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. 2014 Jun 20;20(18):2997–3006. doi: 10.1089/ars.2013.5671

Transcriptional Control of Antioxidant Defense by the Circadian Clock

Sonal A Patel 1, Nikkhil S Velingkaar 1, Roman V Kondratov 1,✉
PMCID: PMC4038985  PMID: 24111970

Abstract

Significance: The circadian clock, an internal timekeeping system, is implicated in the regulation of metabolism and physiology, and circadian dysfunctions are associated with pathological changes in model organisms and increased risk of some diseases in humans. Recent Advances: Data obtained in different organisms, including humans, have established a tight connection between the clock and cellular redox signaling making it among the major candidates for a link between the circadian system and physiological processes. Critical Issues: In spite of the recent progress in understanding the importance of the circadian clock in the regulation of reactive oxygen species homeostasis, molecular mechanisms and key regulators are mostly unknown. Future Directions: Here we review, with an emphasis on transcriptional control, the circadian-clock-dependent control of oxidative stress response system as a potential mechanism in age-associated diseases. We will discuss the roles of the core clock components such as brain and muscle ARNT-like 1, Circadian Locomotor Output Cycles Kaput, the circadian-clock-controlled transcriptional factors such as nuclear factor erythroid-2-related factor, and peroxisome proliferator-activated receptor and circadian clock control chromatin modifying enzymes from sirtuin family in the regulation of cellular and organism antioxidant defense. Antioxid. Redox Signal. 20, 2997–3006.

Introduction

The physiological importance of free radicals, such as reactive oxygen and nitrogen species (ROS/RNS), is well documented (20); the activities of the cardiovascular, respiratory, and immune systems depend on ROS/RNS (i.e., nitric oxide and hydrogen peroxide [H2O2]) levels. ROS/RNS regulate metabolism, secretion, and proliferation of cells. Excessive levels of ROS/RNS lead to oxidation of DNA, proteins, and lipids, affecting the normal functions of these biological macromolecules and cellular structures. Acute and chronic oxidative stress is implicated in the development of age-associated diseases, such as cancer, pathologies of the cardiovascular system, and metabolic syndromes (20).

Production of ROS/RNS is important for cellular signaling and is regulated by enzymatic systems, such as nitric oxide synthases or nicotinamide dinucleotide (NAD) peroxidases, but the majority of cellular ROS are generated in the form of superoxide as a by-product of mitochondrial oxidative phosphorylation (20). Most likely, mitochondria-generated ROS are responsible for oxidative-stress-induced damage. Detoxification of ROS is a function of the antioxidant defense system, which is formed by antioxidant enzymes, such as superoxide dismutases (SODs), catalase, glutathione peroxidase (GPx), and acceptors of free radicals, such as peroxiredoxins (PRDXs), glutathione (GSH), or thioredoxin (TRX) (20). The activity of the antioxidant system is regulated on different levels by multiple mechanisms. The circadian clock was proposed as a system that orchestrates the antioxidant defense (31, 47), and recent data generated through experiments in different organisms support the hypothesis about this evolutionarily conserved role of the circadian system.

The circadian clock generates near 24-h internal rhythms in different biological processes, such as behavior, growth, hormone secretion, and gene expression (58). The circadian clock functions in different organisms, and it is believed that circadian rhythms increase an organism's fitness through synchronization of physiological processes in the organism with periodical changes of the environment (5, 67). The importance of circadian rhythms in humans is supported by the growing list of diseases associated with circadian misalignments (5, 27, 51). Data in model organisms also demonstrate the involvement of the circadian system in the regulation of diverse physiological process, as well as development of diseases upon genetic disruption of the clock. The molecular mechanisms of clock-dependent control of physiology are not well understood. Circadian-clock-dependent regulation of redox status, ROS homeostasis, and antioxidant defense is a natural candidate for such a mechanism. It is unclear whether the circadian clock is involved in the regulation of ROS/RNS generation and in ROS signaling, but increasing data are accumulating on the role of the clock as the oxidative stress response system. Connection between the clock and redox state of the cell is further strengthened by recently observed circadian rhythms in oxidation/reduction of PRDXs (61, 62); it is intriguing that these rhythms are evolutionarily conserved (22) and transcriptionally independent (61, 62). Here we will discuss the orchestration of antioxidant defense and management of oxidative stress by the circadian clock with a special emphasis on transcriptional regulation and the implications in aging, cancer, and metabolic syndromes.

