1. Natural 24-hour biological clock
Written around the edge were things like "Time to make tea",
"Time to feed the chickens", and "You're late!"
J. K. Rowling, Harry Potter and the Chamber of Secrets (1998)
Normal physiology usually has a rhythmical pattern to it, that is, different activities in the living cells normally occur every day and within the limits of fixed time intervals. For example, the morning cortisol release normally occurs between 6 and 8am; the output of diuresis is at its lowest at night and at its highest in the afternoon, the melatonin secretion usually starts at the beginning of the darkness phase (6–9pm), etc.). Circadian rhythm' (from the Latin phrase circa diem', that is, around a day') or circadian biological clock' are terms used to describe the periodically occurring changes in the expression profile, the biochemistry and the physiology of a cell, a tissue or an organism (e.g. the alternating rest-activity cycles; feeding and metabolism rhythms; daily changes in body temperature, pulse rate and blood pressure; nervous system activity; hormone release; elimination of waste, etc.). The levels of the majority of the mRNAs, proteins and metabolites in eukaryotic cells rhythmically rise and fall in a cyclical fashion. The length of the complete cycle is usually close to 24 hours.
According to the definition given by Beatrice Sweeney, one of the pioneers in the field of research of circadian rhythms, "A circadian rhythm is an oscillation in a biochemical, physiological, or behavioural function which under conditions in nature has a period of exactly 24 hours, in phase with the environmental light and darkness, but which continues to oscillate with a period of approximately but usually not exactly 24 hours" [
The phrase biological clock' (often used interchangeably with circadian clock' or circadian rhythm') could be heard so often nowadays, and in contexts so unrelated to science that it is hard to remember that it had always had a strictly defined meaning. In simpler words, it is the biological clock that reminds us that several hours have passed since we have last eaten (feeding time); that 7–9 hours have passed since we have fallen asleep at night (time to wake up); that we have gone without sleep for 16 or more hours (time to go to bed), etc. For some reason, the term biological clock' is popularly (and incorrectly) used as a connotation of the mechanism of ageing (and most commonly – as a reference to the upper limit of reproductive age of women (e.g. "her biological clock is ticking fast, she is desperate")). In order to avoid any such confusion, we will briefly outline the difference between the basic types of biological clocks.
In principle, a biological clock may belong to one of two basic types: 1) oscillators (as is the circadian clock and similar clocking mechanisms that normally work in cycles shorter than 24-h – 12-h, 8-h, etc. (intradian clocks)); and 2) unidirectional (hourglass) clocks (telomere attrition rate, the Hayflick's limit, etc.). Oscillating clocks usually regulate the normal day-to-day functioning of the cell, the tissue and the organism in young as well as in old age. Indeed, as we will see below, as age advances, the regularity of circadian rhythms becomes impaired and more prone to resetting or disruption by minor stimuli, with multiple deleterious consequences. Unidirectional clocks measure the time until individual cells (and, in a more complex manner – the tissues and the organism) are decommissioned by the mechanism of replicative senescence/death of old age.
Many of the normal physiological processes follow a rhythmical circadian pattern, and many aspects of daily life may revolve around circadian changes. For example, the levels of cortisol in mammals and man peak every day almost immediately after waking up from nighttime sleep, enhancing the stress response in the early wakefulness phase. This may be manifested by heightened arousal, including hypersensitivity to various stimuli and/or hypervigilance (the well-known early morning irritability'). The cortisol awakening response may be enhanced by acute and chronic sleep deprivation (having not slept the previous night or and/or chronic loss of sleep); need to awake very early in the morning (e.g. in shift workers taking very early-morning shifts); consumption of alcohol, caffeine, and other substances; and/or stress, producing anxiety and jitteriness, and, sometimes, volatile temper [
In higher eukaryotes, including mammals and man, the central circadian time' is set by the master circadian clock. It is located in the suprachiasmatic nuclei (SCN) in the hypothalamus [
Every eukaryotic cell possesses the requisite molecular machinery of the core circadian clock and may follow the physiologic rhythm for a long time, even in the absence of major cues. The maintenance of the circadian rhythm, however, is better sustained on tissue, organ and organism levels than in single cells, as the correspondence between the central and the peripheral clocks is necessary to ensure the subtle adjustments of the circadian rhythm. Typically, the clock of the organism is rapidly reset in response to specific cues, but cultured cells may rapidly lose the circadian rhythm, sometimes even in the presence of potent clock-adjusting cues [
