Int. J. Mol. Sci. 2013, 14(2), 3026-3049; doi:10.3390/ijms14023026

Nature’s Timepiece—Molecular Coordination of Metabolism and Its Impact on Aging
Andrea Bednářová 1,2,3, Dalibor Kodrík 1,2 and Natraj Krishnan 3,*
Institute of Entomology, Biology Centre, Academy of Science, Branišovská 31, České Budějovice 370 05-CZ, Czech Republic; E-Mails: (A.B.); (D.K.)
Faculty of Science, South Bohemian University, Branišovská 31, České Budějovice 370 05-CZ, Czech Republic
Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, Mississippi State, MS 39762, USA
Author to whom correspondence should be addressed; E-Mail:; Tel.: +1-662-325-2978; Fax: +1-662-325-8837.
Received: 13 December 2012; in revised form: 5 January 2013 / Accepted: 16 January 2013 /
Published: 31 January 2013


: Circadian rhythms are found in almost all organisms from cyanobacteria to humans, where most behavioral and physiological processes occur over a period of approximately 24 h in tandem with the day/night cycles. In general, these rhythmic processes are under regulation of circadian clocks. The role of circadian clocks in regulating metabolism and consequently cellular and metabolic homeostasis is an intensively investigated area of research. However, the links between circadian clocks and aging are correlative and only recently being investigated. A physiological decline in most processes is associated with advancing age, and occurs at the onset of maturity and in some instances is the result of accumulation of cellular damage beyond a critical level. A fully functional circadian clock would be vital to timing events in general metabolism, thus contributing to metabolic health and to ensure an increased “health-span” during the process of aging. Here, we present recent evidence of links between clocks, cellular metabolism, aging and oxidative stress (one of the causative factors of aging). In the light of these data, we arrive at conceptual generalizations of this relationship across the spectrum of model organisms from fruit flies to mammals.
aging; circadian clocks; cellular metabolism; homeostasis; metabolic hormones; oxidative stress; reactive oxygen species

1. Introduction

Circadian rhythms are observed in a wide variety of biological, physiological and metabolic processes in most organisms. These rhythmic cycles are governed by an endogenous circadian clock. Thus, a crucial function of the endogenous circadian system would be to anticipate and adapt to environmental changes in light, temperature, food and even mate availability, and organize behavior and physiology to these changing situations. In addition, the circadian system plays a regulatory role by the temporal coordination of physiological, cellular and molecular processes such that synergistic processes are timed to coincide, whereas processes that are conflicting are temporally separated. There is increasing evidence that a smoothly running endogenous clock is crucial for energy balance in organisms from cyanobacteria to mammals [14]. Diurnal rhythms are entrained by exogenous Zeitgebers (time-givers), especially light/dark (LD) cycles. However, many rhythms also persist in constant darkness (DD) with a periodicity of circa 24 h, due to their endogenous nature. The rhythm can also be entrained by changes in timing of food and temperature (although the period of rhythm can be stable over a wide range of temperature—i.e., it can be temperature compensated) [5]. The importance of the circadian clock for organismal homeostasis was demonstrated by loss of sleep/wake cycles and metabolic defects following targeted disruption of core clock genes in mice [6,7]. Additional roles of clocks in basic cellular pathways have also been elucidated such as regulation of nutrient and energy balance, cell cycle, DNA-damage repair and xenobiotic detoxification [6,8,9]. In view of these data, it should not come as a surprise that disruption of circadian rhythms would increase vulnerability to stressors, accelerate aging and could lead to various pathologies including cancer [1013].

2. The Molecular Clock Network and Homeostasis

Circadian rhythms have been described in both prokaryotes and eukaryotes, and many molecular features associated with the circadian clock are evolutionarily conserved [14]. The molecular clock network consists of transcriptional and translational feedback loops where core clock genes are transcribed and these translational products inhibit their own transcription. These timed transcriptional and translational feedback processes generate the molecular rhythms, which eventually translate to the circadian rhythms observed in most organisms. The basic organization of the circadian clock has a hierarchy—with every cell in the organism having an autonomous clock, and different cells and tissues are synchronized to oscillate with the same phase. This orchestration occurs via the “central” or “master” clock, which is entrained by input from zeitgebers. Genetic analyses have revealed numerous clock genes in different species and most studies to date have focused on understanding the molecular mechanisms of the rhythms generated by these core clock genes. In the fruit fly Drosophila melanogaster, by far the best-studied organism with regard to molecular circadian functioning, the clock system is highly similar to the vertebrate circadian clock [15]. A network of ~150 pacemaker neurons in the brain regulates rest/activity rhythms, which comprise the central clock [16]. The peripheral clocks are located in many cells of the nervous system, retinal photoreceptors, sensory neurons, Malpighian tubules, gut, fat body, etc.[1719]. The core molecular circadian cellular clock consists of CLOCK/CYCLE heterodimer at the node of all interacting feed-back loops. The main players are PERIOD, TIMELESS, VRILLE, PDP1ɛ and CLOCKWORK ORANGE molecules in addition to highly important kinases and phosphatases, that is, DOUBLETIME, CASEIN KINASE 2, SHAGGY, PROTEIN PHOSPHATASE 1 and PROTEIN PHOSPHATASE 2A. The sub-cellular localization and activities of clock proteins are controlled by post-translational modifications, particularly phosphorylation, mediated by specific kinases and phosphatases [20]. Synchronization of the clocks phase to external light/dark (LD) cycle is mediated by a blue light photoreceptive flavin-binding protein CRYPTOCHROME (CRY) [21]. For progression of the circadian cycle, the clock proteins are targeted for degradation by the Ubiquitin-proteasome system [22]. In Caenorhabditis elegans, many of the homologs of the Drosophila clock proteins are involved in development and developmental timing. A recent whole-transcriptome study evaluating circadian variations in transcript levels reported that all canonical clock gene homologs in C. elegans are noncycling [23]. Despite these results, there is evidence that lin-42, the period homolog in C. elegans plays a role in nematode circadian rhythms [24]. Similarly Tim-1 corresponds to timeless, Aha-1 corresponds to CLOCK, CYCLE and CLOCKWORK ORANGE. The C. elegans CES-2 is a basic leucine zipper (bZIP) protein that is the best homolog of D. melanogaster PDP1ɛ, similarly Atf-2 is the homolog of vrille[25]. Of the D. melanogaster kinases and phosphatases playing a role in the circadian central oscillator, doubletime corresponds to both C. elegans kin-20 and kin-19, shaggy is similar to gsk-3, casein kinase 2 consists of kin-3 and kin-10, protein phosphatase 1 has two corresponding genes gsp-1 and gsp-2 and the protein phosphatase regulatory subunit is encoded by sur-6[26,27].

In mammals, the circadian clock resides in the hypothalamic suprachiasmatic nucleus (SCN), which is recognized as being the master clock. The clock network also exists in almost all peripheral tissues, including liver, heart, kidney and blood cells [2831]. Although the SCN is not essential for driving peripheral oscillations, it appears to coordinate peripheral clocks [31]. At the molecular level, the circadian clock consists of an auto-regulatory feed-back loop regulated by specific proteins that are rhythmically translated in an integrated manner [32]. These transcriptional—translational auto-regulatory feedback loops have both positive and negative elements [33,34]. The positive components are two basic helix-loop-helix (bHLH) transcription factors called CLOCK and brain and muscle Arnt-like protein 1 (BMAL1, homologous to CYCLE in Drosophila) [35,36]. The heterodimer activates the transcription of several other clock genes including Period (PER) and Cryptochrome (CRY) [3739]. The resultant PER and CRY proteins form a heterodimer, translocate to the nucleus, and inhibit the activity of CLOCK-BMAL1, thus forming a negative feedback loop. The intracellular clock is thought to directly and/or indirectly regulate the expression of numerous genes [33,34].

The control of circadian rhythms is driven by the transcriptional-translational feedback loops that ensure homeostasis; any dysfunctions in such rhythms have been implicated in serious pathologies such as sleep disorders, cardiovascular diseases, depression, cancer, response to oxidative stress and accelerated aging [4045]. The complexity underlying the mechanism that drives circadian rhythms is one of the key challenges on drawing direct connections between the detailed pathway of how the biologic clock contributes to events that modulate both cellular and metabolic homeostasis. Despite this there is a growing body of evidence that circadian rhythms are connected with the physiological state of an organism, e.g., its nutritional condition, hormonal fluctuation, aging and also certain pathologies. These physiological states might act positively or negatively on the biologic clocks, but these events must be integrated and fine-tuned to ensure homeostasis. The circadian clock must be tightly regulated to modulate a state of dynamic homeostasis at the cellular and metabolic level, which implies that there is a physiological integration of metabolic and circadian rhythms all directed to the maintenance of a fully functioning organism and any disruption of this coordinated control would impact aging.