Molecular Mechanisms of the Circadian Clock

The transcriptional translation feedback loop (TTFL) is the core of molecular circadian clock mechanisms in different organisms (58). For the purpose of the review we will describe the organization of the loop in mammals; detailed reviews on the molecular clockwork in plants and invertebrate animals are available elsewhere. Figure 1 represents the schematic organization of TTFL in mammalian cells. Period circadian protein (PER)1/PER2 and cryptochrome (CRY)1/CRY2 proteins are products of per1/per2 and cry1/cry2 genes, respectively, and have partially redundant functions. PERs and CRYs form a complex (formation of this complex is controlled through phosphorylation-dependent degradation of these proteins), which acts as a specific negative regulator of transcription. The mechanism of PER/CRY-dependent transcription control is not well known. The PER:CRY complex interacts with the brain and muscle ARNT-like 1 (BMAL1):Circadian Locomotor Output Cycles Kaput (CLOCK) complex and is recruited to the BMAL1:CLOCK complex at chromatin, where it suppresses BMAL1:CLOCK-mediated transcription (26). Another possible mechanism is through the regulation of BMAL1 and CLOCK post-translational modifications and stability; indeed, posttranslational modifications and transcription-associated degradation of BMAL1 and CLOCK are critical for their functions as transcriptional factors (34). Irrespective to the exact mechanisms, the PER:CRY complex inhibits transcription of their own genes because these genes are under the control of the BMAL1:CLOCK complex. Thus, by inhibiting their own expression, PERs and CRYs form a negative feedback loop. BMAL1 and CLOCK are basic helix-loop-helix PAS-domain-containing transcriptional factors, acting in the form of a heterodimer. This complex positively regulates the expression of the earlier-mentioned Per and Cry genes and also transcription of the Rev-Erb and Ror genes. REV-ERB and retinoid orphan receptor (ROR) proteins form another feedback loop that regulates negatively and positively transcription of Bmal1, respectively.

FIG. 1.

FIG. 1.

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TTFL formed by circadian clock proteins. Transcriptional factors BMAL1 and CLOCK, acting in the form of a heterodimer, positively regulate transcription of Per, Cry, Rev-Erb, and Ror genes. PERs and CRYs interact with the BMAL1:CLOCK complex and suppress BMAL1:CLOCK-mediated transcription inhibiting the transcription of their own genes. REV-ERB and ROR proteins form another feedback loop that regulates negatively and positively transcription of Bmal1. Elements of circadian clock TTFL also regulate expression of genes that are not core components of the circadian clock; these genes are known as clock-control genes. Transcription of some of these genes is directly regulated by the BMAL1:CLOCK or REV ERB and RORs, while others can be regulated by indirect mechanisms such as through the control of transcriptional factors. BMAL1, brain and muscle ARNT-like 1; CLOCK, Circadian Locomotor Output Cycles Kaput; CRY, cryptochrome; PER, period circadian protein; REV-ERB, NR1D1 (nuclear receptor subfamily 1, group D, member 1); ROR, retinoid orphan receptor; TTFL, transcriptional translation feedback loop.

Elements of circadian clock TTFL also regulate expression of genes that are not core components of the circadian clock; these genes are known as clock-control genes. Transcription of some of these genes is directly regulated by the BMAL1:CLOCK or REV ERB and RORs, while others can be regulated by indirect mechanisms such as through the control of transcriptional factors.