The external cues capable of adjusting the circadian clock (also called Zeitgebers', or time givers') may be endogenous or exogenous. A prime example of exogenous clock-adjusting factor is light. The master clock in the mammalian brain is exquisitely sensitive to light. Even a single short light pulse may suffice for resetting the master clock, provided that the wavelength of the light is shorter than the wavelength of infrared light. The light is perceived by the photoreceptors in the retina; then the signal is transmitted to SCN and subsequently to the pineal gland. The latter is the topological site where melatonin is produced. Melatonin (N-acetyl-5-methoxytryptamine – a tryptophan derivative) is the major hormone regulating the sleep-wakefulness cycle as well as other physiological processes, such as sexual development, sexual behaviour, etc. Melatonin is usually produced in small quantities during the daylight phase of the 24-h cycle in diurnal animals and man and in larger quantities during the darkness phase as light suppresses its synthesis [
Exogenous melatonin may cause sleep phase advancement [
Some hormones may function as endogenous cues for adjustment of the circadian clock. For example, administration of the synthetic cortisol analogue dexamethasone may reset the peripheral circadian clocks in mice [
The exact time at which a phase (e.g. rest phase/activity phase) occurs in the 24-h cycle may vary (sometimes – significantly) between individuals of the same species. Among humans, there have always been people that feel the need to go to bed early in the evening and wake up refreshed and alert early in the morning (the morning lark' chronotype); whereas others feel their best in the late afternoon and evening, do not go to bed until late after midnight and sleep soundly until noon the next day (the night owl' chronotype). Extreme variants of the morning lark' and night owl' chronotypes may be synonymous to advanced and delayed sleep phase disorder. Misalignment between the time in the subjective day when one really must get up (e.g. to go to school or to work) and the time one feels rested; and between the time when one needs to go to bed because they are too tired to stay awake and the time when they ought to go to bed in order to ensure that they have rested for enough hours may cause problems. The latter, however, usually become significant only in the cases when the time points between "desired time" and "actual time" for a phase switch are desynchronised by three or more hours (e.g. one must get up at 7am to get to work on time, therefore, they ought to be in bed by 11pm; but one can't normally go to sleep before 2am and does not feel their best before noon). Nevertheless, the fact that the timing of the rest/activity cycle may be quite different in different people has been brought to public awareness to the point that more flexibility in planning study and work cycles are currently being advocated to ensure than individuals with either of the basic chronotypes have equal chances for performing well in school, at the workplace, and in specific cases, such as examinations and business meetings [
The chronotype is heritable, and in specific cases (see below) the molecular variant implicated in chronotype establishment may be identified. It is, however, moderately changeable and may be learned or 'transitioned to', given enough time. Daily routine may play a major role in the adjustment and even the complete reversal of the chronotype. The fact remains, however, that the chronotype of parents is often similar or identical to the chronotype of the offspring. The latter formed the basis of a hypothesis about the possibility of assortative mating among people with morning' and evening' chronotypes', based on the assumption that persons with the one chronotype could only seldom meet persons with the other chronotype, as their daily routines would dovetail' rather than match [
Frequent changes of the daily routine causing disruption of the circadian rhythm (circadian misalignment) – e.g. travelling across several time zones (jet lag), taking rotating shifts, etc.; acute or chronic stress; or failure to entrain the biological clock because of misguiding environmental cues (e.g. working during the day in badly lit offices and sleeping in the light-polluted environment of large cities) may affect the human organism in many ways. Circadian rhythm disruption may bring about various conditions associated with day/night cycle reversal (chronic insomnia at night and/or daytime sleepiness); disordered food intake and energy expenditure (e.g. undesired weight gain); troubled digestion; hormonal dysregulation and others (for details, see below). Notably, these adverse effects may be independent of sleep deprivation, that is, they may develop even in individuals that get their 7–9 hours of sleep per 24h and their minimum dose of light when they are awake, but these occur 'at the wrong time' of the day. There is also the well-documented condition of 'midwinter insomnia' affecting people living in territories close to the North polar circle, where the sun does not rise above the horizon for weeks and months in the winter [
In some cases, disruption of the circadian rhythms may be dangerous. It infamously known that working at night, especially performing monotonous tasks in a badly lit environment (e.g. driving) may result in occurrence of very short (lasting only a second) episodes of falling asleep, which may have very grave consequences. This may occur regardless of whether the driver had slept enough before they sat behind the wheel or not (albeit is it more likely to occur if they have not).