3. The Integration of Metabolic and Circadian Rhythms for Homeostasis

A central feature in energy homeostasis is the temporal coordination of metabolism. Circadian clocks in fruit flies help coordinate rhythmic feeding behavior and regulate energy consumption and metabolism. Food consumption in Drosophila occurs consistently at specific times of the day (primarily in the morning) and this rhythm in feeding behavior persists in constant darkness [46]. The fat body (a homolog of the mammalian liver and adipose tissue) of flies harbor clocks which are involved in regulating fuel storage and energy balance; the antennae, maxillary palp and proboscis all harbor odor/gustatory receptors under control of clock which regulate taste and feeding, the gastrointestinal tract involved in digestion and nutrient absorption is also under regulation of clocks. Selective and targeted disruption of clock functions in any of these tissues results in disrupted feeding behavior. In case of the nematode C. elegans although circadian rhythms have been described earlier at the behavioral level, yet these rhythms appear to be relatively non-robust. In addition, while the C. elegans genome is predicted to encode homologs of most Drosophila and mammalian core clock components, the roles of these genes appear to be largely restricted to development [47]. Unlike Drosophila or mammals, temperature plays an important role in driving the expression of a large set of genes implicated in metabolic processes in C. elegans[23]. In mammals, diurnal oscillations of various nutrients, blood glucose, lipids and hormones are accompanied by rhythmic activation of diverse metabolic pathways. Transcriptome profiling studies have revealed that the fraction of cyclically expressed transcripts in each peripheral tissue ranges between 5% and 10% of the total population and the vast majority of these genes are tissue specific [4856]. Many hormones involved in metabolism such as insulin [57], glucagon [58], adiponectin [59], corticosterone [60], leptin, and ghrelin [61], have been shown to exhibit circadian oscillation. These studies indicate that circadian signals play a crucial role in control of metabolic rhythms, which ensures energy and nutrient homeostasis at both cellular and organismal levels. The concentrations of various metabolites are sensed by a unique class of transcriptional regulators—the nuclear hormone receptors [6264]. A complex interaction between circadian clock and nuclear receptor signaling exists, which enables rhythmic cycles of metabolites in key metabolic tissues. Nuclear receptors such as REV-ERBα and REV-ERBβ and RORα, β and γ are directly linked to BMAL1 and CLOCK via interconnecting positive and negative transcriptional feedback loops [6567]. Moreover, nuclear receptors implicated in metabolic control such as PPARα and TRα have been shown to act as indirect mediators of BMAL1 and CLOCK to carry out specific outputs in a circadian manner [64,68]. In addition, PER2 itself has been shown to propagate clock information to metabolic genes by directly interacting with and acting as a co-regulator of nuclear receptor-mediated transcription [69]. The rhythmic expression and activity of the metabolic pathways is mainly attributed to the coordinated expression of clock genes along with rhythmic metabolite sensing by nuclear receptors which then feed back again on the clock. With metabolic rhythms and circadian clocks feeding back on each other, the output contributes to cellular homeostasis [70]. The prominent role of the circadian clock in energy metabolism is further demonstrated by obesity and metabolic disorders developed in some clock mutant or knockout mice.

4. Coordination of Central and Peripheral Clocks to Organize Metabolism during Aging

A number of experimental evidences have demonstrated a strong link between metabolism and circadian rhythms and that circadian clocks control the levels of many cellular and circulating metabolites. Despite this, the coupling between metabolism and the circadian clock is complex with more evidence accumulating in favor of a dynamic feed-back loop, wherein the rhythm impacts the metabolic activity and metabolism feeds back to impinge upon the rhythm [71]. While a connection between metabolism and peripheral clocks is more easily apparent, a connection between metabolism and the SCN is not as obvious, because the former are responsive to nutritional stimuli. Several lines of evidence point to a functional link between metabolism and circadian rhythms in the brain. The expression of certain genes encoding metabolic enzymes and transport systems for energy metabolites are under circadian control e.g., glycogen phosphorylase [72,73], cytochrome oxidase, lactate dehydrogenase, etc. The concentration of cellular ATP exhibits a marked fluctuation as a function of light/dark cycle in the SCN, and this in turn stimulates neural activity [74]. Thus, a relationship between neural activity rhythms and metabolic activity rhythms might provide the link between stimuli such as light, food, running, or other sensory stimuli and entrainment of circadian oscillators in the brain. The SCN resets, or entrains peripheral clocks by mechanisms that are not fully understood. While the core circadian clock is common to all tissues whether central or peripheral, the output clock (which governs clock controlled genes- CCGs), or cell processes regulated by the clock, may be tissue, or cell-type specific. Despite this, there is coordination between central and peripheral clocks to ensure a fine tuned, organized metabolism, which would profoundly impact the process of aging.

4.1. Aging, ROS and the Circadian Connection

Aging is characterized by decrements in maximum function and accumulation of mitochondrial DNA mutations, which are best observed in organs such as the brain that contain post-mitotic cells. Oxygen radicals are increasingly considered responsible for part of these aging changes. Comparative studies of animals with different aging rates have shown that the rate of mitochondrial oxygen radical generation is directly related to the steady-state level of oxidative damage to mitochondria and inversely correlated with maximum longevity in higher vertebrates. These two traits link oxidative stress with aging. Many of the detrimental changes associated with aging such as decline in neurotransmitters, reduced motor and sensory systems, fragmented sleep, memory and learning, a gradual decline in general metabolism are linked to the generation of reactive oxygen species (ROS) by mitochondria [75]. In principle, oxidative stress could be related to aging through variations in ROS generation, ROS elimination, or both. Despite this, the rate of aging is not controlled by antioxidants alone, since studies in which genes encoding particular antioxidants are knocked out do not seem to have a major change in their rates of aging compared with ones with intact antioxidant genes [7678]. Increased mean lifespan (MLS) is an index more frequently used than increased maximum lifespan. The increases in MLS suggest that antioxidants can non-specifically protect against many causes of early death—and increase survival—when experiments are performed under sub-optimal conditions. The connections between circadian rhythmicity and energy balance (metabolism) are particularly evident in aging studies. While neurodegenerative diseases and aging frequently coincide with disrupted circadian rhythms and fragmented sleep patterns [79], the most convincing evidences for linking aging phenotype to disrupted circadian rhythms comes from Bmal1−/− mice and per01 fruit flies [12,44]. The mutant mice and fruit flies show distinct signs of early aging and have a reduced lifespan compared to the normal counterparts. The tissues of Bmal1−/− mice and brains of per01 fruit flies also show a high accumulation of ROS, which is consistent with the idea that Bmal1 or per (in case of fruit flies) participates in oxidative stress response [42,43]. C. elegans also has been reported to show a daily variation in response to oxidative and osmotic stress, which provides evidence of rhythmic underlying gene expression which governs these responses to stress [80]. Due to the involvement of mitochondria in oxidative phosphorylation and respiration, these powerhouses of the cell are subject to high levels of ROS production, an inevitable byproduct of respiration. As a result, mitochondrial proteins are central targets of oxidative damage and, when damaged, may contribute to aging disorders such as neurodegeneration [45]. This vicious cycle of ROS-induced damage to mitochondrial DNA, which inevitably leads to reduced respiration efficiency and a further increase in the level of intracellular ROS production is thought to be central to the aging process and the accumulating ROS in the brain probably lead to the age-related neurodegenerative pathologies of Alzheimer’s and Parkinson’s disease. The circadian clock is geared to anticipate any changes in all levels of biological organization and tends to maintain homeostasis. Hence, any state that tends to pull away from the state of homeostasis would be a “stress”, whether it is oxidative stress, ionic or nutritional imbalance or even abrupt and unpredictable changes in the environment. Thus, circadian clocks maintain temporal coordination of the internal milieu whereby conflicts with external or internal environment is lessened and a circadian harmony is created. Additionally circadian rhythms can enhance the efficiency of the component elements of the homeostatic defense that are enhanced when it is most likely or most regularly to be required. Hence, both “reactive” as well as “predictive” homeostatic mechanisms are regulated by the circadian clocks and this ensures a healthy life span during aging (Figure 1).

4.2. Cell Cycle Control and Circadian Clocks

The mammalian CLOCK and BMAL1 proteins have been implicated to play a role in cell cycle control. Embryonic fibroblasts isolated from Clock mutant mice demonstrate a delayed cell cycle entrance after serum starvation. The expression of many genes such as cell cycle inhibitors p21 and p27 was up-regulated, while Cdk2 and cyclins D3 and E1 were downregulated in Clock mutant cells [81]. Thus, these mutations may also impact aging through their effects on cell-cycle regulation, checkpoint proteins and DNA damage repair all of which would have an impact on genome integrity and the aging phenotype.

