, caffeine has been reported to increase the light responsiveness of the mouse circadian pacemaker (van Diepen et al., 2014) and also affects the human circadian clock in vivo and in vitro (Burke et al., 2015). Therefore, synchronizing caffeine with the circadian rhythm may be useful for optimizing its treatment efficacy. ...
Standard-dose caffeine citrate has been routinely prescribed for apnea of prematurity (AOP) management; however, some preterm infants respond well to the therapy while others do not. The AOP phenotype has been attributed solely to the immature control of the respiratory system consequent to preterm birth, but there are also important genetic influences. Based on our previous report, we tested the hypothesis that the human circadian locomotor output cycles kaput ( CLOCK ) gene polymorphisms play a role in the response to caffeine citrate therapy in preterm infants. We also studied the interactions of the circadian clock with aryl hydrocarbon receptor (AHR) signaling pathways in preterm babies who received caffeine citrate. This single-center study collected data from 112 preterm infants (<35 weeks gestational age) between July 2017 and July 2018, including apnea-free ( n = 48) and apneic ( n = 64) groups. Eighty-eight candidate single nucleotide polymorphisms (SNPs) were tested using the MassARRAY system. Association analysis was performed using the PLINK Whole Genome Data Analysis Toolset and SNPStats software. Linkage disequilibrium (LD) and haplotype analyses were performed using Hapview software. No significant intergroup differences in allele distributions or genotype frequencies of CYP1A2 , CYP3A4 , CYP3A5 , and CYP3A7 were detected in our study on preterm babies. Two more SNPs in AHR were found to be associated with determining the response to caffeine citrate therapy in our pediatric patients. Of the 46 candidate SNPs in the CLOCK gene, 26 were found to be associated with determining the response to caffeine treatment in these babies. Interestingly, a significant association was retained for 18 SNPs in the CLOCK gene after false discovery rate correction. Moreover, strong LD formed in those variants in AHR , ADORA2A , and CLOCK genes was confirmed to be significantly associated with a better response to standard-dose caffeine therapy. In summary, CLOCK gene polymorphisms play a role in determining the response to caffeine therapy in premature neonates with AOP. However, whether the AHR and CLOCK signaling pathways crosstalk with each other during caffeine treatment remains largely unclear. Future clinical studies including more immature babies and basic research are needed to explore the mechanism by which circadian rhythms affect the response to caffeine therapy.
... timed physical activity 32 and caffeine 33 can shift the timing of the SCN-driven melatonin rhythm and presumably the endogenous circadian system but do not entrain the circadian system in totally blind people. 34 Caffeine may alter the circadian system's response to light. ...
... 34 Caffeine may alter the circadian system's response to light. 33,35,36 Other variables that affect circadian rhythms Chronotype. Chronotype refers to a preference for or actual behavioural activity timing. ...
Background:
Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms.
Content:
The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology.
Conclusion:
Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.
... This is compounded with caffeine's affinity for cardiac adenosine A 1 receptors, leading to increased ionotropy, and indirect release of catecholamines which in turn can initiate a fight or flight state (Evans and Battisti, 2018). Caffeine antagonizes A 1 receptors in the brain leading to a reduction in cAMP production (Burke et al., 2015). cAMP is a key secondary messenger involved in coordinating circadian rhythm in mammals (Burke et al., 2015) (O'Neill et al., 2008. ...
... Caffeine antagonizes A 1 receptors in the brain leading to a reduction in cAMP production (Burke et al., 2015). cAMP is a key secondary messenger involved in coordinating circadian rhythm in mammals (Burke et al., 2015) (O'Neill et al., 2008. Other mechanisms include inhibition of phosphodiesterases inducing cAMP-dependent signaling and intracellular Ca 2+ release, which affects presynaptic GABA release in SCN (Chen & van den Pol, 1997). ...
As interest in circadian rhythms and their effects continues to grow, there is an increasing need to perform circadian studies in humans. Although the constant
routine is the gold standard for these studies, there are advantages to performing more naturalistic studies. Here, a review of protocols for such studies is
provided along with sample inclusion and exclusion criteria. Sleep routines, drug use, shift work, and menstrual cycle are addressed as screening considerations.
Regarding protocol, best practices for measuring melatonin, including light settings, posture, exercise, and dietary habits are described. The inclusion/exclusion
recommendations and protocol guidelines are intended to reduce confounding variables in studies that do not involve the constant routine. Given practical
limitations, a range of recommendations is provided from stringent to lenient. The scientific rationale behind these recommendations is discussed. However,
where the science is equivocal, recommendations are based on empirical decisions made in previous studies. While not all of the recommendations listed may be
practical in all research settings and with limited potential participants, the goal is to allow investigators to make well-informed decisions about their screening
procedures and protocol techniques and to improve rigor and reproducibility, in line with the objectives of the National Institutes of Health.
... It is the rapidly rising popularity of highly caff einated energy drinks, and their use with alcohol, that has caused concern [15]. Caff eine interferes with sleep homeostasis by antagonizing the A1 and A2A adenosine receptors as mirrored in reduced sleepiness, improved behavioral performance [2]. Caff eine appears to increase the subjective pleasurable eff ects of alcohol, selectively increases positive reinforcing eff ects of self-administered alcohol. ...
... Furthermore, evidence accumulates that caff eine also impacts on human circadian rhythms, as indexed by changes in salivary melatonin levels [16]. Acute caff eine intake in the evening and at night has been shown to delay the onset of melatonin secretion and decrease nighttime melatonin levels [2]. Besides this, alcohol intake is usually combined with circadian disruption. ...
The аim of the research – to investigate the effects of melatonin on oxidative stressbiomarkers malonic dialdehyde (MDA) and oxidatively modified proteins (OMP) inblood, liver and kidneys of rats exposed to subacute alcohol intoxication, its combinationwith constant light exposure, and caffeine intake.Materials and methods. Experiments were performed on 42 male rats weighing180-200 g kept under standard conditions of vivarium and artificial equinox. Subacutealcohol intoxication was induced by intragastric administration of 40 % ethanol at a doseof 7 ml/kg of body weight for 7 days. Caffeine was administered by gavage at a doseof 30 mg/kg of body weight.Results. Ethanol poisoning results in increase in MDA and OMB, and liver was the mostaffected (90 % and 42 % higher than control). The combination of ethanol with caffeinereduced the intensity of oxidative stress in the blood but increased the toxic effectsof ethanol on the liver (MDA and OMP were 116 % and 60 % above control range).The most significant increase in MDA was in the liver and kidneys under combinationof alcohol intoxication with exposure to constant light (139 % and 33 % respectively).There was a decrease in OMB level along with elevation of MDA level in kidneys of allgroups of alcoholized animals.Administration of 5 mg/kg melatonin for 7 days limited the rise in MDA in the bloodand liver of animals and changes in OMB content in the blood liver and kidneys of animalsexposed to ethanol and constant lighting. Melatonin showed to be less effective in theliver and kidneys of rats treated with a combination of ethanol and caffeine.Conclusion. The data obtained are evidence of the pronounced antioxidant melatoninaction and its capacity to prevent toxic effects of ethanol and its combination withconstant lighting and caffeine introduction into organism.
... At the same time, food intake tends to be less and less restricted to our active phase. Moreover, coffee consumption in the evening is becoming quite common and was shown to delay melatonin production and circadian rhythm, beyond its sleep disruptive effects [22,23]. The circadian central and peripheral clocks are entrained by two distinct main cues: light and food intake, respectively. ...
... At the same time, food intake tends to be less and less restricted to our active phase. Moreover, coffee consumption in the evening is becoming quite common and was shown to delay melatonin production and circadian rhythm, beyond its sleep disruptive effects [22,23]. ...
Most living organisms in both the plant and animal kingdoms have evolved processes to stay in tune with the alternation of day and night, and to optimize their physiology as a function of light supply. In mammals, a circadian clock relying on feedback loops between key transcription factors will thus control the temporally regulated pattern of expression of most genes. Modern ways of life have highly altered the synchronization of human activities with their circadian clocks. This review discusses the links between an altered circadian clock and the rise of pathologies. We then sum up the proofs of concept advocating for the integration of circadian clock considerations in chronotherapy for health care, medicine, and pharmacotherapy. Finally, we discuss the current challenges that circadian biology must face and the tools to address them.
... Caffeine is one of the most widely used stimulators, significantly promoting wakefulness. In the past decades, several researchers have documented the effects of caffeine on sleep and the circadian clock [6,[38][39][40]. However, most of these studies were either short-term or did not exclude the influence of the light-dark cycle. ...
... As REM sleep is under strong influence of the circadian clock [49], this may be due to a disturbance of the circadian clock by caffeine on the previous day or due to an influence of caffeine metabolites on the second day. Caffeine is known to phase delay, or slow down the circadian clock [21,22,24,40]. The circadian clock is synchronized to the normal 24 h rhythm by the external light-dark cycle. ...
Background:
Caffeine is a central nervous system stimulant that influences both the sleep-wake cycle and the circadian clock and is known to influence neuronal activity in the lateral hypothalamus, an important area involved in sleep-wake regulation. Light is a strong zeitgeber and it is known to interact with the effect of caffeine on the sleep-wake cycle. We therefore wanted to investigate the long-term effects of a single dose of caffeine under constant dark conditions.
Methods:
We performed long-term (2 days) electroencephalogram (EEG)/electromyogram recordings combined with multi-unit neuronal activity recordings in the peduncular part of the lateral hypothalamus (PLH) under constant darkness in Brown Norway rats, and investigated the effect of a single caffeine treatment (15 mg/kg) or saline control given 1 h after the onset of the endogenous rest phase.
Results:
After a reduction in sleep and an increase in waking and activity in the first hours after administration, also on the second recording day after caffeine administration, rapid eye movement (REM) sleep was still reduced. Analysis of the EEG showed that power density in the theta range during waking and REM sleep was increased for at least two days. Neuronal activity in PLH was also increased for two days after the treatment, particularly during non-rapid eye movement sleep.
Conclusion:
Surprisingly, the data reveal long-term effects of a single dose of caffeine on vigilance states, EEG, and neuronal activity in the PLH. The absence of a light-dark cycle may have enabled the expression of these long-term changes. It therefore may be that caffeine, or its metabolites, have a stronger and longer lasting influence, particularly on the expression of REM sleep, than acknowledged until now.
... Sleep deprivation (induced by experimenter handling) in nocturnal wildtype mice and hamsters reduces the magnitude of light-induced phase shifts of the locomotor rhythm [3][4][5], but enhances these shifts in day-active rodents such as grass rats (Arvicanthis ansorgei) [6]. In humans, restricting sleep opportunity by housing people under short winter-like photoperiods attenuates melatonin phase responses to bright light administration [7,8]; however, early night sleep disruption caused by pharmacological arousal with caffeine has no effect [9]. Drosophila have long been used as platforms for reaching fundamental understandings of both circadian timekeeping and homeostatic sleep regulation [10,11]. ...