Chronic disruption of the rhythm set by the internal clock may put the individual at increased risk for some common diseases with multifactorial genesis. Circadian misalignment may be associated with increased risk for development of insulin resistance (metabolic syndrome, diabetes type 2) [
2. Looping the loop – core machinery of the circadian clock
On a single-cell level, the functioning of the circadian clock is based on periodical oscillations in the levels of several proteins, forming a negatively controlled feedback loop [
The Cry proteins (from cryptochrome') – Cry1 and Cry2 and the Per proteins (from period') – Per1, Per2 and Per3 are negative regulators of the core circadian clock in mammals. Per and Cry proteins also function together, forming heterodimers. The Per/Cry complex switches the expression of Clock and Bmal1 off, downregulating its own transcription as well (Fig. 1) [
Bmal1, Cry and Per proteins have half-lives of only about 3 hours, as they are continually tagged for degradation by E3 ubiquitin ligases [
Npas2 may substitute for Clock in the suprachiasmatic nuclei [
The promoters of the genes regulated by the circadian clock are usually GC-rich [
Clock and Bmal1 proteins are members of the bHLH-PAS family of proteins. They contain a basic helix-loop-helix (bHLH) domain at the N- terminus [reviewed in detail in
The levels of Clock normally oscillate within the 24-h cycle in eukaryotic cells, but the mechanisms for the rhythmical increase and decrease of the levels of Clock mRNA and protein may be different in different species. The levels of expression of Clock remain relatively steady throughout the 24-hour period in the mouse, but the levels of its mRNA and protein may vary significantly between the nuclear and the cytosolic compartment at different times of the day [
The Per/Cry dimer usually suppresses the transcription of day-phase' proteins by binding to their E-box sequences. The peaks of expression of Per and Cry usually occur in anti-phase to the expression peaks of Clock and Bmal1 (Npas2), although the timing may be different for different proteins. In rats Per1 mRNA peaks in early morning, Per3 mRNA – late in the afternoon and Per2 mRNA – in the transition period between the day and the night (at dusk) [
Cry1 and Cry2 may have light-dependent as well as light-independent regulatory functions. The Cry1 gene contains a day-time' element (D-box) as well as night-time' elements (Rev-ErbA/ROR response elements, RRE) [
The proteins of the eukaryotic circadian oscillator are highly conserved, even between distantly related species. Eukaryotic cryptochromes are related structurally and phylogenetically to Class I prokaryotic photolyases [
Besides the core clock machinery, there are also other proteins functioning in the regulation of the circadian rhythm in higher eukaryotes – e.g. Tim1 (Timeless); deleted in oesophageal cancer (Dec) – Dec1 and Dec2; nuclear receptor subfamily 1 group D (Rev-Erb) proteins; retinoic acid-related orphan receptors (RORs), and others [
There are usually several hours of delay between the peak in the mRNA level of core clock genes and the peak of the expression of the corresponding protein. The core clock feedback loop is controlled predominantly by the slower transcription-mediated mechanism, as the associated mRNA and protein peaks occur within several hours of each other and the timings of peak and trough levels are normally predictable. However, the core proteins of the clock machinery are subject to modification at post-translational level [
Circadian cycles have probably arisen early in evolution, as all eukaryotic cells and even some prokaryotes (e.g. Cyanobacteria) exhibit a 24-h rhythmicity in many of their functions. Cyanobacteria are among the oldest organisms currently living on Earth. The Cyanobacteria system for maintenance of the circadian cycle consists of only four proteins – the three proteins of the kai cluster (kaiA, kaiB, and kaiC) and the sensory histidine kinase sasA [
3. Circadian rhythm of the cell cycle
Publius Ovidius Naso, Amores, c. XVI century BC, Book I, XIII, Line 40.
The synthetic phase of the cell cycle in eukaryotic cells occurs predominantly at night (although this may vary in different tissues). Timing of replication to the darkness phase of the day/night cycle is believed to be an adaptive mechanism originating from the early times of eukaryotic life on Earth (the 'escape from light' hypothesis) [
The circadian rhythmicity of entry and exit from the different phases of the cell cycle is especially noticeable in tissues with rapid turnover. For example, dividing cells from colonic mucosa normally enter the G1 phase of the cell cycle in a relatively coordinated fashion in late afternoon/early evening and the percentage of cells in S phase peaks around midnight [
There are tissues in which the different phases of the cell cycle occur at times inconsistent with the general rule that replication occurs at night. For example, in tissues that are well protected from genotoxic effects (e.g. haematopoietic progenitors in the bone marrow - protected by layers of connective tissue, fat and bone and very rarely coming in contact with genotoxic agents) the replication is normally timed during the day. This may be observed in species with differently timed activity/rest cycles. For example, the synthetic phase of the cell cycle in the bone marrow of mice occurs predominantly in the morning, with the mitotic peak occurring in the interval 6am–12am [
The skin, as the outer border of the multicellular body, is subjected in full to the environmental changes typical of the day/night cycle (ambient temperature, levels of UV irradiation, etc.). The proliferation of the progenitor cells in adult epidermis (healthy as well as damaged) occurs in an oscillating fashion, with the completion of the cell cycle significantly accelerated (3–5 times) in the early phases of skin regeneration. In the mouse epidermis, the S-phase occurs predominantly late into the night [
Melatonin is a potent free radical scavenger [