5. Linking Regulators of Aging and the Circadian Clock

The concept that circadian clocks located in the SCN could actually regulate the process of aging is not new [82,83], yet tangible evidences on such a control mechanism has not been forthcoming till recently. Now, there has been certain exciting development in the field of aging and circadian rhythm researches, which brings up important insights into the fascinating connection between physiological rhythmicity, metabolism and aging. These recently investigated factors that regulate aging have links to circadian clocks, and have been briefly dealt with below:

5.1. The NAD+ and Sirtuins Connection

The mitochondrion is the seat of cellular respiration, energy generation and is also crucial for cellular metabolism. Carrier molecules such as ATP and NAD+ are used in oxidation reduction reactions that are critical for maintenance of energy balance. NAD+ is derived from niacin and operates as a coenzyme for multiple cellular dehydrogenases, and its subsequent reduction to NADH precedes its subsequent oxidation by the respiratory chain. Hence, the role of NAD+ as a hydrogen carrier is vital for the production and maintenance of energy stores. Importantly, nicotinamide mononucleotide adenylyl transferase-1 (Nmnat1), an enzyme involved in the biosynthesis of NAD+, protects against axonal degeneration in Wallerian degeneration slow mice (Wlds). These mice have a spontaneous mutation that increases activation of the Nmnat1 protein resulting in elevated NAD+ levels and consequent silent information regulator1 (Sirt1)- dependent protection against axonal injury [84,85]. The observation that Sirt1 activity oscillates suggests that there may be a link between neuroprotection, redox state and circadian rhythmicity [86]. This link is also supported by observations in Drosophila, where administration of paraquat results in reduced clock gene cycling in peripheral tissues and a forkhead box O protein (FOXO)- dependent sensitivity to oxidative stress in the central pacemaker [87]. These studies strongly indicate the importance of the circadian clock in the control of metabolism and aging but also beg the question of what is the level of their interaction at the cellular level.

An important regulator that has recently attracted major attention in the field of aging research is the SIR2 (Silent Information Regulator 2) protein family, now known as “sirtuins” [8892]. These are an evolutionarily conserved family of NAD-dependent protein deacetylases/ADP-ribosyltransferases. In Saccharomyces cerevisiae, C. elegans and D. melanogaster, SIR2 and its orthologs regulate aging and longevity [9397]. There are seven mammalian sirtuins, SIRT1 through SIRT7, and the majority of mammalian sirtuin research has so far focused on the function of the SIR2 ortholog SIRT1 [89,90,92]. While it has not been demonstrated that SIRT1 regulates aging and longevity in mammals, it has been established that SIRT1 plays an important role in the regulation of metabolism in response to nutritional availability in multiple tissues. SIRT1 coordinates physiological programs that allow animals to survive through nutritionally scarce conditions by mediating critical metabolic responses to nutritional cues, particularly in low nutritional conditions such as fasting and caloric restriction [98,99]. This unique aspect of SIRT1 function and the absolute requirement of NAD for its activity place this protein at a central position as a key regulator that connects metabolism and aging. Nakahata et al.[86] found that SIRT1 shows the oscillation of its enzymatic activity and deacetylates both histone H3 and BMAL1, one of the critical regulators of the core clock mechanism, in a circadian manner. SIRT1 physically interacts with CLOCK, another key clock regulator that heterodimerizes with and acetylates BMAL1, and is recruited to the CLOCK:BMAL1 complex as the promoters of circadian clock genes. Asher et al.[100] showed that SIRT1 interacts with and deacetylates PER2, resulting in its degradation. Thus, SIRT1 regulates the amplitude and the duration of circadian gene expression through deacetylation of key circadian clock regulators, such as BMAL1 and PER2 (Figure 2). These studies have demonstrated the first connection between key regulators of aging and circadian rhythm. Furthermore, the core molecular clock machinery has also been demonstrated to be one of the most powerful modifiers of metabolism [6,101].

5.2. PGC-1α

Liver specific deletion of Bmal1 causes loss of rhythmic expression of clock-regulated metabolic genes in the liver and hypoglycemia in the fasting phase of the daily feeding cycle [2]. Hepatic Bmal1 expression is also regulated by PGC-1α (Peroxisome Proliferator Activated Receptor Gamma coactivator 1 Alpha), another SIRT1 target transcription factor that regulates glucose production in the liver and liver-specific PGC-1α knockdown in mice proves that this factor is required for clock function [102]. The transcriptional co-activator PGC-1α is a critical regulator of mitochondrial energy metabolism and biogenesis. Three members of this family have been identified based on sequence similarity to the founding member PGC-1α. PGC-1β is larger than PGC-1α but shares functionally equivalent protein domain features and has many common downstream targets [103]. Both PGC-1α and PGC-1β are expressed preferentially in high oxidative capacity tissues [104]. PRC-1 (PGC-1 related coactivator) is larger again with similar protein domain features but is not enriched in skeletal muscle and heart [105]. Although functionally similar, PGC-1α, PGC-1β and PRC-1 play distinct tissue specific roles in response to stimuli. At this point of time, PGC-1α is the best characterized and can be linked to aging and also as a transcriptional co-activator of nuclear receptors involved in multiple aspects of metabolism, PGC-1α may play a pivotal role in organismal metabolic homeostasis [106]. Remarkably, PGC-1α is responsive to multiple diverse stimuli: (i) changes in nutrient availability [107], (ii) oxidative species [108110], (iii) endocrine signaling through insulin [111], (iv) circadian clock [102], and (v) energetic demand [112] among others. The ability of PGC-1α to respond to these disparate signals indicates that it is the principle medium through which external stimuli are communicated to the mitochondria. Some of the key regulatory factors for PGC-1α activity are as described below (Figure 3).

5.2.1. AMPK

AMP-activated protein kinase (AMPK) is involved in adaptive response to energy deficit. Activation of AMPK induces PGC-1α. AMPK is involved in PGC-1α autoregulation; direct phosphorylation by AMPK promotes PGC-1α dependent induction at the PGC-1α promoter [113]. In addition to activating PGC-1α, AMPK also inhibits mTOR in mammals [114], a nutrient activated factor that regulates PGC-1α gene expression [115]. This dual arrangement allows for a PGC-1α response to energy deficit and to increased nutrient availability. AMPK acts to restore energy balance by enhancing oxidative metabolism, lipid utilization, promoting mitochondrial biogenesis and by inhibiting energy consuming processes. An important mechanism of AMPK function is increasing levels of NAD+, which in turn promote SIRT1 activity (Figure 3). This is accomplished by a pathway promoting mitochondrial fatty acid oxidation [116].

AMPK is also closely tied to clock function, particularly via its interactions with SIRT1 [116] and also through its phosphorylation and destabilization of CRY proteins [117], which involves ubiquitination of CRY1 by the F-box and leucine rich repeat protein, FBXL3. Nuclear localization of AMPK and CRY proteins showed inverse circadian phase [118]. Activation of AMPK caused phase advance in cell culture clock genes in mice [6]. Mice with disrupted AMPKγ3 subunit express impaired clock induction of muscle genes and circadian shifts in energy metabolism [119]. Importantly, these findings also suggest that cryptochromes may be a significant and previously unappreciated mediator of AMPK-dependent metabolic regulation with impact on gluconeogenesis.

5.2.2. TOR

Target of rapamycin (TOR) is a nutrient sensing kinase that promotes cell growth in conditions of nutrient abundance [120]. Inhibition of TOR extends lifespan in yeast, worms and flies [121]. In mammalian cells, PGC-1α gene transcription is regulated by mTOR through interaction of PGC-1α with transcription factor YY1 and mTOR complex I [115]. The ability of cells to respond to changes in nutritional status through TOR is highly conserved and the role of this nutrient sensitive kinase in regulating mitochondrial function is likely to be important in the aging process [122].

5.2.3. SIRT1

Activity of PGC-1α is regulated through inhibitory acetylation by GCN5 [123] and stimulatory deacetylation of SIRT1 [124126]. PGC-1α is regulated by cellular localization, and in response to oxidative stress accumulates in the nucleus in a SIRT1 dependent manner [108]. Deacetylation of PGC-1α is required to sequester it in the nucleus and this cellular redistribution is prevented by nicotinamide, a potent SIRT1 inhibitor [127].

5.2.4. AKT

The serine threonine kinase AKT is a key component of the insulin signaling pathway whose downstream targets include regulators of metabolism, the stress response and apoptosis [128]. AKT is a negative regulator of PGC-1α. AKT positively regulates mTOR (activator of PGC-1α) by direct inhibition of the inhibitory complex TSC1/2 and by inhibition of the mTOR inhibitors AMPK (activator of PGC-1α) and GSK3β (regulator of PGC-1α turnover) [128,129].

5.2.5. GSK3β

The nutrient sensitive kinase GSK3β (Glycogen Synthase Kinase 3 Beta) targets PGC-1α for nuclear proteasomal degradation [108], regulating PGC-1α turnover and thereby mitochondrial function and the process of aging. Regulation of PGC-1α turnover by GSK3β is also a component of the oxidative stress response in cultured cells and in vivo. GSK3β is downstream of the insulin and the Wnt signaling pathways both of which have been negatively associated with longevity [130,131].