Enzymatic Antioxidant Defense System and the Circadian Clock

In aerobic organisms, ROS are produced as a consequence of respiration and substrate oxidation. Exogenous sources of ROS include UV radiation, chemotherapeutic agents, and various pollutants. ROS include hydroxyl radicals, superoxide anions, and various peroxides that are constantly generated in response to external and internal stimuli. ROS have diverse effects on cells. In small amounts, ROS act as secondary messengers and are indispensable for stimulation of cell proliferation and immune defense against bacterial infections; on the contrary, elevated ROS levels are dangerous for an organism and give rise to oxidative stress, resulting in oxidative damage to biological macromolecules and finally cell death through apoptosis or necrosis (20). As such, ROS have been implicated in various diseases, including cancer, aging, neurodegenerative diseases, and atherosclerosis. The antioxidant defense system's role in balancing free radicals is highly essential for sustaining physiological ROS levels. The GSH antioxidant defense system is a predominant guardian against oxidative stress.

A simplified example of ROS-detoxifying pathway is presented in Figure 2. Superoxide anions are converted to H2O2 by SODs. There are three different SODs in mammals with different patterns of intracellular and extracellular distribution. H2O2 can be further detoxified through several different pathways. Catalase, found in all the tissues of all species, converts H2O2 to water. H2O2 can also be reduced by GSH in reaction catalyzed by GPx. Glutathione reductase (GR) uses NAPDH as a substrate to reduce oxidized glutathione (GSSG). The GSH-based system is the most powerful antioxidant system that neutralizes free radicals produced by several toxins. PRDXs scavenge H2O2 and catalyze their own oxidation into PrxSO2/3. This oxidized form is then reduced by TRX to regain its antioxidant ability. Six Prdx genes have been found in mammals. The oxidized TRX in turn is reduced by electrons from nicotinamide dinucleotide phosphate (catalyzed by the thioredoxin reductase [TXNRD]) (73a).

FIG. 2.

FIG. 2.

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Detoxification of superoxide anion. Superoxide anion generated by cells is converted to hydrogen peroxide by SODs. Hydrogen peroxide is further reduced by catalase or through peroxiredoxin or glutathione antioxidant system. Antioxidant enzymes are shown as open boxes; proteins which serve as substrate for redox reactions are shown by gray boxes. CAT, catalase; GSH and GSSG, reduced and oxidized glutathione; GSH Px and GSH R, glutathione peroxidase and reductase; Prx, peroxiredoxin; Sesn, sestrin; SOD, superoxide dismutase; Trx-H and Trx-S-S, reduced and oxidized thioredoxin; Trx-R, thioredoxin reductase.

The circadian rhythms in an organism's daily activities, such as feeding, locomotion, and the sleep/wake cycle, modulate the intensity of metabolic processes during the day (Fig. 3). In agreement with this, reported daily rhythms in body temperature are a reflection of rhythms in metabolism intensity. Metabolism is tightly connected with the generation of ROS as by-products of mitochondrial functions (20). Additionally, detoxification of food-derived xenobiotics also involves ROS production. Thus, the generation of ROS should oscillate as a reflection of the daily activities of organisms. Indeed, rhythms in ROS and products of oxidation have been reported in different tissues (18, 31, 48, 50). The rhythmic generation of oxidants dictates the symmetric response of organisms—rhythmic induction of the antioxidant defense system to balance different demands for reduction and in agreement with that rhythms in oxidative stress response have been observed in flies (52). As illustrated in Figure 2, ROS detoxification is a chain of redox reactions, where products of one reaction serve as substrates in the next reaction. Thus, for example, upregulation of just one enzyme would be inadequate for efficient detoxification. The expression and activity of multiple components of the antioxidant defense system must be coordinated.

FIG. 3.

FIG. 3.