The expression of the genes of the core circadian clock may be developmentally regulated. The cell cycle of undifferentiated cells (e.g. cells of the early embryo, pluripotent stem cells) is probably not controlled by the circadian clock, at least until the onset of differentiation. In mouse embryonic stem cells, the rhythmicity of metabolism is established before the rhythmicity in the expression of the core clock genes [
The timing of the phases of the cell cycle of adult stem cells and progenitor cells also follows a circadian pattern. The rhythmic waves of transcription of the core clock genes in adult epidermal stem cells and in dividing keratinocytes coincide with peaks of expression of specific subsets of genes involved in the proliferation and differentiation of keratinocytes (e.g. KLF-9) and in their capacity to respond to environmental cues (e.g. TGF-beta) [
Undifferentiated cells from rodents and stem cells from primates and man may exhibit very different properties, specifically in the pattern or repair of DNA damage and the cell cycle [
Cancer stem cells may retain the circadian rhythm of cell division, but the properties of the circadian rhythm in them may be somewhat different from the properties in normal cells. Murine cancer stem cells do not exhibit the typical rhythmical pattern of localisation of Per2 to the cell nucleus [
Differentiation of precursor cells may also follow a circadian pattern. In mouse oligodendrocyte precursors the cell division occurred predominantly during the rest (daylight) phase, whereas the cell differentiation occurred during the wakefulness (nighttime) phase [
The expression of core clock genes and clock-controlled genes in cancer cells may significantly deviate from the typical pattern of expression in normal cells. The expression of some of the genes of the core clock machinery may follow a circadian pattern different from the rhythm of nontransformed cells, others may be homogeneously expressed; or their expression may be inhibited or altogether lost (for details see below). Early research in biopsy samples from different types of tumours showed that some types of tumours (e.g. squamous carcinomas in mice and colorectal carcinomas in man) exhibited no variation in the growth rate within the 24-h cycle [
4. Presence of damage in DNA is a potent cue for adjustment of the circadian clock
Persistence of unrepaired damage in DNA in a normal (nontransformed) cell, preparing for division, results in cell cycle arrest, damage assessment, and attempts for repair of damage and/or induction of apoptosis. Acknowledgement of the presence of unrepaired damage in DNA may trigger adjustment of the circadian clock to a time in the 24-h cycle when the routine checks on DNA integrity, damage repair and/or induction of apoptosis are normally carried out (phase shift). Only after the damage is repaired the cell may attempt to pass the cell cycle checkpoints again.
The first experiments showing the potential of DNA damage as a trigger for phase shifting were carried out on dinoflagellates (single-cell phototrophic eukaryotes capable of producing light) – specifically, Gonyaulax polyedra. Irradiation of G. polyedra cultures with white light or monochromatic light from the visible spectrum during the 'low luminescent capacity' phase (daytime) results in enhanced luminescence in the 'high luminescent capacity phase' (at night), with the rhythm continuing steadily for several days when the cultures were kept constantly in the dark, although the amplitude of the rhythm declined after 3–4 days of constant darkness [
Both major damage-associated signalling pathways (p53-associated and ATM-associated) are capable of induction of circadian phase shifts. DNA damage normally dealt with by activation of ATM/ATR-dependent pathways (strand breaks) usually produces advancement of the next phase of the circadian cycle, with the magnitude of the advance dependent on the subjective time of day when the damage occurred. The mechanism is conserved between different species.
In Neurospora crassa, treatment with DNA damaging agents causes advancement of the next circadian phase [
Per1 and Per2 proteins of the mammalian core clock play important roles in the regulation of ATM-Chk2/ATR-Chk1-associated damage response pathways [
Damage that activates the p53-regulated pathways also produces phase advancements. Some of the core clock genes are directly regulated by p53. For example, the promoter of Per2 contains a conserved p53-response element that partially overlaps the E-box where the Bmal1/Clock dimer normally binds. In the presence of damage, p53 bound to the response element in Per2 gene blocks Bmal1/Clock dimer binding to the Per2 promoter, inhibiting the expression of Per2. This results in advancement of the next circadian phase (in which the levels of Per2 are naturally low) [
Many of the p53-associated effects on the circadian cycle are exerted indirectly. The transcription from the Bmal1 promoter was found to be enhanced in the presence of DNA damage, advancing the onset of the next circadian phase [
p53-deficient mice are tumour-prone and short-lived. They cycle normally between the rest/activity phases when housed in complete darkness but the period is shorter than 24h and may be unstable. Light pulses normally rapidly adjusts the core clock in mice kept in complete darkness, causing phase advances or phase delays, depending on the time in the circadian cycle when the light pulse was administered (e.g. a light pulse administered during the subjective night may cause advance of the next (daylight) phase whereas a pulse administered at the end of the subjective day may delay the onset of the nighttime phase). p53-deficient mice exhibited longer phase delays in response to a light pulse than wild type mice and failed to respond to light with phase advances [
5. Circadian oscillations in the levels of gene products directly involved in the regulation of cell division and/or the transition through major cell cycle checkpoints
The devil will come, and Faustus must be damn'd.