Given the important role of circadian rhythms in various biological functions, cues from metabolic and nutrient status may influence biological clocks to modulate aging and disease processes. Studies in mammals have shown that rapamycin affects light entrainment of the mammalian central clock in the SCN in a phase dependent manner [132]. A study on Drosophila[133] also demonstrated that the TOR pathway can not only modulate entrainment of the clock but the free-running clock itself. This work supports the idea that nutrients may influence the central clock in flies and also add to the growing body of knowledge that clock genes play important roles in maintaining metabolic status and acting as an effector in modulating metabolic outputs.

6. Inter-Relationships between Metabolic Hormones, Circadian Timekeeping and Their Links to Aging

There are data available both from insects as well as vertebrate animal models that metabolic hormonal signaling pathways play a role in the circadian timekeeping mechanisms and in managing biological rhythms, which eventually may impact aging. Experimental evidences on the involvement of hormonal machinery in the control of circadian rhythms have been reported from several insects. It is supposed that a number of insect hormones—juvenile hormones (JHs), ecdysteroids and some neurohormones—control important biological rhythms in the insect body [134]. A bit surprisingly, the principal insect genetic model D. melanogaster does not seem to be the main focus, perhaps due to its small size for hormonal studies, and due to a weak effect of photoperiod on phenomena like diapause or reproduction, found in this species [135,136]. Recently, several publications appeared using the firebug Pyrrhocoris apterus (Heteroptera) addressing this topic. In P. apterus, adult diapause is primarily elicited by a short photoperiod and is controlled by JH, a product of the corpora allata endocrine gland [137]. It has been found in P. apterus not a long time ago that the expression of two circadian clock genes—per and Pdp1 (par domain protein 1)—is controlled by photoperiodic signals [138]. An operation involving removal of active corpora allata from the experimental bugs significantly increased the expression of the per gene while the expression of the Pdp1 was significantly suppressed by this intervention. These results were the first experimental proof for the effect of endocrine glands on circadian clock gene expression in insects.

Other candidates among the insect hormones that could play a role in the circadian rhythmicity are adipokinetic hormones (AKHs). These hormones are synthesized and released by the endocrine gland corpora cardiaca (CC) and represent a large neuropeptide family that is primarily responsible for mobilization of energy sources (lipids, carbohydrates, amino acids) in stress situations [139]. This role is accompanied by a plethora of functions on biochemical, physiological and behavioral levels (for review see [140]) including stimulation of heart beat, general locomotion and immune response. A rhythmicity of adipokinetic response was first demonstrated in the house cricket Acheta domesticus by Das and co-workers [141], who found that fat body sensitivity of this species to injection of Grybi-AKH varies in close synchrony with the lipid rhythm. In addition, the AKH content in the CC varies during the day with two peaks in the scotophase (A. domesticus is nocturnal), and one peak in the photophase. The locomotory activity of A. domesticus correlates with circadian changes in levels of neurosecretory proteins in neurosecretory cells of the brain [142].

A range of information demonstrating the role of AKH in a control of circadian rhythms was obtained in P. apterus. It is known that this species burns almost exclusively lipids and that injection of the Pyrap-AKH elicits lipid mobilization [143]. Maxová et al.[144] found that the maximal lipid mobilization in response to AKH occurs during photophase; this circadian rhythm correlates with locomotory activity that shows also the circadian rhythmicity whose endogenous nature has been demonstrated by Hodková [145]. In addition the rhythm in P. apterus locomotory activity is positively correlated also with the rhythmical changes of the AKH content in the CNS [146]. Also the AKH titer in the hemolymph of P. apterus fluctuates during a day [146], but no positive circadian correlation between this rhythm and fluctuation of the AKH content in CC has been recorded. It is supposed that the AKH level in hemolymph reflects the energetic needs of the body and is not directly under clock control. Nevertheless the clock control of AKH functions was demonstrated by the expression in the AKH-producing neurosecretory cells of the CC of the per gene [147], which is involved in the regulation of P. apterus circadian rhythms [148,149]. Additionally, the fact that the circadian changes in AKH level in CC, and in the mobilization of storage lipids and in the walking activity after the AKH treatment persist also in constant darkness [147] support the suggestion about the endogenous nature of AKH parameters.

Lee and Park [150] demonstrated that a free-running circadian rhythm of locomotory activity persists in D. melanogaster with deficiency of the AKH producing cells as well as in the wild-type flies. However, these authors recorded typical bimodal activity peaks in both groups that are sustained also in constant darkness, leading them to conclude that normal functions of AKH do not include the clock-controlled rhythms of locomotory activity in D. melanogaster. Recently, it was reported that overexpression of dAKH results in lifespan extension in D. melanogaster, and also that dAKH levels increase upon caloric restriction impacting lifespan [151]. It remains to be seen if dAKH is regulated directly by the clock or works independent of clock machinery directly impacting fat metabolism and thus aging. A similar effect of food restriction (FR) was observed in mice where FR resulted in elevated circulating levels of glucocorticoids correlated with enhanced lifespan [152]. Resetting of circadian timing in peripheral tissues by glucocorticoid signaling has been reported in mice models [153,154]. A robust phenotype associated with aging is a change in energy utilization, including body fat stores. Increases in body fat mass and deteriorations in insulin sensitivity are associated with aging in many mammalian species as well as in many clinical pathologies, including cardiovascular disease. Data obtained from clock gene mutants indicate a strong circadian mechanism regulating adipose stores, as well as the release of insulin and leptin, which activate anorexiegenic pathways of energy homeostasis and reduce food intake. The nocturnal rise in circulating leptin levels of younger animals are attenuated in older animals [155]. The amplitude as well as phases of metabolic hormones such as insulin, corticosterone and prolactin are disrupted in obese aged rodents, whereas administration of these hormones at specific times of day mimicking the rhythms of younger phenotypes re-establish the metabolic characteristics of younger animals [156]. Finally, there are very strong evidences of links between melatonin, clocks and aging [157]. These studies lead to the speculation of whether timed hormonal injections in aged populations would help in re-setting the energetic processes to allow for minimization of metabolic deficits. Such diverse approaches and studies in different model systems would be indicative of the complex interactions and inter-relationships between metabolic hormones, the clock machinery and the aging process.

7. Conclusions

The quest for new and effective means to delay aging or increase health span during the process of aging and thus delay the onset of aging associated diseases now has a new player in the arena—the circadian clocks. Mechanistic insights in the links between circadian clocks and aging process are being gleaned through studies in Drosophila as well as mammalian systems. With advancing age, animals exhibit numerous circadian disruptions [158162] that contribute to poor health consequences and hastened senescence. While with age a marked dampening of the amplitude of oscillations of circadian clock transcripts is noticed [163], and longevity is diminished by mutations in clock genes [44], longevity can be decelerated by restoration of youthful circadian behavior by transplantation of a fetal clock into the brains of aged animals [164]. Thus, with increased understanding of the mechanisms driving age-related changes in clocks of various model organisms, novel insights concerning the nature of age-related pathologies resulting from loss of temporal precision can be gained. Aged individuals exhibit pronounced deficits in the amplitude and timing of core molecular clock genes and entrainment of the master clock to local time. This deterioration manifests as disruptions in sleep-wake cycle and system-wide physiology. Further studies on the links between circadian clocks and aging will afford greater insight into maximizing health with advancing age.


This study was supported by start-up funds, MSU#012156-014 (NK) from National Science Foundation, EPSCOR and by grant no. P501/10/1215 (DK) from the Czech Science Foundation.

  • Conflict of InterestThe authors declare no conflict of interest.