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Clock and cellular ROS homeostasis. Daily rhythms of activity dictate rhythms in metabolism and ROS production, which can lead to oxidative stress. Clock also regulates pathways, which reduces the effects of oxidative damage and help maintain ROS homeostasis (details in text). ROS, reactive oxygen species.

The circadian clock is the most natural candidate for coordination of daily rhythms of antioxidant defense (Fig. 3). In addition to regulating the expression of antioxidant enzymes and levels of reducing agents, the clock can regulate ROS-induced damage repair, cell survival, and production of secreted antioxidants, such as melatonin. All these clock functions together will contribute to the daily control of ROS homeostasis and efficient antioxidant defense.

Daily rhythms of antioxidant enzymes

Rhythms in GPX and GR (reductase) activities have been observed in many tissues of different organisms. Interestingly, the GPX peak precedes GSSG and GR peaks, consistently with the detoxification chain (18). Marked circadian fluctuation in catalase activity occurs in mouse livers and kidneys with a peak in the mid-dark phase (70); this is in line with evidence that shows rhythmic catalase expression on the protein level revealed by proteomic analysis in mice (66). The TRX system is a very important system in plants and has been shown to be under circadian control; however, little is known about its regulation by the circadian clock in mammals (56).

In the rat hippocampus, CAT and GPx mRNA expression, protein levels, and activity demonstrated oscillations (24). Additionally, mRNA oscillations of Cat, Sod, GPx, GSH-s-transferase, and γ glutamyl cysteine synthase (glutamyl cysteine ligase, GCL) have been reported in mouse livers (75). Various isoforms of glutathione-S-transferase (GST) and glutamyl cysteine synthase (GCS) displayed rhythmicity with a peak during the light phase. In Drosophila heads similar rhythms in mRNA expression and activity of GCL and Gst-D1 have been demonstrated, which was disrupted in clock mutants (6); this further supports the circadian mechanisms of antioxidant enzyme expression.

Rhythmic expression on the mRNA level suggests transcriptional regulation, and in this review we plan to concentrate on transcriptional mechanisms of circadian-clock-dependent control of antioxidant defense. Recently observed evolutionarily conserved non-transcriptional mechanisms of clock regulation of cellular redox balance (61, 62) are beyond the scope of the current review. Next we will discuss the potential molecular mechanisms of the circadian-clock-dependent transcriptional regulation of antioxidant defense.

The transcriptional control of genes involved in antioxidant defense and oxidative stress response by the circadian clock can occur in several ways. Some genes can be under direct regulation by the circadian clock transcriptional factors BMAL1/CLOCK, RORs, and Rev-Erbs. Another set of genes can be regulated by clock-controlled transcriptional factors. Finally, regulation may occur through clock-dependent control of chromatin structure by clock-controlled chromatin-modifying enzymes. In silico analysis of the promoter regions of many antioxidant genes, such as GPx-1, Cat, Sod-1, and TXNRD-1, reveals the presence of E-box elements in rodents and humans, thus indicating that these genes may be under direct transcriptional control of the BMAL1:CLOCK complex (49). A recent study (69) explored potential downstream target genes for BMAL1 in mouse liver, but none of the antioxidant genes were identified as direct targets for BMAL1 in this study.

Nuclear factor erythroid-2-related factor–dependent mechanisms of circadian regulation of antioxidant defense