Christopher Marlowe, Doctor Faustus (1604), Scene XIV, Line 36.
The levels of expression of many proteins associated with checkpoint transition, progression in the cell cycle and/or induction of apoptosis may vary within the 24-h cycle. Among the clock-regulated proteins are the c-Myc family of DNA-binding proteins; checkpoint kinases, cyclins and other positive regulators of the cell cycle; negative regulators of the progression in the cell cycle – e.g. CDK inhibitors (p21 (Waf1), p16 (INK)) and Gadd45; proteins functioning in DNA damage-associated response pathways and the maintenance of genomic integrity (ATM, p53, HMG-family of proteins); pro-apoptotic proteins (e.g. the pro-apoptotic members of the BCL-2 family – Bax, Puma); and others. The expression of these proteins may be directly regulated by the core circadian clock (usually, via E-boxes – e.g. c-Myc, Xpa, and others), or they may be downstream targets for transactivation by the core clock genes, their levels following (usually, with only a small delay) the oscillation pattern of the levels of the core clock proteins.
The expression of p53 does not follow a circadian rhythm, as p53 is a major player in many and varied processes in living cells and must respond differentially to events causing its stabilisation and accumulation [
The expression of c-Myc protein is controlled directly by the proteins of the core clock. c-Myc has affinity to E-box sequences in its target proteins [
The expression of cyclins oscillates within the circadian cycle. The levels of expression of cyclins D1 and E in colonic mucosa typically reach their peak levels in late afternoon/early evening (6pm) before G1/S checkpoint transition; and their lowest levels around midnight, when the M phase is about to begin [
The expression of some of the essential proteins of the complexes recognising DNA damage and implementing DNA repair may vary rhythmically within the 24-h cycle [
Proteins functioning in DNA repair other than NER may be controlled by the circadian clock. The levels of N-methylpurine DNA glycosylase (a BER glycosylase, excising 3-methyladenine and 7-methylguanine from DNA) and O6-methylguanine-DNA-methyltransferase (an enzyme catalysing the direct repair of methylated bases by transferring the methyl groups to its own molecule) also oscillate within the 24-h cycle. The peak and the trough levels of these enzymes, however, rarely differ by 1.5–2 -fold [
Some of the core clock proteins may directly influence the chromatin architecture and dynamics. Clock protein possesses intrinsic histone acetyltransferase activity, acetylating the conserved Lys14 residue of histone H3 as well as other (nonhistone) targets, including its own pairing partner Bmal1 (again, on specific lysine residue – Lys537) [
The levels of some of the proteins functioning in the maintenance and the remodelling of the chromatin structure, such as HMG, may rise and fall rhythmically in the 24-h cycle. Hmgb1 levels oscillate in the retinal photoreceptor cells in rats, with protein levels peaking at midday and reaching their minimum late at night [
The levels of Gadd45α and Gadd45β (proteins involved in damage-associated inhibition of the entry in S-phase of the cell cycle and induction of apoptosis) also oscillate rhythmically during the day [
The levels of pro-apoptotic proteins and proteins of DNA damage-associated response normally oscillate within the 24-h cycle, but the amplitude of the oscillation may be significantly altered in cells that have sustained damage. For example, gamma-irradiation of mouse haematopoietic progenitor cells from bone marrow causes significant increases in the oscillation amplitudes of mRNA and protein of the CDK inhibitor p21 and the major negative regulator of p53, Mdm2. The time points in the circadian cycle when the damage had occurred may also significantly matter. If we may use the above example, gamma-irradiation of haematopoietic progenitors from mouse bone marrow occurring early in the night resulted in higher p21 and Mdm2 mRNA levels than the maximum levels of p21 and Mdm2 achieved when the irradiation occurred during the day [
Differences in the amplitude of the circadian oscillations of the levels of expression of genes associated with response to DNA damage may also exist between cells of the same basic type at different phases of differentiation. Using the above example again, when the levels of the proteins p21, Mdm2, Bax and Puma were quantitated in cells isolated from peripheral blood instead of bone marrow cells, the magnitude of the increase in the levels of p21, Mdm2, Bax and Puma was almost two times higher after irradiation occurring during the day than the levels achieved after nighttime irradiation [
6. Genotype-phenotype correlations for mutations and polymorphisms in genes coding for products of the core circadian machinery
The majority of the studies on the functioning of circadian clocks in vivo were carried out in animal models (Drosophila, rats and mice). Human studies on circadian rhythmicity are exclusively observational. Experiments involving specific setups that may cause disruption of circadian rhythms in human beings are considered unethical, as they entail prolonged periods of complete darkness and/or constant illumination, and because studies have so far shown that the health consequences may be quite serious. The reliability of currently available data about the impact of the disruption of circadian rhythm in humans may, therefore, be questionable. For example, in many earlier studies on the impact of light at night and insufficient lighting during the day the participants were allowed to switch artificial light on and off whenever they wanted to, despite its potential role in the resetting of the circadian clock [