  1. Chen, Z.; Odstrcil, E.A.; Tu, B.P.; McKnight, S.L. Restriction of DNA replication to the reductive phase of the metabolic cycle protects genome integrity. Science 2007, 316, 1916–1919.
  2. Lamia, K.A.; Storch, K.F.; Weitz, C.J. Physiological significance of a peripheral tissue circadian clock. Proc. Natl. Acad. Sci. USA 2008, 105, 15172–15177.
  3. Turek, F.W.; Joshu, C.; Kohsaka, A.; Lin, E.; Ivanova, G.; McDearmon, E.; Laposky, A.; Losee-Olson, S.; Easton, A.; Jensen, D.R.; et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005, 308, 1043–1045.
  4. Woelfle, M.A.; Ouyang, Y.; Phanvijhitsiri, K.; Johnson, C.H. The adaptive value of circadian clocks: An experimental assessment in cyanobacteria. Curr. Biol 2004, 14, 1481–1486.
  5. Pittendrigh, C.S. On Temperature Independence in the Clock System Controlling Emergence Time in Drosophila. Proc. Natl. Acad. Sci. USA 1954, 40, 1018–1029.
  6. Green, C.B.; Takahashi, J.S.; Bass, J. The meter of metabolism. Cell 2008, 134, 728–742.
  7. Takahashi, J.S.; Hong, H.K.; Ko, C.H.; McDearmon, E.L. The genetics of mammalian circadian order and disorder: Implications for physiology and disease. Nat. Rev. Genet 2008, 9, 764–775.
  8. Claudel, T.; Cretenet, G.; Saumet, A.; Gachon, F. Crosstalk between xenobiotics metabolism and circadian clock. FEBS Lett 2007, 581, 3626–3633.
  9. Kang, T.H.; Sancar, A. Circadian regulation of DNA excision repair: Implications for chrono-chemotherapy. Cell Cycle 2009, 8, 1665–1667.
  10. Antoch, M.P.; Gorbacheva, V.Y.; Vykhovanets, O.; Toshkov, I.A.; Kondratov, R.V.; Kondratova, A.A.; Lee, C.; Nikitin, A.Y. Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis. Cell Cycle 2008, 7, 1197–1204.
  11. Gauger, M.A.; Sancar, A. Cryptochrome, circadian cycle, cell cycle checkpoints, and cancer. Cancer Res 2005, 65, 6828–6834.
  12. Kondratov, R.V.; Kondratova, A.A.; Gorbacheva, V.Y.; Vykhovanets, O.V.; Antoch, M.P. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev 2006, 20, 1868–1873.
  13. Lee, C.C. Tumor suppression by the mammalian Period genes. Cancer Causes Control 2006, 17, 525–530.
  14. Gachon, F.; Nagoshi, E.; Brown, S.A.; Ripperger, J.; Schibler, U. The mammalian circadian timing system: From gene expression to physiology. Chromosoma 2004, 113, 103–112.
  15. Helfrich-Forster, C. The circadian clock in the brain: A structural and functional comparison between mammals and insects. J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol 2004, 190, 601–613.
  16. Nitabach, M.N.; Taghert, P.H. Organization of the Drosophila circadian control circuit. Curr. Biol 2008, 18, R84–R93.
  17. Giebultowicz, J.M. Peripheral clocks and their role in circadian timing: Insights from insects. Phil. Trans. R. Soc. B 2001, 356, 1791–1799.
  18. Giebultowicz, J.M. Multiple oscillators. In Molecular Biology of Circadian Rhythms; Sehgal, A., Ed.; John Wiley & Sons: Hoboken, NJ, USA, 2004; pp. 213–230.
  19. Glossop, N.R.; Hardin, P.E. Central and peripheral circadian oscillator mechanisms in flies and mammals. J. Cell Sci 2002, 115, 3369–3377.
  20. Bae, K.; Edery, I. Regulating a circadian clock’s period, phase and amplitude by phosphorylation: Insights from Drosophila. J. Biochem 2006, 140, 609–617.
  21. Stanewsky, R.; Kaneko, M.; Emery, P.; Beretta, B.; Wager-Smith, K.; Kay, S.A.; Rosbash, M.; Hall, J.C. The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila. Cell 1998, 95, 681–692.
  22. Naidoo, N.; Song, W.; Hunter-Ensor, M.; Sehgal, A. A role for the proteasome in the light response of the timeless clock protein. Science 1999, 285, 1737–1741.
  23. van der Linden, A.M.; Beverly, M.; Kadener, S.; Rodriguez, J.; Wasserman, S.; Rosbash, M.; Sengupta, P. Genome-wide analysis of light- and temperature-entrained circadian transcripts in Caenorhabditis elegans. PLoS Biol 2010, 8, e1000503.
  24. Simonetta, S.H.; Golombek, D.A. An automated tracking system for Caenorhabditis elegans locomotor behavior and circadian studies application. J. Neurosci. Methods 2007, 161, 273–280.
  25. Hasegawa, K.; Saigusa, T.; Tamai, Y. Caenorhabditis elegans opens up new insights into circadian clock mechanisms. Chronobiol. Int 2005, 22, 1–19.
  26. Banerjee, D.; Kwok, A.; Lin, S.Y.; Slack, F.J. Developmental timing in C. elegans is regulated by kin-20 and tim-1, homologs of core circadian clock genes. Dev. Cell 2005, 8, 287–295.
  27. Timpano, A.; James, T.; Chin, L. let-7 family microRNAs directly regulate the developmental timing gene lin-42 and the circadian timing gene period. Proceedings of the International Worm Meeting 715, Los Angeles, CA, USA, 24– 28 June 2009.
  28. Ando, H.; Takamura, T.; Matsuzawa-Nagata, N.; Shima, K.R.; Eto, T.; Misu, H.; Shiramoto, M.; Tsuru, T.; Irie, S.; Fujimura, A.; et al. Clock gene expression in peripheral leucocytes of patients with type 2 diabetes. Diabetologia 2009, 52, 329–335.
  29. Kusanagi, H.; Mishima, K.; Satoh, K.; Echizenya, M.; Katoh, T.; Shimizu, T. Similar profiles in human period1 gene expression in peripheral mononuclear and polymorphonuclear cells. Neurosci. Lett 2004, 365, 124–127.
  30. Yamamoto, T.; Nakahata, Y.; Soma, H.; Akashi, M.; Mamine, T.; Takumi, T. Transcriptional oscillation of canonical clock genes in mouse peripheral tissues. BMC Mol. Biol 2004, 5, 18.
  31. Yoo, S.H.; Yamazaki, S.; Lowrey, P.L.; Shimomura, K.; Ko, C.H.; Buhr, E.D.; Siepka, S.M.; Hong, H.K.; Oh, W.J.; Yoo, O.J.; et al. PERIOD2: LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl. Acad. Sci. USA 2004, 101, 5339–5346.
  32. Zheng, X.; Sehgal, A. Probing the relative importance of molecular oscillations in the circadian clock. Genetics 2008, 178, 1147–1155.
  33. Lowrey, P.L.; Takahashi, J.S. Mammalian circadian biology: Elucidating genome-wide levels of temporal organization. Annu. Rev. Genomics Human Genet 2004, 5, 407–441.
  34. Reppert, S.M.; Weaver, D.R. Coordination of circadian timing in mammals. Nature 2002, 418, 935–941.
  35. Bunger, M.K.; Wilsbacher, L.D.; Moran, S.M.; Clendenin, C.; Radcliffe, L.A.; Hogenesch, J.B.; Simon, M.C.; Takahashi, J.S.; Bradfield, C.A. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 2000, 103, 1009–1017.
  36. Gekakis, N.; Staknis, D.; Nguyen, H.B.; Davis, F.C.; Wilsbacher, L.D.; King, D.P.; Takahashi, J.S.; Weitz, C.J. Role of the CLOCK protein in the mammalian circadian mechanism. Science 1998, 280, 1964–1569.
  37. Kume, K.; Zylka, M.J.; Sriram, S.; Shearman, L.P.; Weaver, D.R.; Jin, X.; Maywood, E.S.; Hastings, M.H.; Reppert, S.M. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 1999, 98, 193–205.
  38. Okamura, H.; Miyake, S.; Sumi, Y.; Yamaguchi, S.; Yasui, A.; Muijtjens, M.; Hoeijmakers, J.H.; van der Horst, G.T. Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science 1999, 286, 2531–2534.
  39. Vitaterna, M.H.; Selby, C.P.; Todo, T.; Niwa, H.; Thompson, C.; Fruechte, E.M.; Hitomi, K.; Thresher, R.J.; Ishikawa, T.; Miyazaki, J.; et al. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc. Natl. Acad. Sci. USA 1999, 96, 12114–12119.
  40. Bovbjerg, D.H. Circadian disruption and cancer: Sleep and immune regulation. Brain Behav. Immun. 2003, 17 Suppl 1, S48–50.
  41. Fu, L.; Lee, C.C. The circadian clock: Pacemaker and tumour suppressor. Nat. Rev. Cancer 2003, 3, 350–361.
  42. Gorbacheva, V.Y.; Kondratov, R.V.; Zhang, R.; Cherukuri, S.; Gudkov, A.V.; Takahashi, J.S.; Antoch, M.P. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc. Natl. Acad. Sci. USA 2005, 102, 3407–3412.
  43. Krishnan, N.; Davis, A.J.; Giebultowicz, J.M. Circadian regulation of response to oxidative stress in Drosophila melanogaster. Biochem. Biophys. Res. Commun 2008, 374, 299–303.