Xu et al. in 2012 investigated the expression patterns for antioxidant genes in mice liver and they found that nuclear factor erythroid-2-related factor 2 (Nrf2) expression pattern was highest during daytime and showed a peak at 18:00, similar to D site of albumin promoter (albumin D-box) binding protein hence proving that circadian variations of Nrf2 could modulate cell response to oxidative stress (75). The leucin zipper transcription factors Nrf1 and Nrf2 are present in the cytoplasm in a quiescent state bound to Kelch-like ECH-associated protein 1 (Keap1) (See Fig. 4). Upon activation by oxidative or ER stress, it is released from Keap1 and translocates to the nucleus where along with the small musculo-aponeurotic fibrosarcoma protein it binds to the antioxidant response element of various antioxidant enzymes, such as γ-glutamyl cysteine synthetase, GST, and catalase, hence regulating their transcription (43, 46). Nrf1 and Nrf2 have similar binding specificity and expression profiles; hence, they share mutually overlapping target genes and overlapping activities (46). Upregulation of many antioxidant and detoxification genes is severely impaired in the Nrf2-null mutant mice (40). Nrf1−/− fibroblasts have decreased GSH levels and are hypersensitive to oxidative stress, which correlates with downregulation of γ-glutamyl cysteine synthetase and glutathione synthetase (54). Interestingly, Nrf-2 exhibits circadian patterns in its mRNA expression, similar to Per1, Per2, and Rev-Erb, with peak late in light phase (75), and Nrf-1 contains a GC-rich motif found in most of the clock-controlled genes (9), indicating that these may be under direct transcriptional control of the BMAL1:CLOCK heterodimer.

FIG. 4.

FIG. 4.

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NRF. NRF is a master regulator of antioxidant defense. NRF forms an inactive complex with KEAP-1, which is destroyed by oxidative stress. NRF translocates to the nucleus where it drives the expression of several antioxidant enzymes. The BMAL1:CLOCK complex directly regulates the expression of NRF through E box element in the promoter. KEAP-1, Kelch-like ECH-associated protein 1; NRF, nuclear factor erythroid-2-related factor.

Peroxisome proliferator-activated receptor–dependent mechanisms of circadian regulation of antioxidant defense

Regulation of peroxisome proliferator-activated receptor (PPAR) activity by the circadian clock occurs at several levels (Fig. 5). Pparα mRNA and protein levels exhibit diurnal rhythms in rat liver (57) and in mouse white adipose tissue (WAT) (57), black adipose tissue, and liver (57). PPAR γ exhibits rhythms specifically in WAT and the liver (76). Additionally, PER2 directly interacts with the N-terminal domain of PPARγ and represses its activity (29). Promoter region of Pparα contains BMAL1 binding site making it a likely candidate for the CLOCK:BMAL1 complex to drive its expression (11, 69). Interestingly, PPARα is involved in a positive feedback loop with BMAL1 (10). Similarly, PPARγ induces BMAL1 expression in blood vessels (74).

FIG. 5.

FIG. 5.

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PPAR. PPARα expression is positively regulated by the BMAL1:CLOCK complex and is negatively regulated by PER1. The PPAR complex controls the expression of several antioxidant enzymes. PPAR, peroxisome proliferator-activated receptor.

PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily, and exist as three subtypes: PPARα, PPARβ (or PPARδ), and PPARγ (17). PPARγ is well distributed in adipose tissue and less so in the liver, while PPARα is abundantly expressed in the liver, kidney, and heart. PPARγ and PPARα are not only well known for their function in fatty acid metabolism and adipocyte differentiation but are also implicated in oxidative stress. Several antioxidant enzymes, including SODs and GPxs, are under PPARα transcriptional control (39, 72). PPARγ heterodimerizes with Retinoid X receptor and interacts with the PPAR binding element in the promoter region of catalase and GPx3 in a tissue-specific manner (14, 19, 28, 36). Treatment with PPARγ agonist increases expression of Sod-2 and Gpx-3 in cells, while PPARγ deficiency leads to reduction of the expression (19, 28).

Although very little is known about the clock regulation of PPARs in the control of oxidative stress, it would be highly compelling to study this potential mechanism (Fig. 6) that can aid in control of aging and age-related disorders.

FIG. 6.

FIG. 6.