6.1. Animal models
Mouse models of deficiencies of virtually all genes of the core circadian loop (or variant alleles of these genes) have been established. Not all of these models exhibit altered circadian pattern (cycle shorter or longer than 24 h) when housed in the absence of environmental cues (e.g. constant darkness) or loss of circadian rhythmicity [reviewed in
The phenotype of Bmal1-deficient homozygotes is the most severe of all mouse phenotypes conferred by mutations in circadian clock genes. While loss of both copies of Clock or both copies of any of the Per and Cry genes does not disrupt the circadian rhythms in mice housed constantly in the dark (although it may cause changes in cycle duration), loss of the Bmal1 gene results in almost immediate and complete loss of circadian rhythmicity in constant darkness [
Npas2 deficiency in mice results in slightly shortened circadian cycle without obvious features of accelerated ageing and/or cancer proneness [
Mice carrying mutations in the Clock gene experience lengthening of the circadian cycle and sleep phase delay [
Both genes coding for Per1 and Per2, and Cry1 and Cry2 must be disrupted at the same time to produce a phenotype of deregulation of circadian rhythms in the mouse, as the functions of the protein products in each pair of homologues may partially overlap [
Homozygous Cry1 deficient mutants usually experience cycle shortening when housed in complete darkness, whereas Cry2 homozygous mutants exhibit lengthening of the circadian cycle [reviewed in
Cry1 homozygous knockout mice, Cry1/Cry2 double knockout mice and Per2 homozygous mutant mice are cancer-prone (spontaneously or following genotoxic challenge) [
There is an intriguing interference between the deficiency of Cry1/Cry2 in mice and the carriership of inactivating mutations in the Tp53 gene. Both conditions, when inherited independently, result in cancer proneness and decreased lifespan [
6.2. Human phenotypes associated with carriership of polymorphic variants of core clock genes
Some rare disorders characterised by abnormal timing of sleep phase and/or duration may be associated with carriership of variant alleles of genes coding for proteins of the circadian clock. The Ser662Gly mutation in the human PER2 gene (rs121908635, associated with advanced sleep phase syndrome 1) modifies a phosphorylation site in the PER2 protein [
The natural short sleeper' human phenotype is associated with heterozygous carriership of the mutation Pro385Arg in the DEC2 gene [
The C allele of the 3111C/T noncoding polymorphism (rs1801260) in the 3'-UTR of the human CLOCK gene has been associated with eveningness' (that is, feeling best and fittest in the hours of afternoon to evening/night, usually accompanied by sleep phase delay), as opposed to morningness', which is characterised by preference for the hours of early morning to early afternoon and sleep phase advancement [
An association between the variant (A) allele of the Rev-ErbA1 polymorphism rs2314339 (G>A) and the risk for abdominal obesity was identified in two different populations (specifically, of Spanish Mediterranean and of North American origin). Specifically, the risk for abdominal obesity was estimated to be about 1.5 times lower for individuals with A-allele containing genotypes (AA, AG) than in G-allele homozygous carriers. The Rev-ErbA1 rs2314339 genotype did not correlate with energy intake (eating patterns, dietary preference) [
Inherited polymorphisms in core clock genes may constitute a genetic factor associated with increased risk for development of various tumours. Carriership of the 3111C/T polymorphism in the human CLOCK1 gene has been linked to increased susceptibility for colon cancer [
7. Association between the disruption of circadian rhythm and the risk of occurrence of common diseases and conditions (diseases of middle and advanced age)
Since many physiological processes occur rhythmically within the 24-h cycle, it could be expected that the disruption of the circadian rhythm may increase the risk for development of multiple diseases and conditions. Indeed, data from mouse models (see above) suggests that the dysfunction of the basic players in the constitution of the circadian rhythm may increase the risk for metabolic syndrome, diabetes, cancer and cardiovascular disease. The International Agency for Research on Cancer (IARC) published in 2007 a statement to the effect that "... Shiftwork that involves circadian disruption is probably carcinogenic to humans..." [IARC shiftwork statement]. Industrialisation is unavoidably associated with disruption of the day/night cycle as it increases the proportion of people involved in indoor jobs during the day (which means insufficient amounts of daylight) and staying up late at night in an environment saturated with artificial lighting. Typical evening activities in modern societies are usually associated with consumption of the major meal of the day late in the evening (or even the night) and increased frequency of snacking between meals (usually, on foods rich in carbohydrate and fat). To this adds the effect of night shift work and the opportunities for travelling long distances by air flight (associated with jet lag syndrome). It could be expected that the effect of disrupted circadian rhythms on human health would greatly increase in the near future.