... While previous studies in humans may argue against this possibility [7,8], it is important to note that in those studies, attenuation of circadian responses was achieved through the aggregate effect of partial sleep deprivation as well as photoperiodic history (with increased exposure to ambient evening light during the short nights) [8]; see author discussion. Whatever the dichotomy, a larger point generally emerges when comparing the phase-shifts to light made by diurnal and nocturnal animals who have slept and those who have not: whether in a fly, mouse, hamster, rat or human, an increase in sleep pressure caused by sleep deprivation modulates the size of the phase-shift by only 25-30% [3][4][5][6][7][8][9]. In so many words, light-mediated repositioning of the circadian pacemaker's phase-while under some influence of the sleep homeostatoccurs largely independently of sleep homeostasis, a proposition commensurate with a voluminous literature documenting several functional dissociations between the circadian pacemaker and sleep homeostat e.g., [12][13][14][15][16][17]. ...
Previous investigations in humans and rodent animal models have assessed the interplay of sleep in the circadian system’s phase responses to nighttime light exposure. The resulting data have been mixed, but generally support a modulatory role for sleep in circadian photic resetting (not an absolute requirement). Drosophila have been historically used to provide important insights in the sleep and circadian sciences. However, no experiments to date have evaluated how immediate sleep need or recent sleep history affects their pacemaker’s phase readjustments to light. We did so in the current study by (1) forcing separate groups of animals to stay awake for 1 or 4 h after they were shown a broadspectrum pulse (15 min during the first half of the night, 950 lux), or (2) placing them on a restricted sleep schedule for a week before light presentation without any subsequent sleep disruption. Forced sleep restriction, whether acute or chronic, did not alter the size of light-induced phase shifts. These data are consistent with observations made in other diurnal animals and raise the possibility, more broadly, that phototherapies applied during sleep—such as may be necessary during the winter months—may still be efficacious in individuals experiencing sleep-continuity problems such as insomnia.
... Nutritional factors have many effects on the circadian clock. For example, caffeine can create time fluctuations (18) it is known that caffeine can also have role to accelerate synchronization to new time zones after jetlag (17). Moreover, aligning feeding/fasting cycles with clock-regulated metabolic changes optimizes metabolism, and studies with experimental animals showed that feeding at inappropriate times also disrupts the organization of the circadian system by adverse nutritional conditions and various stimulants, thus contributing to adverse metabolic consequences and chronic disease development (cancer, type 2 Diabetes, heart disease, etc.) (17). ...
... Caffeine is also widely used in many societies (23). Caffeine consumption in the evening delayed the circadian rhythm and extends the time-dependent gene expression in vivo and in vitro (18,46,47). Therefore, careful use of caffeine can accelerate the drift of circadian rhythm after travelling across time zones (46). ...
The circadian rhythm works as a clock that regulates many physiological processes including metabolism, sleep, neurobehavior, epigenetic and hormone secretion so that disruption of the circadian rhythm causes adverse effects on human health. The mutations in DNA increase the risk of developing cancer (a genetic disease caused by genome damage). Cancer formation is also caused by disruption of the circadian rhythm. Therefore, a cell's ability to properly respond to DNA damage and repair DNA is critical in preventing cancer formation. Prevention of DNA damage is important for the occurrence of cancer. Epidemiological and experimental evidence explain the variation of dietary intake effects in cancer prevalence. Dietary factors may affect the efficiency of DNA repair, their effectiveness on epigenetic mechanisms, as well as circadian rhythm and inhibit cancer formation. The purpose of this review is to reveal the effects of nutrition on circadian rhythm and DNA repair, emphasize the scarcity of existing studies, and pave the way for possible experimental studies. There are very few studies in this field, and the future studies of nutrients that affect circadian rhythm are very valuable in order to find new solutions in cancer treatment. Nutrition may have many effects on the circadian system and DNA repair, and ultimately help reduce the burden of chronic diseases.
... Limited work has explored caffeine's impact on sleep and circadian rhythms [11]. Biologically, caffeine affects the sleep-wake cycle, stimulating the central nervous system to block adenosine receptors and delay homeostatic sleep pressure [12]. ...
... Biologically, caffeine affects the sleep-wake cycle, stimulating the central nervous system to block adenosine receptors and delay homeostatic sleep pressure [12]. For example, Burke et al. [11] found that evening caffeine consumption delayed the release of melatonin. Although past research has established significant associations between adult caffeine use and adverse sleep behaviors, the impact of adolescent caffeine use on developing sleep patterns remains overall understudied [13]. ...
Adolescent caffeine use and its implications for developmental changes in sleep and circadian rhythms is under-researched. A majority of adolescents report consuming caffeine and yet the United States has not established federal guidelines for this age group. This widely used stimulant is primarily studied using self-report methodologies; however, there is no standardized method for collecting self-report caffeine data and past studies’ findings have limited generalizability and comparability, making it challenging to examine the effects of caffeine use on adolescents’ sleep. This review discusses methods and measures used for assessing caffeine in the field with adolescents: questionnaires, interviews, and diaries. Based on the review, recommendations for future methodologies and approaches are discussed.
... Skipping breakfast and eating late at night can result in a shift of the circadian clock to nighttime, increasing the risk of obesity and diabetes (7). Various functional food components have been reported to contribute to the regulation of the circadian clock, for instance, caffeine (8), and flavonoids (9,10). Functional food components can contribute to the regulation of the circadian clock and are thought to have beneficial effects on health from a chrono-nutritional perspective. ...
Paramylon, a β-1,3-glucan storage polysaccharide derived from Euglena gracilis , has various health benefits, such as anti-obesity effects and modulation of immune function. However, whether paramylon intake affects the circadian clock remains unknown. In this study, we examined the effect of paramylon intake on the circadian clock. The results showed that the paramylon intake regulated peripheral clocks in mice. Furthermore, cecal pH and short-chain fatty acid concentrations after paramylon intake were measured. The correlation between changes in the expression of clock-related genes and alterations in the intestinal environment was confirmed. In addition, peripheral clock entrainment by paramylon intake was not observed in antibiotic-treated mice whose gut microbiota was weakened. These findings suggest that the regulation of the circadian clock by paramylon intake was mediated by changes in gut microbiota. In addition, the entraining effect of paramylon intake was also confirmed in mice bred under conditions mimicking social jetlag, which implies that paramylon intake may contribute to recovery from social jetlag. Thus, the appropriate consumption of paramylon may have a beneficial effect on health from a chrono-nutritional perspective.
... Another crucial lifestyle factor would be the use of stimulants and hypnotics which, on top of altering sleep homeostasis, can cause circadian changes [3,125]. Individuals already experiencing circadian misalignment or sleep disturbances (e.g. ...
Delayed sleep–wake phase disorder (DSWPD) is a circadian rhythm sleep disorder characterised by a delay in the main sleep period, with patients experiencing difficulty getting to sleep and waking up at socially appropriate times. This often causes insomnia and compromised sleep, results in impairment to daytime function and is associated with a range of comorbidities. Besides interventions aimed at ameliorating symptoms, there is good evidence supporting successful phase advancement with bright light therapy or melatonin administration. However, no treatment to date addresses the tendency to phase delay, which is a common factor amongst the various contributing causes of DSWPD. Circadian phase markers such as core body temperature and circulating melatonin typically correlate well with sleep timing in healthy patients, but numerous variations exist in DSWPD patients that can make these unpredictable for use in diagnostics. There is also increasing evidence that, on top of problems with the circadian cycle, sleep homeostatic processes actually differ in DSWPD patients compared to controls. This naturally has ramifications for management but also for the current approach to the pathogenesis itself in which DSWPD is considered a purely circadian disorder. This review collates what is known on the causes and treatments of DSWPD, addresses the pitfalls in diagnosis and discusses the implications of current data on modified sleep homeostasis, making clinical recommendations and directing future research.
... It has also been found to have a disrupting effect on the body's circadian rhythm. [10] While caffeine consumption has short-term performance benefits, overuse can lead to insomnia or worsen preexisting symptoms. ...
Since the outbreak of the COVID-19 pandemic, the world has come to a standstill, with enforcement of the lockdown, several regulations, and restrictions that brought significant change to people's lifestyles, and induced waves of panic and delirium in individuals everywhere. This unfunded cross-sectional survey-based study aims to evaluate the pandemic's impact on sleep patterns in a sample of the general population worldwide. An online survey was constructed , composing of 31 questions. The Athens scale was used to estimate nocturnal sleep dysfunction and daytime dysfunction. The survey's target population was 13 years and above. 300 responses were received .A majority of the participants reported that they sleep late, have an increased screen time , and used electronics . 45% of the participants said they have insomnia and 55% of the participants claimed they did not have insomnia. Despite the majority claiming to not have insomnia, on employing the Athens scale to calculate individuals' insomnia scores, the results were quite contradictory .Nighttime routines and alarm usage were also monitored. .Therefore, this study has enabled to observe that there has been a definite impact in the sleep cycles of certain individuals since the beginning of the pandemic. Limitations of this study include sample size, random sampling and lack of additional profound data
... Melatonin (N-acetyl-5-methoxytryptamine) is a pineal gland hormone which has an extremely wide range of physiological functions, one of which is potent antioxidant action evidenced by numerous in vitro and in vivo studies [8]. Melatonin secretion by the pineal gland is controlled by an endogenous circadian rhythm, rising at night and suppressed by light [9]. Some studies showed the impact of evening caffeine intake on human circadian rhythms resulting in decreased nighttime melatonin levels [10]. ...
Objective. To study the content of reduced glutathione (GSH), activities of glutathione peroxidase (GP) and glutathione-S-transferase enzymes (GST) in blood and liver of rats exposed to subacute alcohol intoxication, its combination with caffeine intake or constant light exposure, and the possibility of their correction with melatonin.Materials and methods. Experiments were performed on 42 male rats weighing 180-200 g kept under standard conditions of the vivarium and artificial equinox. Alcohol intoxication was induced by intragastric administration 40 % ethanol at a dose of 7 ml/kg of body weight for 7 days. Caffeine was administered by gavage at a dose of 30 mg/kg of body weight.Results. Ethanol poisoning and its combination with caffeine intake or exposure to constant light resulted in a decrease in GSH level and GP activity in RBCs and liver, besides the combination of ethanol+light resulted in more pronounced depletion of the parameters. The combination of ethanol with caffeine resulted in less reduction of GSH level in the blood (by 25%) but more depletion of GSH in the liver (by 45% vs. control) than in ethanol-treated rats. There was an elevation of GST activity in the liver of all groups of alcoholized animals. Administration of 5 mg/kg melatonin for 7 days limited depletion in GSH and prevented the changes in GP and GST activities in the blood and liver of all groups of animals.Conclusions. Melatonin administration prevented ethanol-induced toxicity in rats exposed to ethanol and its combination with caffeine or constant light for 7 days by limiting the depletion in GSH and preventing the changes in GP and GST activities in the blood and liver of all groups of animals.