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SIRT1. (A) CLOCK acetylates its transcriptional partner BMAL1 following BMAL1:CLOCK-dependent regulation of the expression of NAMPT—a rate-limiting enzyme in NAD+ production pathway. NAD+ regulates activity of SIRT1 deacetylase that deacetylates BMAL1, thus forming a feedback loop. (B) SIRT1 deacetylates and regulates the activities of transcriptional factors, such as PGC1a, FOXO3a, and p53, and these transcriptional factors in turn regulate the expression of several antioxidant enzymes. Additionally, oxidative stress leads to a change in chromatin localization of SIRT1 and hence a change in the global transcriptional program. FOXO, forkhead box; NAD, nicotinamide dinucleotide; NAMPT, nicotinamide phosphor-ribosyltransferase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SIRT, sirtuin.

Antioxidant activity of circadian-clock-controlled hormone melatonin

Melatonin is a hormone produced and released by the pineal glands in a circadian manner; melatonin plays a role in many physiological processes including regulation of circadian rhythms and sleep homeostasis (32, 64). Melatonin is one of the most efficient antioxidants; as a free radical scavenger, melatonin has the following advantages: it is able to cross the cellular plasmatic membrane, it can reduce a broad spectrum of ROS/RNS, and it can facilitate the action of other scavengers. Finally, melatonin is a terminal scavenger, so it cannot be reduced back to its original state and cannot initiate oxidation of other substrates (30, 64, 71). This activity is evolutionarily conserved in contrast to many other melatonin activities, including hormone activity and regulation of cell death and proliferation, which is reported mostly in vertebrates. The clinical efficiency of melatonin has been tested in animal models of diseases associated with increased oxidative stress, such as neurodegeneration, cancer, and cardiovascular diseases. According to several reports, melatonin efficiently prevents the development or reduces the severity of these diseases (3, 42, 73). Melatonin was proposed as a potential therapeutic agent; a detailed discussion of melatonin clinical applications can be found in recent reviews (30, 68).

In vertebrates, melatonin production is controlled by the circadian clock. Arylalkylamine N-acetyltransferase (AANAT) is the rate-limiting enzyme in melatonin biosynthesis. AANAT expression is regulated on multiple levels, and these regulations are species specific; different mechanisms operate in nocturnal and diurnal organisms. The mRNA level is regulated on both the transcriptional and post-transcriptional levels. Protein production is also regulated through internal ribosome entry site-mediated control of translation and post-translational regulation of degradation (45). Thus, circadian-clock-generated rhythms in melatonin may contribute to daily rhythms of antioxidant defense.

Clock and chromatin modifications

Recently, a strong correlation has been established between circadian clock regulation and Sirtuin 1 (SIRT1) (Fig. 6A). CLOCK is a histone acetyl transferase protein (19a) that acetylates BMAL1 at lysine 537 (37). This acetylation is counterbalanced by SIRT1, which binds to the BMAL1:CLOCK complex and deacetylates BMAL1 (59). In turn, the BMAL1:CLOCK complex regulates SIRT1 activity. SIRT1 is NAD+-dependent deacetylase, and NAD+ level exhibits circadian rhythms in nicotinamide phosphor-ribosyltransferase (NAMPT)–dependent manner. NAMPT is a rate-limiting enzyme in the NAD+ salvage pathway. The nampt gene promoter contains E-boxes to which the BMAL1:CLOCK complex can bind in a circadian manner resulting in rhythmic expression of NAMPT (60, 65).

SIRTs are ubiquitously expressed in various tissues (the brain, heart, liver, pancreas, skeletal muscle, spleen, and adipose tissues); they have been implicated in a number of diverse functions, such as DNA repair, stress response, chromatin silencing, aging, metabolism, and cell proliferation (38). Their expression patterns are influenced by both external (e.g., caloric restriction and exercise) and internal stimuli (oxidative stress in cells) (13).

A link between SIRT1 and oxidative stress has been established by numerous studies in a variety of tissues. For example, SIRT1 expression enhances tolerance to oxidative stress in neuronal cells (12) and in the hearts of transgenic mice (1), and negates the harmful effects of ROS in renal tubular cells (35). Another homolog of SIRT1, SIRT3, has also been found to provide resistance to oxidative stress (7). SIRT1 can provide protection from oxidative damage in a number of ways as illustrated in Figure 6B.