  44. Krishnan, N.; Kretzschmar, D.; Rakshit, K.; Chow, E.; Giebultowicz, J. The circadian clock gene period extends healthspan in aging Drosophila melanogaster. Aging 2009, 1, 937–948.
  45. Krishnan, N.; Rakshit, K.; Chow, E.S.; Wentzell, J.S.; Kretzschmar, D.; Giebultowicz, J.M. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants. Neurobiol. Dis 2012, 45, 1129–1135.
  46. Xu, K.; Zheng, X.; Sehgal, A. Regulation of feeding and metabolism by neuronal and peripheral clocks in Drosophila. Cell Metab 2008, 8, 289–300.
  47. Jeon, M.; Gardner, H.F.; Miller, E.A.; Deshler, J.; Rougvie, A.E. Similarity of the C. elegans developmental timing protein LIN-42 to circadian rhythm proteins. Science 1999, 286, 1141–1146.
  48. Akhtar, R.A.; Reddy, A.B.; Maywood, E.S.; Clayton, J.D.; King, V.M.; Smith, A.G.; Gant, T.W.; Hastings, M.H.; Kyriacou, C.P. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol 2002, 12, 540–550.
  49. Duffield, G.E.; Best, J.D.; Meurers, B.H.; Bittner, A.; Loros, J.J.; Dunlap, J.C. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr. Biol 2002, 12, 551–557.
  50. Kornmann, B.; Preitner, N.; Rifat, D.; Fleury-Olela, F.; Schibler, U. Analysis of circadian liver gene expression by ADDER, a highly sensitive method for the display of differentially expressed mRNAs. Nucleic Acids Res 2001, 29, E51–E51.
  51. McCarthy, J.J.; Andrews, J.L.; McDearmon, E.L.; Campbell, K.S.; Barber, B.K.; Miller, B.H.; Walker, J.R.; Hogenesch, J.B.; Takahashi, J.S.; Esser, K.A. Identification of the circadian transcriptome in adult mouse skeletal muscle. Physiol. Genomics 2007, 31, 86–95.
  52. Panda, S.; Antoch, M.P.; Miller, B.H.; Su, A.I.; Schook, A.B.; Straume, M.; Schultz, P.G.; Kay, S.A.; Takahashi, J.S.; Hogenesch, J.B. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 2002, 109, 307–320.
  53. Schibler, U.; Ripperger, J.; Brown, S.A. Peripheral circadian oscillators in mammals: Time and food. J. Biol. Rhythms 2003, 18, 250–260.
  54. Storch, K.F.; Lipan, O.; Leykin, I.; Viswanathan, N.; Davis, F.C.; Wong, W.H.; Weitz, C.J. Extensive and divergent circadian gene expression in liver and heart. Nature 2002, 417, 78–83.
  55. Ueda, H.R.; Matsumoto, A.; Kawamura, M.; Iino, M.; Tanimura, T.; Hashimoto, S. Genome-wide transcriptional orchestration of circadian rhythms in Drosophila. J. Biol. Chem 2002, 277, 14048–14052.
  56. Zvonic, S.; Floyd, Z.E.; Mynatt, R.L.; Gimble, J.M. Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis. Obesity (Silver Spring) 2007, 15, 539–543.
  57. La Fleur, S.E.; Kalsbeek, A.; Wortel, J.; Buijs, R.M. A suprachiasmatic nucleus generated rhythm in basal glucose concentrations. J Neuroendocrinol 1999, 11, 643–652.
  58. Ruiter, M.; La Fleur, S.E.; van Heijningen, C.; van der Vliet, J.; Kalsbeek, A.; Buijs, R.M. The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior. Diabetes 2003, 52, 1709–1715.
  59. Ando, H.; Yanagihara, H.; Hayashi, Y.; Obi, Y.; Tsuruoka, S.; Takamura, T.; Kaneko, S.; Fujimura, A. Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology 2005, 146, 5631–5636.
  60. De Boer, S.F.; Van der Gugten, J. Daily variations in plasma noradrenaline, adrenaline and corticosterone concentrations in rats. Physiol. Behav 1987, 40, 323–328.
  61. Bodosi, B.; Gardi, J.; Hajdu, I.; Szentirmai, E.; Obal, F., Jr; Krueger, J.M. Rhythms of ghrelin, leptin, and sleep in rats: Effects of the normal diurnal cycle, restricted feeding, and sleep deprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004, 287, R1071–R1079.
  62. Chawla, A.; Repa, J.J.; Evans, R.M.; Mangelsdorf, D.J. Nuclear receptors and lipid physiology: Opening the X-files. Science 2001, 294, 1866–1870.
  63. Francis, G.A.; Fayard, E.; Picard, F.; Auwerx, J. Nuclear receptors and the control of metabolism. Annu. Rev. Physiol 2003, 65, 261–311.
  64. Yang, X. A wheel of time: The circadian clock, nuclear receptors, and physiology. Genes Dev 2010, 24, 741–747.
  65. Guillaumond, F.; Dardente, H.; Giguere, V.; Cermakian, N. Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J. Biol. Rhythms 2005, 20, 391–403.
  66. Preitner, N.; Damiola, F.; Lopez-Molina, L.; Zakany, J.; Duboule, D.; Albrecht, U.; Schibler, U. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 2002, 110, 251–260.
  67. Sato, T.K.; Panda, S.; Miraglia, L.J.; Reyes, T.M.; Rudic, R.D.; McNamara, P.; Naik, K.A.; FitzGerald, G.A.; Kay, S.A.; Hogenesch, J.B. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 2004, 43, 527–537.
  68. Teboul, M.; Guillaumond, F.; Grechez-Cassiau, A.; Delaunay, F. The Nuclear Hormone Receptors Family Round the Clock. Mol. Endocrinol 2008, 22, 2573–2582.
  69. Schmutz, I.; Ripperger, J.A.; Baeriswyl-Aebischer, S.; Albrecht, U. The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. Genes Dev 2010, 24, 345–357.
  70. Meermeier, N.; Krishnan, N. Circadian regulation of cellular homeostasis—implications for cell metabolism and clinical diseases. Med. Hypotheses 2012, 79, 17–24.
  71. Roenneberg, T.; Merrow, M. Circadian systems and metabolism. J. Biol. Rhythms 1999, 14, 449–459.
  72. Harley, C.W.; Farrell, R.C.; Rusak, B. Daily variation in the distribution of glycogen phosphorylase in the suprachiasmatic nucleus of Syrian hamsters. J. Comp. Neurol 2001, 435, 249–258.
  73. Harley, C.; Rusak, B. Daily variation in active glycogen phosphorylase patches in the molecular layer of rat dentate gyrus. Brain Res 1993, 626, 310–317.
  74. Yamazaki, S.; Ishida, Y.; Inouye, S. Circadian rhythms of adenosine triphosphate contents in the suprachiasmatic nucleus, anterior hypothalamic area and caudate putamen of the rat--negative correlation with electrical activity. Brain Res 1994, 664, 237–240.
  75. Harman, D. Free radical theory of aging: Increasing the average life expectancy at birth and the maximum life span. J. Anti-Aging Med 1999, 2, 199–208.
  76. Ho, Y.S.; Magnenat, J.L.; Bronson, R.T.; Cao, J.; Gargano, M.; Sugawara, M.; Funk, C.D. Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia. J. Biol. Chem 1997, 272, 16644–16651.
  77. Melov, S.; Coskun, P.; Patel, M.; Tuinstra, R.; Cottrell, B.; Jun, A.S.; Zastawny, T.H.; Dizdaroglu, M.; Goodman, S.I.; Huang, T.T.; et al. Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc. Natl. Acad. Sci. USA 1999, 96, 846–851.
  78. Shefner, J.M.; Reaume, A.G.; Flood, D.G.; Scott, R.W.; Kowall, N.W.; Ferrante, R.J.; Siwek, D.F.; Upton-Rice, M.; Brown, R.H., Jr. Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy. Neurology 1999, 53, 1239–1246.
  79. Barnard, A.R.; Nolan, P.M. When clocks go bad: Neurobehavioral consequences of disrupted circadian timing. PLoS Genet 2008, 4, e1000040.
  80. Simonetta, S.H.; Romanowski, A.; Minniti, A.N.; Inestrosa, N.C.; Golombek, D.A. Circadian stress tolerance in adult Caenorhabditis elegans. J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol 2008, 194, 821–828.
  81. Miller, B.H.; McDearmon, E.L.; Panda, S.; Hayes, K.R.; Zhang, J.; Andrews, J.L.; Antoch, M.P.; Walker, J.R.; Esser, K.A.; Hogenesch, J.B.; Takahashi, J.S. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc. Natl. Acad. Sci. USA 2007, 104, 3342–3347.
  82. Everitt, A.V. The hypothalamic-pituitary control of ageing and age-related pathology. Exp. Gerontol 1973, 8, 265–277.
  83. Dilman, V.M. Age-associated elevation of hypothalamic, threshold to feedback control, and its role in development, ageing, and disease. Lancet 1971, 1, 1211–1219.
  84. Araki, T.; Sasaki, Y.; Milbrandt, J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 2004, 305, 1010–1013.
  85. Mack, T.G.; Reiner, M.; Beirowski, B.; Mi, W.; Emanuelli, M.; Wagner, D.; Thomson, D.; Gillingwater, T.; Court, F.; Conforti, L.; et al. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat. Neurosci 2001, 4, 1199–1206.