... Extracellular adenosine in the brain builds up as a correlate of time awake and is thus a strong molecular correlate of the sleep homeostat (Porkka-Heiskanen et al., 1997), Adenosine signalling through A 1 and A 2A receptors encodes sleep need (Lazarus et al., 2019). However, several groups have shown that adenosine, and adenosine receptor antagonists including caffeine, directly regulate circadian timing in several rodents and in humans, independently of their effects on sleep/ wake physiology (Oike et al., 2011;van Diepen et al., 2014;Burke et al., 2015;Ruby et al., 2018). We previously described a signalling pathway downstream of adenosine receptors that directly regulates entrainment and identified adenosine A 1 / A 2A receptor antagonists that specifically altered clock gene expression and circadian rhythms in vitro and in vivo via the Ca 2+ -ERK-AP-1 pathway (Jagannath et al., 2021). ...
Circadian entrainment in mice relies primarily on photic cues that trigger the transcription of the core clock genes Period1/2 in the suprachiasmatic nucleus (SCN), thus aligning the phase of the clock with the dawn/dusk cycle. It has been shown previously that this pathway is directly regulated by adenosine signalling and that adenosine A 2A /A 1 receptor antagonists can both enhance photic entrainment and phase shift circadian rhythms of wheel-running behaviour in mice. In this study, we tested the ability of CT1500, a clinically safe adenosine A 2A /A 1 receptor antagonist to effect circadian entrainment. We show that CT1500 lengthens circadian period in SCN ex vivo preparations. Furthermore, we show in vivo that a single dose of CT1500 enhances re-entrainment to a shifted light dark cycle in a dose-dependent manner in mice and also phase shifts the circadian clock under constant dark with a clear time-of-day related pattern. The phase response curve shows CT1500 causes phase advances during the day and phase delays at dusk. Finally, we show that daily timed administration of CT1500 can entrain the circadian clock to a 24 h rhythm in free-running mice. Collectively, these data support the use of CT1500 in the treatment of disorders of circadian entrainment.
... High-fat diets are the best-known circadian rhythm disruptors and can lead to the reversal of feeding patterns and perturbed metabolic parameters [117,[119][120][121][122]. The relative distribution of macronutrients in diet can also contribute to central and peripheral clock modulation in humans [115,123]. Other nutrients have been investigated for their role in circadian remodelling; a ketogenic diet increases the activation of CCGs via CLOCK-BMAL1 activation, high sodium and high salt intake causes a phase delay in BMAL1 and CRY1 and PER2 peak expression and caffeine and theophylline lengthen the period of the cellular circadian clock [124][125][126][127]. ...
Obesity is a chronic and relapsing public health problem with an extensive list of associated comorbidities. The worldwide prevalence of obesity has nearly tripled over the last five decades and continues to pose a serious threat to wider society and the wellbeing of future generations. The pathogenesis of obesity is complex but diet plays a key role in the onset and progression of the disease. The human diet has changed drastically across the globe, with an estimate that approximately 72% of the calories consumed today come from foods that were not part of our ancestral diets and are not compatible with our metabolism. Additionally, multiple nutrient-independent factors, e.g., cost, accessibility, behaviours, culture, education, work commitments, knowledge and societal set-up, influence our food choices and eating patterns. Much research has been focused on ‘what to eat’ or ‘how much to eat’ to reduce the obesity burden, but increasingly evidence indicates that ‘when to eat’ is fundamental to human metabolism. Aligning feeding patterns to the 24-h circadian clock that regulates a wide range of physiological and behavioural processes has multiple health-promoting effects with anti-obesity being a major part. This article explores the current understanding of the interactions between the body clocks, bioactive dietary components and the less appreciated role of meal timings in energy homeostasis and obesity.
... In addition to light, changes in eating and sleeping schedules, and consumption of stimulants, such as caffeine, can also affect circadian rhythm (Lee & Kim, 2019). Nocturnal caffeine intake has similar effects to changes in circadian rhythm caused by 3 h exposure to 3,000 lux bright light (Burke et al., 2015). Since disturbance of the circadian rhythm in humans is generally associated with sleep disturbance, most treatments for disturbed circadian rhythm consist of improving sleep quality. ...
The rhythmic pattern of biological processes controlled by light over 24 h is termed the circadian rhythm. Disturbance of circadian rhythm due to exposure to light at night (LAN) disrupts the sleep-wake cycle and can promote cardiovascular disease, diabetes, cancer, and metabolic disorders in humans. We studied how dim LAN affects the circadian rhythm and metabolism using male Drosophila. Wild-type flies exposed to the dim light of 10 lux at night displayed altered 24 h sleep-wake behavior and expression patterns of circadian rhythm genes. In addition, the flies became more vulnerable to metabolic stress, such as starvation. Whole-body metabolite analysis revealed decreased amounts of branched-chain amino acids (BCAAs), such as isoleucine and valine. The dim light exposure also increased the expression of branched-chain amino acid aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKDC) enzyme complexes that regulate the metabolism of BCAAs. Flies with the Bcat heterozygous mutation were not vulnerable to starvation stress, even when exposed to dim LAN, and hemolymph BCAA levels did not decrease in these flies. Furthermore, the vulnerability to starvation stress was also suppressed when the Bcat expression level was reduced in the whole body, neurons, or fat body during adulthood using conditional GAL4 and RNA interference. Finally, the metabolic vulnerability was reversed when BCAAs were fed to wild-type flies exposed to LAN. Thus, short-term dim light exposure at night affects the expression of circadian genes and BCAA metabolism in Drosophila, implying a novel function of BCAAs in suppressing metabolic stress caused by disrupted circadian rhythm.
... Caffeine might also contribute to late sleep and circadian timing. Furthermore, consumption of a caffeine dose equivalent to that in a double espresso 3 h before habitual bedtime in healthy adults induced a ~40-min phase delay of the circadian melatonin rhythm 192 . The magnitude of that delay was nearly half the size of the delay induced by evening exposure to bright light. ...
Traditional risk factors for obesity and the metabolic syndrome, such as excess energy intake and lack of physical activity, cannot fully explain the high prevalence of these conditions. Insufficient sleep and circadian misalignment predispose individuals to poor metabolic health and promote weight gain and have received increased research attention in the past 10 years. Insufficient sleep is defined as sleeping less than recommended for health benefits, whereas circadian misalignment is defined as wakefulness and food intake occurring when the internal circadian system is promoting sleep. This Review discusses the impact of insufficient sleep and circadian misalignment in humans on appetite hormones (focusing on ghrelin, leptin and peptide-YY), energy expenditure, food intake and choice, and risk of obesity. Some potential strategies to reduce the adverse effects of sleep disruption on metabolic health are provided and future research priorities are highlighted. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic functions. Furthermore, modern working patterns, lifestyles and technologies are often not conducive to adequate sleep at times when the internal physiological clock is promoting it (for example, late-night screen time, shift work and nocturnal social activities). Efforts are needed to highlight the importance of optimal sleep and circadian health in the maintenance of metabolic health and body weight regulation.
... Home sample DLMO kits have been proven to produce reliable DLMO data and may be favored in clinical practice due to their low sample costs 15,16 . However, apart from light, there are other behaviors and pharmacological agents that have shown to mask, suppress, or promote DLMO and nighttime melatonin levels, such as caffeine 17 , as well as morning 18 and late night exercise 19 . Since a suspected circadian misalignment is not uncommon in patients with mood disorders, such as depression, anxiety and bipolar disorder 20,21 , clinicians should be aware that certain anti-depressants may influence endogenous melatonin profiles. ...
Background. Changing lifestyles and the widespread use of artificial lighting have contributed to the disruption of circadian rhythms in modern society. As various aspects of affect and cognition are also controlled by circadian rhythms, this is of concern. Thus, circadian phase assessment is increasingly applied in the diagnostic process in clinical practice, as knowledge of circadian timing and the etiology of symptoms associated with circadianVer misalignment inform treatment choices. However, clinicians should be aware that certain psychopharmaceuticals may influence endogenous melatonin profiles. Other pharmacological agents and behaviors have shown to mask, suppress, or promote DLMO and nighttime melatonin levels (e.g. caffeine, bright light, exercise). Moreover, health and nutritional organizations are increasingly emphasizing certain foods and dietary supplements (e.g. magnesium, tryptophan) that contain melatonin or boost the body's natural melatonin production. Although it remains unclear whether the increase in melatonin through these foods and supplements can enhance sleep or cause a significant phase shifting effect for accurate diagnosis, it is important to consider possible masking effects when assessing DLMO and treating circadian misalignment. To date, a comprehensive overview of findings relevant for the application in routine clinical care is lacking. Aim. To review the melatonin altering effect of common behaviors, supplements and pharmaceuticals, which are relevant in clinical cases where circadian phase assessments are indicated. Findings will highlight the possible melatonin promoting and/or inhibiting pathways of certain behaviors or substances. We will end by providing suggestions for clinical practice and future research studies. Methods. First, a "mini systematic review" was conducted, in which a sample of papers was synthesized. This ensured that in the full review all important keywords are included in the search strings, and that the most useful and relevant information will be extracted. Next, the full systematic literature search will be conducted in the online databases of PubMed and EMBASE. To collect all relevant studies, we will search abstract, title and keyword fields, and if available, the corresponding Mesh term (for PubMed) and/or Emtree term (for EMBASE). Separate searches for the three main topics of this review will be conducted: 1) (Psycho)pharmaceuticals and substances; 2) food, beverages, and supplements; and 3) behaviors (light exposure, exercise, meal timing, and sleep scheduling). Results. Appendix A of the present systematic review protocol contains a comprehensive overview of the generated search strings.
... We asked that the window be consistent during the study period. Water and medications were allowable any time but, because of the potential of caffeine and artificial sweeteners to affect circadian rhythm [17,18], coffee, tea, chewing gum, and diet beverages were discouraged during the fasting window. ...
Purpose:
Cancer-related fatigue is a prevalent, debilitating condition that can persist for months or years after treatment. In a single-arm clinical trial, the feasibility and safety of a time-restricted eating (TRE) intervention were evaluated among cancer survivors, and initial estimates of within-person change in cancer-related fatigue were obtained.
Methods:
Participants were 4-60 months post-cancer treatment, were experiencing fatigue (≥ 3 on a scale 0-10), and were not following TRE. TRE entailed limiting all food and beverages to a self-selected 10-h window for 14 days. Participants reported their eating window in a daily diary and completed the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Brief Fatigue Inventory (BFI), and symptom inventory pre- and post-intervention. This study was pre-registered at clinicaltrials.gov in January 2020 (NCT04243512).
Results:
Participants (n=39) were 61.5 ± 12.4 years old and 1.8 ± 1.3 years post-treatment; 89.7% had had breast cancer. The intervention was feasible in that 36/39 (92.3%) of participants completed all questionnaires and daily diaries. It was also safe with no severe adverse events or rapid weight loss (average loss of 1.1 ± 2.3 pounds, p=0.008). Most adhered to TRE; 86.1% ate within a 10-h window at least 80% of the days, and the average eating window was 9.33 ± 1.05 h. Fatigue scores improved 5.3 ± 8.1 points on the FACIT-F fatigue subscale (p<0.001, effect size [ES]=0.55), 30.6 ± 35.9 points for the FACIT-F total score (p<0.001, ES=0.50), and -1.0 ± 1.7 points on the BFI (p<0.001, ES=-0.58).