Numerous studies conducted in humans showed that disruption of the physiological circadian rhythm may significantly increase the risk of various tumours - specifically, cancer of the mammary gland, the prostate gland, the colon and rectum; and the lung [
The potential for adjustment of the core clock by external cues (light) may also play a role in the constitution of cancer risk. The overall incidence of cancer has been reported to be lower among the totally blind compared to the general population [
The cancer risk conferred by disruption of circadian rhythms may be modifiable by other factors, including other risk factors. For example, there have been reports about increased risk for lung cancer among selected groups with chronically disrupted circadian cycle (night shift workers) [
Besides the impact on the risk for development of cancer, disruption of circadian rhythms may be partially responsible for differential outcomes when cancer has already developed. Studies conducted in mice demonstrated that light at night may stimulate the growth of carcinoma of the mammary gland [
In some tumours (the already mentioned colorectal, breast and prostate cancers, but also in thyroid carcinoma) have been observed somatic mutations of the core genes of the circadian clock and/or the auxiliary clock genes [
The expression of DEC1 is severely downregulated or the gene copies are deleted in over 50% of the cancers of the oesophagus [
Studies conducted in patients with chronic lymphocytic leukemia (CLL) showed that in tumour cells the expression of BMAL1, PER1 and PER2 was downregulated, whereas the expression of c-MYC and cyclin D1 was upregulated [
The levels of expression of core clock proteins may serve as predictors of individual outcomes in cancer. High BMAL1 levels in the primary tumour in patients with colorectal cancer were associated with longer overall survival (>1.5 times) than the overall survival rates in patients with tumours with low BMAL1 levels [
High levels of expression of CRY1 in patients with colorectal cancer were associated with lower overall survival rates [
Disruption of the oscillating rhythm of expression of some of the core clock proteins may be associated with more rapid cancer progression. For example, homogeneous (non-oscillating) expression of BMAL1 or PER2 in breast cancers may be associated with increased rates of lymph node metastasis and more aggressive course of the disease [
It has been proposed that the growth rate of tumours was different at different times of the 24-h cycle [
The circadian clock has been found to play a role in the pathogenesis of multifactorial diseases and conditions other than cancer as well. As was already mentioned above, disruption of the circadian rhythm in animals and man has been linked with deregulation of feeding patterns/energy expenditure and with disordered glucose metabolism. Weight gain and/or failure to lose weight are common consequences of the disruption of the day/night rhythm [
Environmental factors other than light, temperature and food intake may directly or indirectly affect the circadian rhythm. Such factor is, for example, tobacco smoke. BMAL1 was rapidly acetylated and subsequently degraded in the lungs of mice exposed to cigarette smoke and in human patients with chronic obstructive pulmonary disease (COPD), compared with non-smoking mice and COPD-free human controls [
Normally, the pulse rate and blood pressure significantly decrease (dip) at night, when one's asleep. Individuals that do not experience the nighttime drop in blood pressure (non-dippers) are believed to be at elevated risk for vascular incidents [
The short-term and long-term consequences of brain injury often include disruption of the day/night rhythm [
The levels of cortisol and melatonin may significantly change before and after surgery, not only because of the activation of the stress response, but also because of specific effects of general anaesthesia. The sleep disorders commonly seen in postoperative patients are usually related to circadian rhythm disruption produced by deregulation of cortisol and body temperature homeostasis, as well as by direct deregulation of melatonin synthesis [
Disruption of the normal circadian rhythm is a very common finding in mood disorders and the expression of core clock genes may be drastically altered in patients with depression [
The circadian clock may be responsible for the diurnal oscillations in the inflammatory responses to acute infection. It is known that some of the markers for infection oscillate during the 24-h cycle (e.g. different types of fever may regularly peak at the same time every day). This is usually attributed to features of the germinative cycle of the infectious agent. Nevertheless, it was shown that mice infected with Salmonella typhimurium showed higher rates of bowel and spleen colonisation when infected early in the rest period (in the morning) compared with mice infected in the evening [
The circadian pattern of expression of core clock genes shows signs of gross deregulation in aged cells [
The melatonin levels are decreased, the circadian rhythm in melatonin secretion is lost and rest-activity rhythm is grossly disturbed in patients with Alzheimer's disease [
Excessive daytime sleepiness commonly seen in patients with Parkinson's disease is believed to be associated with disturbances in resetting of the master clock by light cues and functional disengagement of the secretion of melatonin by the pineal gland from the rhythmic signals set by the master clock, eventually resulting in decreased amplitude between the daytime and night time levels of melatonin [
8. Putting chronobiological concepts at work - chronological nutrition and cancer chronotherapy
8.1. Snack around the clock, or how chronological nutrition reinvented normal eating
With the emergence of the concept of healthy' or successful' ageing, there have been many suggestions about how to increase the chances of being among the lucky few' that preserve their mental and physical capacities until very old age. Some of these suggestions make sense, other are, at best, questionable [