  86. Nakahata, Y.; Kaluzova, M.; Grimaldi, B.; Sahar, S.; Hirayama, J.; Chen, D.; Guarente, L.P.; Sassone-Corsi, P. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 2008, 134, 329–340.
  87. Zheng, X.; Yang, Z.; Yue, Z.; Alvarez, J.D.; Sehgal, A. FOXO and insulin signaling regulate sensitivity of the circadian clock to oxidative stress. Proc. Natl. Acad. Sci. USA 2007, 104, 15899–15904.
  88. Blander, G.; Guarente, L. The Sir2 family of protein deacetylases. Annu. Rev. Biochem 2004, 73, 417–435.
  89. Dali-Youcef, N.; Lagouge, M.; Froelich, S.; Koehl, C.; Schoonjans, K.; Auwerx, J. Sirtuins: The “magnificient seven”, function, metabolism and longevity. Ann. Med 2007, 39, 335–345.
  90. Imai, S.; Guarente, L. Sirtuins: A universal link between NAD, metabolism and aging. In The Molecular Biology of Aging; Guarente, L., Partridge, L., Wallace, D., Eds.; Cold Spring Harbor Laboratory Press: New York, NY, USA, 2007; pp. 39–72.
  91. Michan, S.; Sinclair, D. Sirtuins in mammals: Insights into their biological function. Biochem. J 2007, 404, 1–13.
  92. Schwer, B.; Verdin, E. Conserved metabolic regulatory functions of sirtuins. Cell Metab 2008, 7, 104–112.
  93. Astrom, S.U.; Cline, T.W.; Rine, J. The Drosophila melanogaster sir2+ gene is nonessential and has only minor effects on position-effect variegation. Genetics 2003, 163, 931–937.
  94. Howitz, K.T.; Bitterman, K.J.; Cohen, H.Y.; Lamming, D.W.; Lavu, S.; Wood, J.G.; Zipkin, R.E.; Chung, P.; Kisielewski, A.; Zhang, L.L.; et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003, 425, 191–196.
  95. Rogina, B.; Helfand, S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA 2004, 101, 15998–16003.
  96. Tissenbaum, H.A.; Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001, 410, 227–230.
  97. Wood, J.G.; Rogina, B.; Lavu, S.; Howitz, K.; Helfand, S.L.; Tatar, M.; Sinclair, D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004, 430, 686–689.
  98. Bordone, L.; Guarente, L. Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nat. Rev. Mol. Cell. Biol 2005, 6, 298–305.
  99. Imai, S. The NAD World: A new systemic regulatory network for metabolism and aging—Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem. Biophys 2009, 53, 65–74.
  100. Asher, G.; Gatfield, D.; Stratmann, M.; Reinke, H.; Dibner, C.; Kreppel, F.; Mostoslavsky, R.; Alt, F.W.; Schibler, U. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 2008, 134, 317–328.
  101. Ramsey, K.M.; Marcheva, B.; Kohsaka, A.; Bass, J. The clockwork of metabolism. Annu. Rev. Nutr 2007, 27, 219–240.
  102. Liu, C.; Li, S.; Liu, T.; Borjigin, J.; Lin, J.D. Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature 2007, 447, 477–481.
  103. Lin, J.; Puigserver, P.; Donovan, J.; Tarr, P.; Spiegelman, B.M. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem 2002, 277, 1645–1648.
  104. Scarpulla, R.C. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev 2008, 88, 611–638.
  105. Andersson, U.; Scarpulla, R.C. Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol. Cell. Biol 2001, 21, 3738–3749.
  106. Handschin, C.; Spiegelman, B.M. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature 2008, 454, 463–469.
  107. Ichida, M.; Nemoto, S.; Finkel, T. Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma Coactivator-1 alpha (PGC-1alpha). J. Biol. Chem 2002, 277, 50991–50995.
  108. Anderson, R.M.; Barger, J.L.; Edwards, M.G.; Braun, K.H.; O’Connor, C.E.; Prolla, T.A.; Weindruch, R. Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response. Aging Cell 2008, 7, 101–111.
  109. St-Pierre, J.; Drori, S.; Uldry, M.; Silvaggi, J.M.; Rhee, J.; Jager, S.; Handschin, C.; Zheng, K.; Lin, J.; Yang, W.; et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006, 127, 397–408.
  110. Valle, I.; Alvarez-Barrientos, A.; Arza, E.; Lamas, S.; Monsalve, M. PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc. Res 2005, 66, 562–573.
  111. Southgate, R.J.; Bruce, C.R.; Carey, A.L.; Steinberg, G.R.; Walder, K.; Monks, R.; Watt, M.J.; Hawley, J.A.; Birnbaum, M.J.; Febbraio, M.A. PGC-1alpha gene expression is down-regulated by Akt- mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle. FASEB J 2005, 19, 2072–2074.
  112. Russell, A.P.; Feilchenfeldt, J.; Schreiber, S.; Praz, M.; Crettenand, A.; Gobelet, C.; Meier, C.A.; Bell, D.R.; Kralli, A.; Giacobino, J.P.; Deriaz, O. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 2003, 52, 2874–2881.
  113. Jager, S.; Handschin, C.; St-Pierre, J.; Spiegelman, B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. USA 2007, 104, 12017–12022.
  114. Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 2008, 30, 214–226.
  115. Cunningham, J.T.; Rodgers, J.T.; Arlow, D.H.; Vazquez, F.; Mootha, V.K.; Puigserver, P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 2007, 450, 736–740.
  116. Canto, C.; Gerhart-Hines, Z.; Feige, J.N.; Lagouge, M.; Noriega, L.; Milne, J.C.; Elliott, P.J.; Puigserver, P.; Auwerx, J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009, 458, 1056–1060.
  117. Jordan, S.D.; Lamia, K.A. AMPK at the crossroads of circadian clocks and metabolism. Mol. Cell. Endocrinol. 2012. in press.
  118. Lamia, K.A.; Sachdeva, U.M.; DiTacchio, L.; Williams, E.C.; Alvarez, J.G.; Egan, D.F.; Vasquez, D.S.; Juguilon, H.; Panda, S.; Shaw, R.J.; et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 2009, 326, 437–440.
  119. Vieira, E.; Nilsson, E.C.; Nerstedt, A.; Ormestad, M.; Long, Y.C.; Garcia-Roves, P.M.; Zierath, J.R.; Mahlapuu, M. Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle. Am. J. Phyiol. Endocrinol. Metab 2008, 295, 1032–1037.
  120. Wullschleger, S.; Loewith, R.; Hall, M.N. TOR signaling in growth and metabolism. Cell 2006, 124, 471–484.
  121. Anderson, R.M.; Weindruch, R. Metabolic reprogramming in dietary restriction. Interdiscip. Top. Gerontol 2007, 35, 18–38.
  122. Schieke, S.M.; Finkel, T. Mitochondrial signaling, TOR, and life span. Biol. Chem 2006, 387, 1357–1361.
  123. Lerin, C.; Rodgers, J.T.; Kalume, D.E.; Kim, S.H.; Pandey, A.; Puigserver, P. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab 2006, 3, 429–438.
  124. Nemoto, S.; Fergusson, M.M.; Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J. Biol. Chem 2005, 280, 16456–16460.
  125. Rodgers, J.T.; Lerin, C.; Haas, W.; Gygi, S.P.; Spiegelman, B.M.; Puigserver, P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005, 434, 113–118.
  126. Gerhart-Hines, Z.; Rodgers, J.T.; Bare, O.; Lerin, C.; Kim, S.H.; Mostoslavsky, R.; Alt, F.W.; Wu, Z.; Puigserver, P. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 2007, 26, 1913–1923.
  127. Bitterman, K.J.; Anderson, R.M.; Cohen, H.Y.; Latorre-Esteves, M.; Sinclair, D.A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem 2002, 277, 45099–45107.
  128. Bhaskar, P.T.; Hay, N. The two TORCs and Akt. Dev. Cell 2007, 12, 487–502.
  129. Hahn-Windgassen, A.; Nogueira, V.; Chen, C.C.; Skeen, J.E.; Sonenberg, N.; Hay, N. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol. Chem 2005, 280, 32081–32089.
  130. Kenyon, C. The plasticity of aging: Insights from long-lived mutants. Cell 2005, 120, 449–460.
  131. Liu, H.; Fergusson, M.M.; Castilho, R.M.; Liu, J.; Cao, L.; Chen, J.; Malide, D.; Rovira, I.I; Schimel, D.; Kuo, C.J.; et al. Science 2007, 317, 803–806.
  132. Cao, R.; Lee, B.; Cho, H.Y.; Saklayen, S.; Obrietan, K. Photic regulation of the mTOR signaling pathway in the suprachiasmatic circadian clock. Mol. Cell. Neurosci 2008, 38, 312–324.
  133. Zheng, X.; Sehgal, A. AKT and TOR signaling set the pace of the circadian pacemaker. Curr. Biol 2010, 20, 1203–1208.