Conclusion:
A 10-h TRE intervention was feasible and safe among survivors, and fatigue improved with a moderate effect size after two weeks.
Limitations:
This was a single-arm study, so it is possible that expectation effects were present for fatigue outcomes, independent of effects of TRE per se. However, this feasibility trial supports evaluation of TRE in randomized controlled trials to address persistent cancer-related fatigue.
... Clearly, caffeine can have a masking effect on several different behaviors, but again circadian rhythms and homeostatic sleep are also directly impacted by the drug. Caffeine can impact the endogenous rhythm (Oike et al., 2011;Burke et al., 2015) and also alter the response of the SCN to light entrainment (Ruby et al., 2018). For homeostatic sleep, caffeine has been shown to attenuate the build-up of sleep propensity during the waking hours (Landolt et al., 2004). ...
Environmental cues (e.g., light-dark cycle) have an immediate and direct effect on behavior, but these cues are also capable of “masking” the expression of the circadian pacemaker, depending on the type of cue presented, the time-of-day when they are presented, and the temporal niche of the organism. Masking is capable of complementing entrainment, the process by which an organism is synchronized to environmental cues, if the cues are presented at an expected or predictable time-of-day, but masking can also disrupt entrainment if the cues are presented at an inappropriate time-of-day. Therefore, masking is independent of but complementary to the biological circadian pacemaker that resides within the brain (i.e., suprachiasmatic nucleus) when exogenous stimuli are presented at predictable times of day. Importantly, environmental cues are capable of either inducing sleep or wakefulness depending on the organism’s temporal niche; therefore, the same presentation of a stimulus can affect behavior quite differently in diurnal vs. nocturnal organisms. There is a growing literature examining the neural mechanisms underlying masking behavior based on the temporal niche of the organism. However, the importance of these mechanisms in governing the daily behaviors of mammals and the possible implications on human health have been gravely overlooked even as modern society enables the manipulation of these environmental cues. Recent publications have demonstrated that the effects of masking weakens significantly with old age resulting in deleterious effects on many behaviors, including sleep and wakefulness. This review will clearly outline the history, definition, and importance of masking, the environmental cues that induce the behavior, the neural mechanisms that drive them, and the possible implications for human health and medicine. New insights about how masking is affected by intrinsically photosensitive retinal ganglion cells, temporal niche, and age will be discussed as each relates to human health. The overarching goals of this review include highlighting the importance of masking in the expression of daily rhythms, elucidating the impact of aging, discussing the relationship between dysfunctional masking behavior and the development of sleep-related disorders, and considering the use of masking as a non-invasive treatment to help treat humans suffering from sleep-related disorders.
... These substances are of particular concern because of the potential side effects, especially related to long-term use: resetting of circadian rhythms, cardiac dysrhythmias, blood pressure variances, gastrointestinal disturbances, and cognitive abnormalities. [29][30][31] Lack of sleep and side effects of sleep/wake aids can negatively impact personal safety and, furthermore, may affect patient safety, as evidenced by 15% of participants reporting sometimes, often, or always making near-miss errors and 19% of participants reporting sometimes or often making errors during clinical nursing experiences. Researchers did not inquire about the types of errors made, but any errors during clinical practice are of concern; and while researchers cannot directly attribute near-miss and actual errors to lack of effective sleep hygiene practices, the correlation is certainly present and concerning. ...
Background: Nursing students are prone to inadequate sleep but not fully aware of personal health risks, potential safety and quailty of care issues. Poor sleep hygiene can impact cognition, aleartness, cognitive speed, and accuracy of tasks completion, lower grades, fatigue and depression.Methods: This descriptive study addressed quantitative data from a 4-point Likert scale and open-ended questions. Nursing students from the National Student Nurse Association enrolled in an associate or baccalaureate program and having had at least one clinical experience were invited to particiate in the study.Results: Results indicate the amount of sleep needed is not being achieved. Participants reported ingesting substances to stay awake and to induce sleep. Nineteen percent of students reported making an error during a clinical experience.Conclusions: Students may be naive in thinking short- and long-term use of sleep-inducing aides and stimulants for wakefulness pose no risks to personal safety and safety of patients. By identifying and addressing systemic causes of nursing students lack of sleep using a comprehensive approach to educate, impose consequences, and promote sleep hygiene at the local and national levels, students will have fewer reasons and justifications for not achieving adequate sleep.
... Of further note, caffeine influences human circadian timing [32]. Evening caffeine consumption delays the human circadian melatonin rhythm [33], and the phase of circadian activity through ryanodine receptors in mouse brain slices containing the suprachiasmatic nucleus [34]. Growing evidence indicates that perturbation of the circadian clock has a significant detrimental effect on immune response with a negative impact on the development and progression of RA [35]. ...
The current ideal goal of rheumatoid arthritis (RA) management is to resolve joint and systemic inflammation by using pharmacological interventions, assuming this will correspondingly lead to overall well-being. Nonetheless, it has emerged that a substantial number of RA patients do not reach optimal disease control. Thus suggesting the holistic management of subjective symptoms might be overlooked. This poses significant medical challenges; hence the proposal of incorporating lifestyle interventions as part of a multidimensional approach. Among these aspects, both patients and physicians perceive the important role of nutrition. This review shall examine how caffeine, one of the most studied bioactive components of the most widely consumed beverages, may potentially interfere with RA management. In particular, the mechanism by which caffeine affects RA pathogenesis, as a trigger for RA onset or flare, including its influence on rheumatic drug metabolism and the most common RA comorbidities and constitutional symptoms are outlined, highlighting important knowledge gaps and unmet research needs.
... Chrononutrition provides an alternative for synchronizing the body's peripheral circadian clock and amplifying the rhythms of the clock system . Various food components including caffeine (Burke et al., 2015), prebiotics (Cheng et al., 2020), tea polyphenols (Qi et al., 2017), proanthocyanidins (Ribas-Latre et al., 2015), harmine (Kondoh et al., 2014), and lithium (Li et al., 2012) could induce phase shifts in the hypothalamus, as well as shape the oscillatory amplitude and period of both central and peripheral clocks in murine models. Other than functional foods, restricted feeding time and intermittent fasting could increase the resistance of hippocampal neurons to neurotoxins and ameliorate cognitive deficits in AD/PD mouse models (Amigo et al., 2017;Anson et al., 2003). ...
Emerging evidence suggests that both disruption of circadian rhythms and gut dysbiosis are closely related to aging-associated neurodegenerative diseases. Over the last decade, the microbiota-gut-brain axis has been an emerging field and revolutionized studies in pathology, diagnosis, and treatment of neurological disorders. Crosstalk between the brain and gut microbiota can be accomplished via the endocrine, immune, and nervous system. Recent studies have shown that the composition and diurnal oscillation of gut microbiota are influenced by host circadian rhythms. This provides a new perspective for investigating the microbiome-gut-brain axis. We aim to review current understanding and research on the dynamic interaction between circadian rhythms and the microbiome-gut-brain axis. Furthermore, we will address the possible neurodegenerative disease contribution through circadian rhythms and microbiome-gut-brain axis crosstalk.
... Although the human phase response curve to light is well characterized in carefully controlled laboratory studies (Minors et al., 1991), erratic light exposure and sleep patterns (Sallinen et al., 2017), inter-individual differences in response to light (Stone et al., 2020), and use of countermeasures like caffeine (Burke et al., 2015) by pilots and flight attendants makes it difficult to predict how adaptation may occur in practice. For example, long-haul flights can involve north/south directionality over the poles, leading to constant light or constant dark exposure during a flight. ...
This article describes the factors that cause sleep issues in aviation and spaceflight. There are many causes of sleep disruption that are common to both domains, including, irregular schedules, circadian misalignment, and inadequate sleep environment. There are also factors that are unique to each type of operation that may lead to the manifestation of sleep disorders among these populations. Each of these factors, and their subsequent impact on sleep, are reviewed in this article.
... For example, consumption of carbohydrate-rich foods can induce a phase shift in the liver (Hirao et al. 2009;Furutani et al. 2015). In addition, there are many reports indicating that caffeine alters the circadian clock of a variety of organisms, including humans (Oike et al. 2011;Narishige et al. 2014;Burke et al. 2015). Caffeine prolongs the free-running period of locomotor activity in mice (Oike et al. 2011) and alters the phase of peripheral clocks (Narishige et al. 2014). ...
Context
The mammalian circadian clock system regulates physiological function. Crude drugs, containing Polygalae Radix, and Kampō, combining multiple crude drugs, have been used to treat various diseases, but few studies have focussed on the circadian clock.
Objective
We examine effective crude drugs, which cover at least one or two of Kampō, for the shortening effects on period length of clock gene expression rhythm, and reveal the mechanism of shortening effects.
Materials and methods
We prepared 40 crude drugs. In the in vitro experiments, we used mouse embryonic fibroblasts from PERIOD2::LUCIFERASE knock-in mice (background; C57BL/6J mice) to evaluate the effect of crude drugs on the period length of core clock gene, Per2, expression rhythm by chronic treatment (six days) with distilled water or crude drugs (100 μg/mL). In the in vivo experiments, we evaluated the free-running period length of C57BL/6J mice fed AIN-93M or AIN-93M supplemented with 1% crude drug (6 weeks) that shortened the period length of the PERIOD2::LUCIFERASE expression rhythm in the in vitro experiments.
Results
We found that Polygalae Radix (ED50: 24.01 μg/mL) had the most shortened PERIOD2::LUCIFERASE rhythm period length in 40 crude drugs and that the CaMKII pathway was involved in this effect. Moreover, long-term feeding with AIN-93M+Polygalae Radix slightly shortened the free-running period of the mouse locomotor activity rhythm.
Discussion and conclusions
Our results indicate that Polygalae Radix may be regarded as a new therapy for circadian rhythm disorder and that the CaMKII pathway may be regarded as a target pathway for circadian rhythm disorders.
... 38,39 Previous studies also proved that alcohol and caffeine could influence human circadian rhythms. 40,41 In addition, life stress could affect the hypothalamus-pituitary-adrenal axis in MD 42 and disrupt the circadian rhythm. 43 Decreased deep sleep 26 and obstructive sleep apnea 44 were also linked to MD and circadian disruption. ...
Objectives:
The underlying etiology of Meniere's disease (MD) is not completely clear, but the precipitated triggers may alter the circadian clock in patients with MD. This study aims to survey the expression of circadian clock genes in peripheral blood (PB) leukocytes of MD patients.
Methods:
We investigated the expression of nine circadian clock genes in the PB leukocytes of patients with MD and normal controls using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).
Results:
We observed significantly lower expression of PER1 gene and higher expression of CLOCK gene in MD patients than those in normal controls (p < 0.05). PER1 did not associate with the degree of dizziness handicap in the patients with MD, but a lower expression of PER1 was significantly correlated with higher pure tone average (PTA) and speech reception threshold of the affected ear (p < 0.05). Patients with PTA > 30 dB had significantly lower PER1 expression than those with PTA ≤30 dB in the affected ear (p < 0.05). Our qRT-PCR result was validated by fewer positively stained leukocytes for PER1 protein in the MD patients using the immunocytochemical study.