Studies conducted by Oberdoerffer et al. showed that under oxidative stress, redistribution of SIRT1 occurs at the chromatin level such that upon DNA damage, SIRT1 redistributes to chromatin at DNA break sites and promotes DNA repair; thus, SIRT1 contributes to genomic stability and prevents age-related transcriptional changes (63). SIRT1 has also been found to regulate the activity of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, FOXO3a, and p53 transcriptional factors known to be involved in the regulation of antioxidant enzyme expression (38). The expression of different Sods, Cat, Prdxs, and Trxs and TrxRs is regulated by these transcriptional factors in a tissue- and stress-dependent manner.

Circadian clock and diseases

Disruption of circadian rhythms through shift work or frequent time zone traveling significantly increases the risk of several types of cancers in humans (27). Experiments in model organisms also suggest a connection between the circadian clock and cancer (4, 55); however, interpretation of these data is complicated by the fact that different laboratories used different circadian clock mutants and different models of tumorigenesis (77). Circadian-clock-dependent control of cell cycle, DNA damage checkpoints, DNA repair, and cell death is considered among possible molecular mechanisms and has been recently reviewed (41, 44). Oxidative stress is an important contributor to tumorigenesis; in animal models, increased oxidative stress resulted in increased risk of cancer, while reduction of oxidative damage could delay or prevent cancer development (20).

Cardiovascular diseases, metabolic syndromes, and obesity are interrelated; risks of these diseases also increase in rotating workers (5, 15, 23). Data on the pathological changes observed in animal models of circadian disruption are generally in agreement with epidemiologic data in humans. Desynchronization of the circadian rhythms in metabolism, misalignment of hormone secretion, and changes in feeding behavior were proposed as underlying mechanisms. All of the just-mentioned diseases are also associated with elevated oxidative stress, and antioxidant treatment can reduce the severity of these diseases in experimental models (2).

The free radical theory of aging is one of the most widely investigated hypotheses of aging and still a subject of debate (8, 33). According to this theory, free radicals that are generated predominantly as a result of metabolic activity damage macromolecular components of cells. With time, damage accumulates, resulting in reduced functional activity of the cell and the entire organism. Detoxification of ROS by the antioxidant defense system attenuates oxidative-stress-induced damage and delays aging and the development of age-associated diseases; accordingly, deterioration of antioxidant defense results in an accelerated rate of aging. While the free radical theory of aging (along with its numerous modifications) has been challenged (8), there is a significant amount of evidence in support of this theory (78).

A reciprocal regulation of the aging process by the circadian clock has been demonstrated in mammals and flies (53). Disruption of the circadian clock genes through genetic mechanisms leads to accelerated aging and reduced lifespan in mice (4, 21, 25, 48). Forced circadian desynchronization through environmental intervention (forced phase shift of the circadian cycle) increases mortality in aged rodents (16). The most severe phenotype of accelerated aging was observed in Bmal1-deficient mice, suggesting that Bmal1 may also have clock-independent functions (48). Increased levels of ROS were reported in different tissues of Bmal1-deficient mice. Treatment of Bmal1-deficient mice with antioxidants delayed aging and increased their lifespan, supporting the importance of the circadian clock as an antioxidant defense system (49). Thus, the circadian clock acts as a gerosuppressor system, at least partially through the regulation of antioxidant defense.