8.2. Timing anticancer treatments to the circadian rhythm in order to achieve a good therapeutic response with minimum adverse effects - cancer chronotherapy
The risks for occurrence and the severity of the adverse effects in anticancer therapy may be different when the same genotoxic agents are administered at different times within the 24-h cycle. This is, in a nutshell, the basis of chronotherapy (abbreviated from chronomodulated therapy), one of the modern branches of anticancer therapy. As was already mentioned above, the timing of the different phases in the cell cycle in cancer and non-cancer cells of the same tissue may significantly vary (or even in cases when it varies only slightly, it might be just enough to make all the difference). Cancer chronotherapy attempts at synchronisation of the delivery of the genotoxic agent to the peak of DNA synthetic activity in cancer cells, so as to achieve maximum inhibitory effect on tumour growth and (hopefully) much less severe suppression of the proliferation of normal cells. Even in cases when the peaks of DNA synthetic activity tend to overlap between cancer and non-cancer cells of the same tissue, the (presumably) much higher proliferative activity of cancer cells would ensure that they are affected by the genotoxic agent more than normal cells. Chronotherapy is believed to be associated with lower risk for therapy-associated adverse reactions, or, if the adverse effects occur, they are expected to be milder [
As with chronological nutrition, the concept of chronotherapy is not a modern invention. The first documented cases of cancer chronotherapy in human patients intended to achieve maximum response with minimum adverse effects date back to the 70-ties of the XX century [
As anticancer therapy developed steadily in the last decades of the XX century and the first decade of the XXI century, the hypothesis of scheduling genotoxic treatments to the times of the day when cancer cells were most susceptible to damage was supported with more experimental results. Nevertheless, definitive data illustrating the benefits from timed anticancer treatments began to be published only in the late 90-ties of the XX century. The largest body of information obtained so far is for metastatic colorectal cancer treated with oxaliplatin-5-fluorouracil-leucovorin combined regimens (FOLFOX) or irinotecan-5-fluorouracil- leucovorin (FOLFIRI). The first results of chronomodulated cancer therapy were highly encouraging. The objective response to therapy and the median survival were found to be significantly higher in patients treated with chronomodulated FOLFOX combined regimen for metastatic colorectal cancer than with conventional (flat-infusion) FOLFOX [
Timing of delivery of irinotecan as a single agent was also found to be important for the individual tolerability of the drug (at present – in animal models). The tolerability of irinotecan in mice with osteosarcoma was found to be at its best at Zeitgeber time (ZT) 15, and at its worst at ZT3 [
Nevertheless, similarly to the relationship between the individual capacity for DNA repair, the response to anticancer therapies and the risk for toxicity effects; the association between the chronomodulated vs. conventional therapy and the outcomes in terms of response and adverse effects turned out to be not that straightforward as they initially looked. Some of the studies in patients with metastatic colorectal cancer receiving the same combined regimen (FOLFOX) did not elicit significant differences between the survival rates of patients receiving the same regimen in conventional and chronomodulated settings [
The occurrence and the severity of adverse effects of genotoxic therapy may have radically different prognostic value as markers for therapeutic response in chronomodulated and conventional therapy. For example, it is known that the occurrence of adverse effects, such as neutropenia in patients receiving anticancer treatments is not uncommon and may be dangerous, even life-threatening. However, in patients on conventional chemotherapy neutropenia may be a predictor of good treatment response – presumably because high toxicity may indicate that the proliferation of tumour cells is also severely affected by the genotoxic treatment. It was reported that the development of severe adverse effects, such as neutropenia, fatigue and weight loss in the course of FOLFOX for metastatic colorectal cancer was associated with better survival in patients on conventional regimens, but poorer survival in patients on chronotherapy [
There are also other unexpected effects of chronotherapy with regards to dissimilar responses in different groups of patients. Women often have better survival rates than men after various diseases and may have better responses to different therapies. This may be related to the fact that women usually stick to the prescribed treatment schedules and tend to drop off any kind of treatment less often than men. It is, therefore, notable that men were reported to fare better than women in the majority of studies of cancer chronotherapy, with respect to therapy-related toxic effects and the outcomes after therapy [
Targeted stimulation or suppression of the expression of proteins of the core circadian clock may find potential use in the therapy of common human diseases in the near future. It has been repeatedly reported that sensitivity to anticancer therapies may be modulated by the expression levels of core clock genes. In human cancer cell lines transfected with PER1 the proportion of cells in S-phase decreased rapidly, whereas the proportion of cells in G2/M phase increased [
This research was supported by Grant No. DFNI-B01/2 at the National Science Fund, Ministry of Education and Science of Republic of Bulgaria.
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