Conclusion:
Our study implies the alteration of the circadian clock in patients with MD. In particular, the downregulation of PER1 correlated with the degree of hearing loss in the affected ear. PER1 in PB leukocytes may be a potential marker for the progression of hearing loss in MD.
... In 2015, Burke and colleagues showed that evening caffeine consumption delays the human circadian melatonin rhythm in vivo and that chronic application of caffeine lengthens the circadian period of molecular oscillations in vitro (Burke et al., 2015). Results from this study showed that a caffeine dose equivalent to that in a double espresso consumed 3 hours before habitual bedtime induced a ~40-minute phase delay of the circadian melatonin rhythm in humans. ...
A midair collision in the early morning hours of December 6, 2018 resulted in the tragic deaths of six US Marine Corps aircrew members and the loss of two aircraft, a KC-130 tanker and an F/A-18. The mishap occurred around 2 AM during a routine nighttime air refueling training mission off the coast of Japan. In the investigation that followed, fatigue was identified as a major contributor; the transition from day to night flights was called out as a problem area that continues to plague aviation commands. Subsequent investigations confirmed findings and requested help from the Naval Postgraduate School (NPS) Crew Endurance Team to study the problem and make recommendations for safer transition from day to night flight operations.
The study goal was to provide recommendations to the fleet regarding the limitations and best practices for shifting aviators from day to night operations. After reviewing the scientific literature, NPS designed a study to determine the efficacy of high energy visible (HEV) light exposure in shifting the circadian rhythms of study participants. The project was a hybrid study of military aviators who, as graduate students at NPS, continued their normal daily schedules but came into the laboratory for 6 to 8 hours on three consecutive evenings. The study attempted to replicate the patterns of aviators who could potentially be required to abruptly shift to night flight operations.
Results showed that a single 4-hour exposure of blue-enriched white light (~1000 lux) successfully delayed the circadian phase of all participants an average of 1 hour 19 minutes (range 53 minutes to 1 hour 56 minutes). Melatonin onset was delayed in all participants. This circadian shift is estimated to be a 10-fold increase over what would be achieved without the HEV light. Light was shown to have an alerting effect with participants reporting less sleepiness and reduced subjective workload with improved flight performance.
Conclusions from the literature review and our study indicate that circadian entrainment in military operational settings should use light management as the dominant method for shifting the circadian clock. In general, it is expected that higher rates of adaptation (i.e., more rapid entrainment) will occur by aligning and applying multiple synchronization methods simultaneously, i.e., light management combined with strategically timed exercise, meals, melatonin, and caffeine. Based on these conclusions, we developed general recommendations and two circadian synchronization plans for crewmembers switching from day to night operations. One plan shows a schedule that prepares for night operations shifting over multiple days. The other shows a schedule for crewmembers required to shift abruptly without notice. These plans warrant further development in an operational environment to ensure they can be implemented safely and effectively.
... As the A 1 receptor is the dominant form within the SCN, elevated adenosine, as occurs following sleep deprivation, inhibits the effect of light on the circadian system (Figure 3), whilst adenosine A 1 /A 2A antagonists enhance photic responses [52]. Caffeine, which has A 1 /A 2A antagonism properties, both enhances photic shifts in humans and counters the effects of sleep deprivation on the clock in mice [52,63,68,69]. This pathway provides a molecular framework by which the major drives that control sleep/wake transitions interact, namely the circadian (Process C) and homeostatic (Process S) drives [70,71], thus allowing sleep history to shape photic entrainment processes [52]. ...
Circadian rhythms are essential for the survival of all organisms, enabling them to predict daily changes in the environment and time their behaviour appropriately. The molecular basis of such rhythms is the circadian clock, a self-sustaining molecular oscillator comprising a transcriptional–translational feedback loop. This must be continually readjusted to remain in alignment with the external world through a process termed entrainment, in which the phase of the master circadian clock in the suprachiasmatic nuclei (SCN) is adjusted in response to external time cues. In mammals, the primary time cue, or “zeitgeber”, is light, which inputs directly to the SCN where it is integrated with additional non-photic zeitgebers. The molecular mechanisms underlying photic entrainment are complex, comprising a number of regulatory factors. This review will outline the photoreception pathways mediating photic entrainment, and our current understanding of the molecular pathways that drive it in the SCN.
Obstructive sleep apnea is the most common sleep-related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life and work performance as well as an increased risk of death. Standard treatment seems to have limited effects on cardiovascular and metabolic aspects of the disease, emphasising the need for early diagnosis and additional therapeutic approaches. Recent evidence suggests that the dysregulation of circadian rhythms, processes with endogenous rhythmicity that are adjusted to the environment through various cues, is involved in the pathogenesis of comorbidities. In patients with obstructive sleep apnea, altered circadian gene expression patterns have been demonstrated. Obstructive respiratory events may promote circadian dysregulation through the effects of sleep disturbance and intermittent hypoxia, with subsequent inflammation and disruption of neural and hormonal homeostasis. In this review, current knowledge on obstructive sleep apnea, circadian rhythm regulation, and circadian rhythm sleep disorders is summarised. Studies that connect obstructive sleep apnea to circadian rhythm abnormalities are critically evaluated. Furthermore, pathogenetic mechanisms that may underlie this association, most notably hypoxia signalling, are presented. A bidirectional relationship between obstructive sleep apnea and circadian rhythm dysregulation is proposed. Approaching obstructive sleep apnea as a circadian rhythm disorder may prove beneficial for the development of new, personalised diagnostic, therapeutic and prognostic tools. However, further studies are needed before the clinical approach to obstructive sleep apnea includes targeting the circadian system.
Researchers have been exploring the influence of light on health in office settings for over two decades; however, a greater understanding of physiological responses and technology advancements are shifting the way researchers study the influence of light in realistic environments. New technologies paired with Ecological Momentary Assessments (EMAs) administered via smartphones provide ways to collect information about individual light exposure and occupant response throughout the day. The study aims to document occupant response to tunable lighting in a real office environment, including potential beneficial or adverse health and well-being effects. Twenty-three office employees agreed to participate in a twelve-week study examining occupant response to two lighting conditions (static vs. dynamic). No significant differences were observed for any of the measures, highlighting the importance and complexity of in-situ studies conducted in realistic environments. While prior office studies have shown a significant influence on daytime sleepiness and sleep quality, research has not shown mood or stress to be significantly impacted by lighting conditions. Correlation analyses regarding lighting satisfaction, environmental satisfaction, and visual comfort demonstrate a significant relationship between certain items that may inform future studies. Further, the high correlation means it is reasonable to assume that many environmental factors in offices can influence occupant behavior and well-being.
Longitudinal changes in brain structure and lifestyle can affect sleep phenotypes. However, the influence of the interaction between longitudinal changes in brain structure and lifestyle on sleep phenotypes remains unclear. Genome-wide association study dataset of longitudinal changes in brain structure was obtained from published study. Phenotypic data of lifestyles and sleep phenotypes were obtained from UK Biobank cohort. Using genotype data from UK Biobank, we calculated polygenetic risk scores of longitudinal changes in brain structure phenotypes. Linear/logistic regression analysis was conducted to evaluate interactions between longitudinal changes in brain structure and lifestyles on sleep duration, chronotype, insomnia, snoring and daytime dozing. Multiple lifestyle × longitudinal changes in brain structure interactions were detected for 5 sleep phenotypes, such as physical activity×caudate_age2 for daytime dozing (OR = 1.0389, P = 8.84 × 10-3) in total samples, coffee intake×cerebellar white matter volume_age2 for daytime dozing (OR = 0.9652, P = 1.13 × 10-4) in females. Besides, we found 4 overlapping interactions in different sleep phenotypes. We conducted sex stratification analysis and identified one overlapping interaction between female and male. Our results support the moderate effects of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes, and deepen our understanding of the pathogenesis of sleep disorders.
Despite much attention on digital media use and young peoples’ sleep, the literature on digital media and its impact on sleep in older adolescents and young adults remains to be synthesized. We conducted a systematic review of studies including young people aged 16–25 years. We searched Medline, Web of Science, and CINAHL for observational studies, identifying 60 studies. These studies were assessed for methodological quality. Only studies rated as moderate or high-quality studies were included (n = 42). A narrative synthesis summarized the impact of digital media use on eight sleep outcomes: Bedtime; Sleep onset latency or problems falling asleep; Sleep duration; Early awakening; Sleep disturbance; Daytime tiredness and function; Sleep deficits; Sleep quality. In summary, digital media use was associated to shorter sleep duration and poorer sleep quality. These associations were found for general screen use and use of mobile phone, computer, internet, and social media, but not for television, game console, and tablet use. Most studies investigating bedtime or nighttime use found associations to poor sleep outcomes. Later bedtime and daytime tiredness were associated with mobile phone use at night. Additional research is warranted to draw solid conclusions about the causal direction and to understand the underlying mechanisms.
‘Management of Sleep Disorders in Psychiatry’ provides an in-depth and evidence-based review of sleep-wake disorders included in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) that are associated with a range of psychiatric disorders including mood, anxiety, psychotic, neurocognitive, eating, and substance use disorders. It also includes special sections on sleep-wake disorders associated with pediatric and neurological disorders, and reviews forensic issues encountered in the practice of psychiatry as they relate to sleep disorders. The book is unique in its focus on clinical assessment and management of sleep-wake disorders, and provides in-depth insight into the impact of disturbed sleep and wakefulness on clinical course and treatment outcomes of comorbid psychiatric conditions. Treatments reviewed include both evidence-based pharmacological and behavioral strategies to address sleep-wake disorders in patients with psychiatric disorders. Case vignettes are added to assist in the understanding of key clinical concepts of sleep and psychiatric comorbidity and multiple-choice questions are added for self-assessment. This comprehensive text aims to cater to the needs of the clinicians in a wide range of medical specialties including psychiatrists, sleep medicine physicians, psychologists, primary care physicians, and neurologists who strive to improve the sleep and clinical outcomes of their patients with psychiatric disorders.
Growing evidence from animal and human research indicates the importance of homeostatic regulation of the circadian clock in the body. Dysfunction of the circadian clock caused by jet lag or night-shift work increases the risk of obesity, diabetes, cardiovascular diseases, and cancer. Thus, it is important to consider the circadian clock function for prevention of these diseases. Chrono-nutrition is a recently established research field that examines the relationship between the timing of food/nutrition and health. It is well known that breakfast skipping and late-night meals are independent risk factors for diabetes and cardiovascular diseases. Chrono-nutrition also advocates research on nutrition and the biological clock and the social implementation of the research. Breakfast can advance the phase of the peripheral clock, but late dinner can delay it. Moreover, many functional foods and nutrients, such as caffeine and polyphenols, regulate the circadian clock. In this review, we discuss how diet/nutrition entrains the peripheral clock and the relationship between meal timing and health outcomes. In addition, the effects of time-restricted feeding/eating on metabolism and related diseases are discussed. Lastly, we introduce “personalized chrono-nutrition,” that uses recent progress of technology such as sensors and the artificial intelligence/internet of things (AI/IOT) to promote personalized chrono-nutritional suggestions and health systems.