Figure 7 illustrates connections between the clock, antioxidant defense, oxidative stress, and diseases. The circadian clock orchestrates the activities of the antioxidant defense and oxidative stress response systems through the earlier-discussed mechanisms. Circadian misalignment caused by mutations, aging, or environmental interventions compromises the antioxidant defense, which leads to oxidative stress. Oxidation of DNA may result in accumulation of mutations, which can initiate cancer. Oxidized proteins and lipids, if not degraded, can form extra- and intracellular deposits. Severe damage can also lead to cell death. These degenerative processes are major contributors to heart attack, stroke, arthrosclerosis, and diabetes. Oxidative damage can provoke cell and tissue senescence and accelerate the aging process. Degeneration induced by chronic or acute oxidative stress can also provoke inflammatory response, and inflammation will further contribute to the development of aging and age-associated pathologies.

FIG. 7.

FIG. 7.

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Connection between the circadian clock, oxidative stress, and diseases. Circadian-clock-dependent orchestration of antioxidant defense contributes to the organism's response to oxidative stress. Circadian disruption results in oxidative damage of biological macromolecules, which leads to mutations, affects cell physiological functions, death and proliferation, which contributes to the pathology of cardiovascular diseases, cancer, metabolic syndromes, and aging.

Conclusions

We have reviewed the recent progress in transcriptional mechanisms of the circadian-clock-orchestrated antioxidant defense. The circadian clock is also involved in transcription-independent regulation of the redox system: indeed, rhythms in the PRDX redox state have been reported. While the mechanism is still unknown, it is clear that these rhythms do not depend on the circadian transcriptional–translational feedback loop. Circadian orchestration of antioxidant defense is species specific and most likely tissue specific, mirroring rhythms of metabolic activities of the organism and tissue. The next important question is how to apply this knowledge to medical practice? Oxidative stress without any doubt is a significant contributor to the pathologies of various organs and systems, and potentially the major cause of aging. Multiple attempts using a variety of antioxidants and antioxidative strategies to treat or prevent pathologies have been ventured with a sundry rate of success. One of the reasons why some of these attempts fail is that the activities of different components of the antioxidant defense system must be coordinated. The circadian clock must be considered as a potential target for intervention as a natural coordinator of the antioxidant defense. However, more studies on the mechanisms, with an emphasis on tissue specificity, are necessary to guarantee the optimal control and regulation of the antioxidant defense through manipulations of the circadian clock.

Abbreviations Used

AANAT

arylalkylamine N-acetyltransferase

ARE

antioxidant response element

BMAL1

brain and muscle ARNT-like 1

Cat

catalase

CLOCK

Circadian Locomotor Output Cycles Kaput

CRY

cryptochrome

Dbp

D site of albumin promoter (albumin D-box) binding protein

FOXO

forkhead box

GCL

glutamyl cysteine ligase

GCS

glutamyl cysteine synthase

GPx

glutathione peroxidase

GR

glutathione reductase

GSH Px, GSH R

glutathione peroxidase and reductase

GSH

glutathione

GSSG

oxidized glutathione

GST

glutathione-S-transferase

H2O2

hydrogen peroxide

Keap1

Kelch-like ECH-associated protein 1

MAF

musculo-aponeurotic fibrosarcoma

NAD

nicotinamide dinucleotide

NADPH

nicotinamide dinucleotide phosphate

NAMPT

Nicotinamide phosphor-ribosyltransferase

NRF

nuclear factor erythroid-2-related factor

PER

period circadian protein

PGC-1α

peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PPAR

peroxisome proliferator-activated receptor

PPRE

PPAR binding element

PRDX

peroxiredoxin

REV-ERB

NR1D1 (nuclear receptor subfamily 1, group D, member 1)

ROR

retinoid orphan receptor

ROS/RNS

reactive oxygen species/reactive nitrogen species

Sesn

sestrin

SIRT

sirtuin

SOD

superoxide dismutase

TRX

thioredoxin

Trx-H, Trx-S-S

reduced and oxidized thioredoxin

TTFL

transcriptional translation feedback loop

TXNRD, Trx-R

thioredoxin reductase

WAT

white adipose tissue

Acknowledgments

This work was supported by funds from NIH (5R01AG039547) and from GRHD Center CSU.

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