Objectives:
In the present study, we conducted a systematic review and meta-analysis to assess whether people who achieved less than seven hours of sleep were more likely to develop periodontal disease (PD).
Sources:
We executed electronic searches in the PubMed, EMBASE, and Cochrane Library, as well as a manual search of articles published by leading journals in related fields, for observational studies, published in English from January 1, 1966 to March 31, 2021.which evaluated the relationship between sleep duration and PD. The Agency for Healthcare Research and Quality (AHRQ) quality evaluation scale was used for the cross-sectional studies, and the random effects model was used to summarize the effect sizes in the included studies with a 95% confidence interval (CI).
Results:
A total of 6 cross-sectional studies met the inclusion criteria, totaling 107,777 participants, of which 69,773 had PD. The results of the present indicated that shorter sleep duration (< 7 hours) is significantly associated with PD (Odd ratio (OR), 1.19; 95% CI, 1.16-1.23; P < 0.001; I2 , 0.0%, I2 interval, 0-75%.). The strength of the sensitivity analysis and cumulative meta-analysis confirmed the reliability of the results.
Conclusion:
Although the inclusion of only six studies makes it difficult to explore whether there is a publication bias, we found that insufficient sleep duration was closely related to PD, and we therefore speculated that getting enough sleep may help prevent PD.
The body's circadian system comprises the central (CNS) and peripheral (organ) clocks that allow metabolic, physiological, and behavioral functions to oscillate between daylight and darkness. Thus, the internal circadian clock of mammals drives the rhythms of biological activity throughout the body, generating changes in internal signals that control enzymatic, hormonal, and metabolic functions. Therefore, imbalances between the circadian clock and an imbalanced daily schedule in an individual's daily activities are related to the development of various metabolic diseases, such as obesity, diabetes, cancer, and cardiovascular diseases. Chrononutrition, a tool to alleviate these changes, has clinical and therapeutic potential in regulating the circadian rhythm, modifying dietary patterns, and promoting the intake of chronobiotics. This chapter reviews the molecular mechanisms of compounds present in food (including nutrients, phenolic acids, lipophilic compounds, flavonoids, and others), which can be considered effective chronobiotic potentials for preventing and treating metabolic disorders against circadian misalignment.
Parkinson's disease is a neurodegenerative disorder predominately affecting midbrain dopaminergic neurons that results in a broad range of motor and non-motor symptoms. Sleep complaints are among the most common non-motor symptoms, even in the prodromal period. Sleep alterations in Parkinson's disease patients may be associated with dysregulation of circadian rhythms, intrinsic 24-hour cycles that control essential physiological functions, or with side effects from L-Dopa medication, and physical and mental health challenges. The impact of circadian dysregulation on sleep disturbances in Parkinson's disease is not fully understood; as such we review the systems, cellular and molecular mechanisms that may underlie circadian perturbations in Parkinson's disease. We also discuss the potential benefits of chronobiology-based personalized medicine in the management of Parkinson's disease both in terms of behavioural and pharmacological interventions. We propose that a fuller understanding of circadian clock function may shed an important new light on the aetiology and symptomatology of the disease and may allow for improvements of quality of life for the millions of people with Parkinson's disease.
The time-dependent effects of caffeine intake on physiological functions remain to be investigated, although various effects of caffeine on physiological functions have been document. Therefore, the present study investigated the optimal timing of caffeine intake to produce an efficient anti-obesity effect. We prepared a high-fat diet (HFD) or HFD supplemented with 0.03% caffeine (HFD-caf) and regulated twice-daily 8-hour time-restricted feeding. Male Institute of Cancer Research mice were divided into three groups: group fed HFD alone (control), group fed HFD-caf at the beginning of the active period (BF-caf), and group fed HFD-caf at the end of the active period (DN-caf). The BF-caf group (42.8 ± 1.5 g) showed lower body weight than the other groups (control, 49.7 ± 2.1 g; DN-caf, 47.1 ± 1.3 g), although the three groups showed similar HFD intake levels. Therefore, caffeine intake at the beginning of the active period suppressed HFD-induced body weight gain.
O sono é um estado fisiológico, cíclico, determinante para a saúde. O objetivo deste estudo foi identificar a relação entre qualidade do sono, estado nutricional e frequência do consumo alimentar dos estudantes de graduação de uma universidade pública do sudoeste da Bahia. Para avaliação da qualidade do sono foi utilizado o Índice de Qualidade do sono de Pittsburgh. A avaliação do estado nutricional foi verificada pelo Índice de Massa Corporal (IMC) a partir de medidas auto referidas. A frequência do consumo de alimentos in natura/minimamente processados, processados e ultra processados foi investigada por meio de instrumento adaptado. Foram avaliados 122 estudantes, com idade média de 22,5 ± 4,03 anos, prevalecendo o sexo feminino. A maioria dos acadêmicos teve má qualidade do sono. Quanto ao estado nutricional, foram classificados, na maioria, como eutróficos. Em relação à frequência de consumo alimentar, o feijão e o arroz são consumidos regularmente pela maioria dos estudantes. Já a ingestão diária de frutas, legumes e verduras foi verificada em menos de 50% da amostra. Em contrapartida, observou-se alta frequência no consumo de processados e ultraprocessados. A qualidade do sono não foi associada ao estado nutricional e aos hábitos alimentares, apesar de outros estudos encontrarem essas relações.
The circadian system is responsible for internal functions and regulation of the organism according to environmental cues (zeitgebers). Circadian rhythm dysregulation or chronodisruption has been associated with several diseases, from mental to autoimmune diseases, and with life quality change. Following this, some therapies have been developed to correct circadian misalignments, such as light therapy and chronobiotics. In this manuscript, we describe the circadian‐related diseases so far investigated, and studies reporting relevant data on this topic, evidencing this relationship, are included. Despite the actual limitations in published work, there is clear evidence of the correlation between circadian rhythm dysregulation and disease origin/development, and, in this way, clock‐related therapies emerge as great progress in the clinical field. Future improvements in such interventions can lead to the development of successful chronotherapy strategies, deeply contributing to enhanced therapeutic outcomes. Circadian rhythm dysregulation or chronodisruption has been associated with several diseases. Some therapies have been developed to correct circadian misalignments, such as light therapy and chronobiotics. Clock‐related therapies emerge as great progress in the clinical field and can lead to the development of successful chronotherapy strategies, contributing to enhanced therapeutic outcomes.
Background:
Growing evidence indicates that sleep characteristics predict future substance use and related problems. However, most prior studies assessed a limited range of sleep characteristics, studied a narrow age span, and included few follow-up assessments. Here, we used six annual assessments from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study, which spans adolescence and young adulthood with an accelerated longitudinal design, to examine whether multiple sleep characteristics in any year predict alcohol and cannabis use the following year.
Methods:
The sample included 831 NCANDA participants (423 females; baseline age 12-21 years). Sleep variables included circadian preference, sleep quality, daytime sleepiness, the timing of midsleep (weekday/weekend), and sleep duration (weekday/weekend). Using generalized linear mixed models (logistic for cannabis; ordinal for binge severity), we tested whether each repeatedly measured sleep characteristic (years 0-4) predicted substance use (alcohol binge severity or cannabis use) the following year (years 1-5), covarying for age, sex, race, visit, parental education, and previous year's substance use.
Results:
Greater eveningness, more daytime sleepiness, later weekend sleep timing, and shorter sleep duration (weekday/weekend) all predicted more severe alcohol binge drinking the following year. Only greater eveningness predicted a greater likelihood of any cannabis use the following year. Post-hoc stratified exploratory analyses indicated that some associations (e.g., greater eveningness and shorter weekend sleep duration) predicted binge severity only in female participants, and that middle/high school versus post-high school adolescents were more vulnerable to sleep-related risk for cannabis use.
Conclusions:
Our findings support the relevance of multiple sleep/circadian characteristics in the risk for future alcohol binge severity and cannabis use. Preliminary findings suggest that these risk factors vary based on developmental stage and sex. Results underscore a need for greater attention to sleep/circadian characteristics as potential risk factors for substance use in youth and may inform new avenues to prevention and intervention.
This report was written by the adult researchers, with contributions from young people from the country panels. It aims to draw together and reflect upon the learning from the project, as well as signposting to a wider range of project resources. In what follows, we provide an overview of key themes and messages from the study, foregrounding young people’s research and their creative and artistic work. We then go on to examine the role of the PAR within the project and how this shaped the ways in which evidence was produced and analysed. Finally, we present a set of recommendations for three main sets of key stakeholders.
When the project started in April 2020, the impacts of the COVID-19 pandemic were yet to be tested. Since this time, the research evidence base has grown considerably. It is now well established that the crisis has had significant, far-reaching impacts on young people’s education (Blaskó & Schnepf, 2021, OECD, 2021), their physical and mental health and wellbeing (Carroll et al., 2020; Loades et al., 2020; Duan et al., 2020 Gadermann et al., 2021), and their family lives and peer relationships (Biroli et al, 2020; Branquinho et al, 2020; Lebow et al, 2020; Cluver et al, 2020). There is also stark evidence that it is often young people with pre-existing vulnerabilities, including from families experiencing poverty or violence and young people with special educational needs and disabilities for whom the effects of the crisis have been felt the most (Crawley et al, 2020; Gupta & Jawanda, 2020; Imran et al, 2020; Rosenthal et al, 2020; Thorisdottir et al, 2021).
Significance
We generated high-resolution multiorgan expression data showing that nearly half of all genes in the mouse genome oscillate with circadian rhythm somewhere in the body. Such widespread transcriptional oscillations have not been previously reported in mammals. Applying pathway analysis, we observed new clock-mediated spatiotemporal relationships. Moreover, we found a majority of best-selling drugs in the United States target circadian gene products. Many of these drugs have relatively short half-lives, and our data predict which may benefit from timed dosing.
Photic and non-photic stimuli have been shown to shift the phase of the human circadian clock. We examined how photic and non-photic time cues may be combined by the human circadian system by assessing the phase advancing effects of one evening dose of exogenous melatonin, alone and in combination with one session of morning bright light exposure.
Randomized placebo-controlled double-blind circadian protocol. The effects of four conditions, dim light (∼1.9 lux, ∼0.6 Watts/m(2))-placebo, dim light-melatonin (5 mg), bright light (∼3000 lux, ∼7 Watts/m(2))-placebo, and bright light-melatonin on circadian phase was assessed by the change in the salivary dim light melatonin onset (DLMO) prior to and following treatment under constant routine conditions. Melatonin or placebo was administered 5.75 h prior to habitual bedtime and 3 h of bright light exposure started 1 h prior to habitual wake time.
Sleep and chronobiology laboratory environment free of time cues.
Thirty-six healthy participants (18 females) aged 22 ± 4 y (mean ± SD).
Morning bright light combined with early evening exogenous melatonin induced a greater phase advance of the DLMO than either treatment alone. Bright light alone and melatonin alone induced similar phase advances.
Information from light and melatonin appear to be combined by the human circadian clock. The ability to combine circadian time cues has important implications for understanding fundamental physiological principles of the human circadian timing system. Knowledge of such principles is important for designing effective countermeasures for phase-shifting the human circadian clock to adapt to jet lag, shift work, and for designing effective treatments for circadian sleep-wakefulness disorders.
Burke TM; Markwald RR; Chinoy ED; Snider JA; Bessman SC; Jung CM; Wright Jr KP. Combination of light and melatonin time cues for phase advancing the human circadian clock. SLEEP 2013;36(11):1617-1624.
Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors - either directly or indirectly - have now entered the clinic. However, only one adenosine receptor-specific agent - the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) - has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.
Daily cyclical expression of thousands of genes in tissues such as the liver is orchestrated by the molecular circadian clock, the disruption of which is implicated in metabolic disorders and cancer. Although we understand much about the circadian transcription factors that can switch gene expression on and off, it is still unclear how global changes in rhythmic transcription are controlled at the genomic level. Here, we demonstrate circadian modification of an activating histone mark at a significant proportion of gene loci that undergo daily transcription, implicating widespread epigenetic modification as a key node regulated by the clockwork. Furthermore, we identify the histone-remodelling enzyme mixed lineage leukemia (MLL)3 as a clock-controlled factor that is able to directly and indirectly modulate over a hundred epigenetically targeted circadian "output" genes in the liver. Importantly, catalytic inactivation of the histone methyltransferase activity of MLL3 also severely compromises the oscillation of "core" clock gene promoters, including Bmal1, mCry1, mPer2, and Rev-erbα, suggesting that rhythmic histone methylation is vital for robust transcriptional oscillator function. This highlights a pathway by which the clockwork exerts genome-wide control over transcription, which is critical for sustaining temporal programming of tissue physiology.
Circadian clocks orchestrate 24-h oscillations of essential physiological and behavioral processes in response to daily environmental changes. These clocks are remarkably precise under constant conditions yet highly responsive to resetting signals. With the molecular composition of the core oscillator largely established, recent research has increasingly focused on clock-modifying mechanisms/molecules. In particular, small molecule modifiers, intrinsic or extrinsic, are emerging as powerful tools for understanding basic clock biology as well as developing putative therapeutic agents for clock-associated diseases. In this review, we will focus on synthetic compounds capable of modifying the period, phase, or amplitude of circadian clocks, with particular emphasis on the mammalian clock. We will discuss the potential of exploiting these small molecule modifiers in both basic and translational research.
AIthough intraclass correlation coefficients (lCCs) are commonIy used in behavioral measurement, pychometrics, and behavioral genetics, procodures available for forming inferences about ICC are not widely known. Following a review of the distinction between various forms of the ICC, this article presents procedures available for calculating confidence intervals and conducting tests on ICCs developed using data from one-way and two-way random and mixed-efFect analysis of variance models. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
To identify common genetic variants that predispose to caffeine-induced insomnia and to test whether genes whose expression changes in the presence of caffeine are enriched for association with caffeine-induced insomnia.
A hypothesis-free, genome-wide association study.
Community-based sample of Australian twins from the Australian Twin Registry.
After removal of individuals who said that they do not drink coffee, a total of 2,402 individuals from 1,470 families in the Australian Twin Registry provided both phenotype and genotype information.
A dichotomized scale based on whether participants reported ever or never experiencing caffeine-induced insomnia. A factor score based on responses to a number of questions regarding normal sleep habits was included as a covariate in the analysis. More than 2 million common single nucleotide polymorphisms (SNPs) were tested for association with caffeine-induced insomnia. No SNPs reached the genome-wide significance threshold. In the analysis that did not include the insomnia factor score as a covariate, the most significant SNP identified was an intronic SNP in the PRIMA1 gene (P = 1.4 × 10⁻⁶, odds ratio = 0.68 [0.53 - 0.89]). An intergenic SNP near the GBP4 gene on chromosome 1 was the most significant upon inclusion of the insomnia factor score into the model (P = 1.9 × 10⁻⁶, odds ratio = 0.70 [0.62 - 0.78]). A previously identified association with a polymorphism in the ADORA2A gene was replicated.
Several genes have been identified in the study as potentially influencing caffeine-induced insomnia. They will require replication in another sample. The results may have implications for understanding the biologic mechanisms underlying insomnia.
Caffeine is the most widely consumed centralnervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonine neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.
Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell-cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour.
The circadian rhythms of melatonin and body temperature are set to an earlier hour in women than in men, even when the women and men maintain nearly identical and consistent bedtimes and wake times. Moreover, women tend to wake up earlier than men and exhibit a greater preference for morning activities than men. Although the neurobiological mechanism underlying this sex difference in circadian alignment is unknown, multiple studies in nonhuman animals have demonstrated a sex difference in circadian period that could account for such a difference in circadian alignment between women and men. Whether a sex difference in intrinsic circadian period in humans underlies the difference in circadian alignment between men and women is unknown. We analyzed precise estimates of intrinsic circadian period collected from 157 individuals (52 women, 105 men; aged 18-74 y) studied in a month-long inpatient protocol designed to minimize confounding influences on circadian period estimation. Overall, the average intrinsic period of the melatonin and temperature rhythms in this population was very close to 24 h [24.15 ± 0.2 h (24 h 9 min ± 12 min)]. We further found that the intrinsic circadian period was significantly shorter in women [24.09 ± 0.2 h (24 h 5 min ± 12 min)] than in men [24.19 ± 0.2 h (24 h 11 min ± 12 min); P < 0.01] and that a significantly greater proportion of women have intrinsic circadian periods shorter than 24.0 h (35% vs. 14%; P < 0.01). The shorter average intrinsic circadian period observed in women may have implications for understanding sex differences in habitual sleep duration and insomnia prevalence.
Circadian rhythms are ubiquitous in eukaryotes, and coordinate numerous aspects of behaviour, physiology and metabolism, from sleep/wake cycles in mammals to growth and photosynthesis in plants. This daily timekeeping is thought to be driven by transcriptional-translational feedback loops, whereby rhythmic expression of 'clock' gene products regulates the expression of associated genes in approximately 24-hour cycles. The specific transcriptional components differ between phylogenetic kingdoms. The unicellular pico-eukaryotic alga Ostreococcus tauri possesses a naturally minimized clock, which includes many features that are shared with plants, such as a central negative feedback loop that involves the morning-expressed CCA1 and evening-expressed TOC1 genes. Given that recent observations in animals and plants have revealed prominent post-translational contributions to timekeeping, a reappraisal of the transcriptional contribution to oscillator function is overdue. Here we show that non-transcriptional mechanisms are sufficient to sustain circadian timekeeping in the eukaryotic lineage, although they normally function in conjunction with transcriptional components. We identify oxidation of peroxiredoxin proteins as a transcription-independent rhythmic biomarker, which is also rhythmic in mammals. Moreover we show that pharmacological modulators of the mammalian clock mechanism have the same effects on rhythms in Ostreococcus. Post-translational mechanisms, and at least one rhythmic marker, seem to be better conserved than transcriptional clock regulators. It is plausible that the oldest oscillator components are non-transcriptional in nature, as in cyanobacteria, and are conserved across kingdoms.
During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.
A striking feature of the circadian clock is its flexible yet robust response to various environmental conditions. To analyze the biochemical processes underlying this flexible-yet-robust characteristic, we examined the effects of 1,260 pharmacologically active compounds in mouse and human clock cell lines. Compounds that markedly (>10 s.d.) lengthened the period in both cell lines, also lengthened it in central clock tissues and peripheral clock cells. Most compounds inhibited casein kinase Iepsilon (CKIepsilon) or CKIdelta phosphorylation of the PER2 protein. Manipulation of CKIepsilon/delta-dependent phosphorylation by these compounds lengthened the period of the mammalian clock from circadian (24 h) to circabidian (48 h), revealing its high sensitivity to chemical perturbation. The degradation rate of PER2, which is regulated by CKIepsilon/delta-dependent phosphorylation, was temperature-insensitive in living clock cells, yet sensitive to chemical perturbations. This temperature-insensitivity was preserved in the CKIepsilon/delta-dependent phosphorylation of a synthetic peptide in vitro. Thus, CKIepsilon/delta-dependent phosphorylation is likely a temperature-insensitive period-determining process in the mammalian circadian clock.
Caffeine is one of the most widely consumed stimulants in the world and has been proposed to promote wakefulness by antagonizing function of the adenosine A2A receptor. Here, we show that chronic administration of caffeine reduces and fragments sleep in Drosophila and also lengthens circadian period. To identify the mechanisms underlying these effects of caffeine, we first generated mutants of the only known adenosine receptor in flies (dAdoR), which by sequence is most similar to the mammalian A2A receptor. Mutants lacking dAdoR have normal amounts of baseline sleep, as well as normal homeostatic responses to sleep deprivation. Surprisingly, these mutants respond normally to caffeine. On the other hand, the effects of caffeine on sleep and circadian rhythms are mimicked by a potent phosphodiesterase inhibitor, IBMX (3-isobutyl-1-methylxanthine). Using in vivo fluorescence resonance energy transfer imaging, we find that caffeine induces widespread increase in cAMP levels throughout the brain. Finally, the effects of caffeine on sleep are blocked in flies that have reduced neuronal PKA activity. We suggest that chronic administration of caffeine promotes wakefulness in Drosophila, at least in part, by inhibiting cAMP phosphodiesterase activity.
The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder.
The circadian clock controls daily oscillations of gene expression at the cellular level. We report the development of a high-throughput circadian functional assay system that consists of luminescent reporter cells, screening automation, and a data analysis pipeline. We applied this system to further dissect the molecular mechanisms underlying the mammalian circadian clock using a chemical biology approach. We analyzed the effect of 1,280 pharmacologically active compounds with diverse structures on the circadian period length that is indicative of the core clock mechanism. Our screening paradigm identified many compounds previously known to change the circadian period or phase, demonstrating the validity of the assay system. Furthermore, we found that small molecule inhibitors of glycogen synthase kinase 3 (GSK-3) consistently caused a strong short period phenotype in contrast to the well-known period lengthening by lithium, another presumed GSK-3 inhibitor. siRNA-mediated knockdown of GSK-3β also caused a short period, confirming the phenotype obtained with the small molecule inhibitors. These results clarify the role of GSK-3β in the period regulation of the mammalian clockworks and highlight the effectiveness of chemical biology in exploring unidentified mechanisms of the circadian clock.
• screening
• small molecule library
• kinase
Circadian clocks are complex biochemical systems that cycle with a period of approximately 24 hours. They integrate temporal information regarding phasing of the solar cycle, and adjust their phase so as to synchronize an organism's internal state to the local environmental day and night. Nocturnal light is the dominant regulator of this entrainment. In mammals, information about nocturnal light is transmitted by glutamate released from retinal projections to the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Clock resetting requires the activation of ionotropic glutamate receptors, which mediate Ca2+ influx. The response induced by such activation depends on the clock's temporal state: during early night it delays the clock phase, whereas in late night the clock phase is advanced. To investigate this differential response, we sought signalling elements that contribute solely to phase delay. We analysed intracellular calcium-channel ryanodine receptors, which mediate coupled Ca2+ signalling. Depletion of intracellular Ca2+ stores during early night blocked the effects of glutamate. Activators of ryanodine receptors induced phase resetting only in early night; inhibitors selectively blocked delays induced by light and glutamate. These findings implicate the release of intracellular Ca2+ through ryanodine receptors in the light-induced phase delay of the circadian clock restricted to the early night.
We examined the temporal modulation of intracellular calcium release channels in the suprachiasmatic nucleus (SCN). We found a circadian rhythm in [3H]ryanodine binding that was specific to the SCN. The peak in the rhythm occurred at CT 7 and was due to an increase in Bmax, which correlated well with immunoblots showing an increase in RyR-2 expression in the SCN. Double immunohistochemical studies showed that RyR-2 was expressed exclusively in neurons. Ryanodine and caffeine applied around CT 7-9 advanced the clock phase in a hamster brain slice preparation. No rhythm of IP3R was seen in any of the brain areas studied. Our results indicate that RyR-2 exhibits an endogenous rhythm, which influences the intracellular calcium dynamics and thus modulates SCN activity.
Caffeine and bright light effects on nighttime melatonin and temperature levels in women were tested during the luteal phase of the menstrual cycle (n=30) or the pseudo luteal phase for oral contraceptive users (n=32). Participants were randomly assigned to receive either bright (5000 lux) or dim room light (<88 lux) between 20:00 and 08:00 h under a modified constant routine protocol. Half the subjects in each lighting condition were administered either caffeine (100 mg) or placebo in a double-blind manner at 20:00, 23:00, 02:00 and 05:00 h. Results showed that the combination of bright light and caffeine enhanced nighttime temperature levels to a greater extent than did either caffeine or bright light alone. Both of the latter groups had higher temperature levels relative to the dim light placebo condition and the two groups did not differ. Temperature levels in the bright light caffeine condition were maintained at near peak circadian levels the entire night in the luteal and pseudo luteal phase. Melatonin levels were reduced throughout the duration of bright light exposure for all women. Caffeine reduced the onset of melatonin levels for women in the luteal phase, but it had little effect on melatonin levels for oral contraceptive users. The results for women in the luteal phase of the menstrual cycle are consistent with our previous findings in men. The results also suggest that oral contraceptives may alter the effects of caffeine on nighttime melatonin levels.
Endogenous circadian clocks are robust regulators of physiology and behavior. Synchronization or entrainment of biological clocks to environmental time is adaptive and important for physiological homeostasis and for the proper timing of species-specific behaviors. We studied subjects in the laboratory for up to 55 days each to determine the ability to entrain the human clock to a weak circadian synchronizing stimulus [scheduled activity-rest cycle in very dim (approximately 1.5 lux in the angle of gaze) light-dark cycle] at three approximately 24-h periods: 23.5, 24.0, and 24.6 h. These studies allowed us to test two competing hypotheses as to whether the period of the human circadian pacemaker is near to or much longer than 24 h. We report here that imposition of a sleep-wake schedule with exposure to the equivalent of candle light during wakefulness and darkness during sleep is usually sufficient to maintain circadian entrainment to the 24-h day but not to a 23.5- or 24.6-h day. Our results demonstrate functionally that, in normally entrained sighted adults, the average intrinsic circadian period of the human biological clock is very close to 24 h. Either exposure to very dim light and/or the scheduled sleep-wake cycle itself can entrain this near-24-h intrinsic period of the human circadian pacemaker to the 24-h day.
The 17beta-estradiol (E2) receptor isoforms [estrogen receptor (ER) alpha and ERbeta] bind E2 and selective ER modulators (SERMs) as homodimers (alpha/alpha or beta/beta) or heterodimers (alpha/beta) to regulate gene expression. Although recent studies have shown that ER homodimers regulate unique sets of E2-responsive genes, little information exists regarding the transcriptional actions of the ERalpha/beta heterodimer. This paper describes the development of a U2OS human osteosarcoma (osteoblast) cell line stably expressing both ERalpha and ERbeta isoforms at a ratio of 1:4, a ratio reported to exist in normal, mature osteoblast cells derived from cancellous bone. The regulation of endogenous genes by E2 and 4-hydroxy-tamoxifen were measured in these cells using gene microarrays and real-time RT-PCR. Both E2 and 4-hydroxy-tamoxifen were shown to regulate unique sets of endogenous genes in the U2OS-ERalpha/beta heterodimer cell line (20% and 27% of total, respectively), compared with all the genes regulated in U2OS-ER homodimer cell lines. Furthermore, two novel E2-regulated genes, retinoblastoma binding protein 1 and 7-dehydrocholesterol reductase, were found to contain estrogen response element-like sequences that directly bind the ERalpha/beta heterodimer. These results suggest that the expression of both ER isoforms, forming functional ERalpha/beta heterodimers, result in unique patterns of gene regulation, many of which are distinct from the genes regulated by the ER homodimers.
Caffeine, a component of tea, coffee and cola, induces wakefulness. It binds to adenosine A1 and A2A receptors as an antagonist, but the receptor subtype mediating caffeine-induced wakefulness remains unclear. Here we report that caffeine at 5, 10 and 15 mg kg(-1) increased wakefulness in both wild-type mice and A1 receptor knockout mice, but not in A2A receptor knockout mice. Thus, caffeine-induced wakefulness depends on adenosine A2A receptors.
Caffeine is the most widely used stimulant in Western countries. Some people voluntarily reduce caffeine consumption because it impairs the quality of their sleep. Studies in mice revealed that the disruption of sleep after caffeine is mediated by blockade of adenosine A2A receptors. Here we show in humans that (1) habitual caffeine consumption is associated with reduced sleep quality in self-rated caffeine-sensitive individuals, but not in caffeine-insensitive individuals; (2) the distribution of distinct c.1083T>C genotypes of the adenosine A2A receptor gene (ADORA2A) differs between caffeine-sensitive and -insensitive adults; and (3) the ADORA2A c.1083T>C genotype determines how closely the caffeine-induced changes in brain electrical activity during sleep resemble the alterations observed in patients with insomnia. These data demonstrate a role of adenosine A2A receptors for sleep in humans, and suggest that a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep.
The mammalian circadian clockwork is modeled as transcriptional and posttranslational feedback loops, whereby circadian genes
are periodically suppressed by their protein products. We show that adenosine 3′,5′-monophosphate (cAMP) signaling constitutes
an additional, bona fide component of the oscillatory network. cAMP signaling is rhythmic and sustains the transcriptional
loop of the suprachiasmatic nucleus, determining canonical pacemaker properties of amplitude, phase, and period. This role
is general and is evident in peripheral mammalian tissues and cell lines, which reveals an unanticipated point of circadian
regulation in mammals qualitatively different from the existing transcriptional feedback model. We propose that daily activation
of cAMP signaling, driven by the transcriptional oscillator, in turn sustains progression of transcriptional rhythms. In this
way, clock output constitutes an input to subsequent cycles.
Caffeine is the most commonly used psychoactive stimulant worldwide. It reduces sleep and sleepiness by blocking access to the adenosine receptor. The level of adenosine increases during sleep deprivation, and is thought to induce sleepiness and initiate sleep. Light-induced phase shifts of the rest–activity circadian rhythms are mediated by light-responsive neurons of the suprachiasmatic nucleus (SCN) of the hypothalamus, where the circadian clock of mammals resides. Previous studies have shown that sleep deprivation reduces circadian clock phase-shifting capacity and decreases SCN neuronal activity. In addition, application of adenosine agonists and antagonists mimics and blocks, respectively, the effect of sleep deprivation on light-induced phase shifts in behaviour, suggesting a role for adenosine. In the present study, we examined the role of sleep deprivation in and the effect of caffeine on light responsiveness of the SCN. We performed in vivo electrical activity recordings of the SCN in freely moving mice, and showed that the sustained response to light of SCN neuronal activity was attenuated after 6 h of sleep deprivation prior to light exposure. Subsequent intraperitoneal application of caffeine was able to restore the response to light. Finally, we performed behavioural recordings in constant conditions, and found enhanced period lengthening during chronic treatment with caffeine in drinking water in constant light conditions. The data suggest that increased homeostatic sleep pressure changes circadian pacemaker functioning by reducing SCN neuronal responsiveness to light. The electrophysiological and behavioural data together provide evidence that caffeine enhances clock sensitivity to light.
Background and purpose:
Caffeine is one of the most commonly used psychoactive substances. Circadian rhythms consist of the main suprachiasmatic nucleus (SCN) clocks and peripheral clocks. Although caffeine lengthens circadian rhythms and modifies phase changes in SCN-operated rhythms, the effects on caffeine on the phase, period and amplitude of peripheral organ clocks are not known. In addition, the role of cAMP/Ca(2+) signalling in effects of caffeine on rhythm has not been fully elucidated.
Experimental approach:
We examined whether chronic or transient application of caffeine affects circadian period/amplitude and phase by evaluating bioluminescence rhythm in PER2::LUCIFERASE knock-in mice. Circadian rhythms were monitored in vitro using fibroblasts and ex vivo and in vivo for monitoring of peripheral clocks.
Key results:
Chronic application of caffeine (0.1-10 mM) increased period and amplitude in vitro. Transient application of caffeine (10 mM) near the bottom of the decreasing phase of bioluminescence rhythm caused phase advance in vitro. Caffeine (0.1%) intake caused a phase delay under light-dark or constant dark conditions, suggesting a period-lengthening effect in vivo. Caffeine (20 mg·kg(-1) ) at daytime or at late night-time caused phase advance or delay in bioluminescence rhythm in the liver and kidney respectively. The complicated roles of cAMP/Ca(2+) signalling may be involved in the caffeine-induced increase of period and amplitude in vitro.
Conclusions and implications:
Caffeine affects circadian rhythm in mice by lengthening the period and causing a phase shift of peripheral clocks. These results suggest that caffeine intake with food/drink may help with food-induced resetting of peripheral circadian clocks.
The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle [1], and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise. In addition, we find that later chronotypes show larger circadian advances when exposed to only natural light, making the timing of their internal clocks in relation to the light-dark cycle more similar to earlier chronotypes. These findings have important implications for understanding how modern light exposure patterns contribute to late sleep schedules and may disrupt sleep and circadian clocks.
1.1. Phase shifts of the ocular circadian rhythm in isolated eyes of the marine snail, Bulla gouldiana were produced by 3- and 6-hr pulses of agents that increase or mimic cyclic AMP (cAMP) activity.2.2. The magnitude and direction of phase shifts depended upon the circadian phase of the rhythm, and the phase response curve was similar to that produced by membrane hyperpolarizing treatments in this species.3.3. Phase shifts induced by cAMP were eliminated by a depolarizing agent, tetraethylammonium, applied simultaneously to experimental and control eyes.4.4. As in other species, cAMP may regulate circadian rhythms in Bulla, possibly through effects on membrane potential.