  134. Steel, C.G.; Vafopoulou, X. Physiology of circadian systems. In Insect Clocks, 3rd ed.; Saunders, D.S., Ed.; Elsevier: Amsterdam, The Netherlands, 2002; pp. 115–188.
  135. Saunders, D.S.; Henrich, V.C.; Gilbert, L.I. Induction of diapause in Drosophila melanogaster: Photoperiodic regulation and the impact of arrhythmic clock mutations on time measurement. Proc. Natl. Acad. Sci. USA 1989, 86, 3748–3752.
  136. Denlinger, D.L. Regulation of diapause. Annu. Rev. Entomol 2002, 47, 93–122.
  137. Socha, R. Pyrrhocoris apterus (Heteroptera)—an experimental model species: A review. Eur. J. Entomol 1993, 90, 241–286.
  138. Dolezel, D.; Zdechovanova, L.; Sauman, I.; Hodkova, M. Endocrine-dependent expression of circadian clock genes in insects. Cell Mol. Life Sci 2008, 65, 964–969.
  139. Gade, G.; Hoffmann, K.H.; Spring, J.H. Hormonal regulation in insects: Facts, gaps, and future directions. Physiol. Rev 1997, 77, 963–1032.
  140. Kodrik, D. Adipokinetic hormone functions that are not associated with insect flight. Physiol. Entomol 2008, 33, 171–180.
  141. Das, S.; Meier, O.W.; Woodring, J.P. Diel rhythms of adipokinetic hormone, fat body response, and haemolymph lipid and sugar levels in the house cricket. Physiol. Entomol 1993, 18, 233–239.
  142. Cymborowski, B. Daily changes in synthesis and accumulation of neurosecretion in the brain of the house crickets. J. Interdisciplin. Cycle Res 1983, 14, 111–116.
  143. Kodrik, D.; Socha, R.; Simek, P.; Zemek, R.; Goldsworthy, G.J. A new member of the AKH/RPCH family stimulates locomotory activity in the firebug Pyrrhocoris apterus (Heteroptera). Insect Biochem. Mol. Biol 2000, 30, 489–498.
  144. Maxova, A.; Kodrik, D.; Zemek, R.; Socha, R. Diel changes in adipokinetic response and walking activity of Pyrrhocoris apterus (L.) (Heteroptera) in relation to physiological status and wing dimorphism. Eur. J. Entomol 2001, 98, 433–438.
  145. Hodkova, M. Regulation of diapause and reproduction in Pyrrhocoris apterus (L.) (Heteroptera)—neuroendocrine outputs (mini-review). Entomol. Sci 1999, 2, 563–566.
  146. Kodrik, D.; Socha, R.; Syrova, Z. Developmental and diel changes of adipokinetic hormone in CNS and haemolymph of the flightless wing-polymorphic bug, Pyrrhocoris apterus (L.). J. Insect Physiol 2003, 49, 53–61.
  147. Kodrik, D.; Socha, R.; Syrova, Z.; Zemek, R. The effect of constant darkness on the content of adipokinetic hormone, adipokinetic response and walking activity in macropterous females of Pyrrhocoris apterus (L.). Physiol. Entomol 2005, 30, 248–255.
  148. Hodkova, M.; Syrova, Z.; Dolezel, D.; Sauman, I. Period gene expression in relation to seasonality and circadian rhythms in the linden bug, Pyrrhocoris apterus (Heteroptera). Eur. J. Entomol 2003, 100, 267–273.
  149. Syrova, Z.; Sauman, I.; Giebultowicz, J.M. Effects of light and temperature on the circadian system controlling sperm release in moth Spodoptera littoralis. Chronobiol. Int 2003, 20, 809–821.
  150. Lee, G.; Park, J.H. Hemolymph sugar homeostasis and starvation-induced hyperactivity affected by genetic manipulations of the adipokinetic hormone-encoding gene in Drosophila melanogaster. Genetics 2004, 167, 311–323.
  151. Katewa, S.D.; Demontis, F.; Kolipinski, M.; Hubbard, A.; Gill, M.S.; Perrimon, N.; Melov, S.; Kapahi, P. Intramyocellular fatty-acid metabolism plays a critical role in mediating responses to dietary restriction in Drosophila melanogaster. Cell Metab 2012, 16, 97–103.
  152. Klebanov, S.; Diais, S.; Stavinoha, W.B.; Suh, Y.; Nelson, J.F. Hyperadrenocorticism, attenuated inflammation, and the life-prolonging action of food restriction in mice. J. Gerontol. A Biol. Sci. Med. Sci 1995, 50, B78–B82.
  153. Balsalobre, A.; Brown, S.A.; Marcacci, L.; Tronche, F.; Kellendonk, C.; Reichardt, H.M.; Schutz, G.; Schibler, U. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 2000, 289, 2344–2347.
  154. Le Minh, N.; Damiola, F.; Tronche, F.; Schutz, G.; Schibler, U. Glucocorticoid hormones inhibit food-induced phaseshifting of peripheral circadian oscillators. EMBO J 2001, 20, 7128–7136.
  155. Downs, J.L.; Urbanski, H.F. Aging-related sex-dependent loss of the circulating leptin 24-h rhythm in the rhesus monkey. J. Endocrinol 2006, 190, 117–127.
  156. Cincotta, A.H.; Schiller, B.C.; Landry, R.J.; Herbert, S.J.; Miers, W.R.; Meier, A.H. Circadian neuroendocrine role in age-related changes in body fat stores and insulin sensitivity of the male Sprague-Dawley rat. Chronobiol. Int 1993, 10, 244–258.
  157. Bubenik, G.A.; Konturek, S.J. Melatonin and aging: Prospects for human treatment. J. Physiol. Pharmacol 2011, 62, 13–19.
  158. Benloucif, S.; Masana, M.I.; Dubocovich, M.L. Light-induced phase shifts of circadian activity rhythms and immediate early gene expression in the suprachiasmatic nucleus are attenuated in old C3H/HeN mice. Brain Res 1997, 747, 34–42.
  159. Davidson, A.J.; Yamazaki, S.; Arble, D.M.; Menaker, M.; Block, G.D. Resetting of central and peripheral circadian oscillators in aged rats. Neurobiol. Aging 2008, 29, 471–477.
  160. Li, H.; Satinoff, E. Changes in circadian rhythms of body temperature and sleep in old rats. Am. J. Physiol 1995, 269, R208–R214.
  161. Valentinuzzi, V.S.; Scarbrough, K.; Takahashi, J.S.; Turek, F.W. Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice. Am. J. Physiol 1997, 273, R1957–R1964.
  162. Weinert, D.; Waterhouse, J. Daily activity and body temperature rhythms do not change simultaneously with age in laboratory mice. Physiol. Behav 1999, 66, 605–612.
  163. Rakshit, K.; Krishnan, N.; Guzik, E.M.; Pyza, E.; Giebultowicz, J.M. Effects of aging on the molecular circadian oscillations in Drosophila. Chronobiol. Int 2012, 29, 5–14.
  164. Hurd, M.W.; Ralph, M.R. The significance of circadian organization for longevity in the golden hamster. J. Biol. Rhythms 1998, 13, 430–436.
Ijms 14 03026f1 200
Figure 1. A schematic representation of the role of clocks in cellular tasks resulting from predictive/reactive synchrony or desynchrony impacting cellular homeostasis and consequently affecting healthy aging. Light-dark cycles as well as nutrition play an important role as zeitgebers (time-givers) resulting in synchronous functioning of the clock and clock controlled genes (CCGs) which regulate metabolism by coordinating anabolic and catabolic reactions, repair functions, combating/avoiding unfavorable stress situations as well as gating specific physiological, cellular and molecular events in a temporal fashion to achieve cellular metabolic homeostasis. Situations which impact the clock, such as shift-work, disturbance in the nutritional cues of even mutations in certain clock genes result in circadian desynchrony impairing the organisms ability to predict/react to changing demands of physiology which unbalances cellular homeostasis by metabolic dysregulation, reactive oxygen species (ROS) generation, affecting repair mechanisms leading to damage accumulation and apoptosis. This results in accelerated aging and propensity for age-related pathologies.

Click here to enlarge figure

Figure 1. A schematic representation of the role of clocks in cellular tasks resulting from predictive/reactive synchrony or desynchrony impacting cellular homeostasis and consequently affecting healthy aging. Light-dark cycles as well as nutrition play an important role as zeitgebers (time-givers) resulting in synchronous functioning of the clock and clock controlled genes (CCGs) which regulate metabolism by coordinating anabolic and catabolic reactions, repair functions, combating/avoiding unfavorable stress situations as well as gating specific physiological, cellular and molecular events in a temporal fashion to achieve cellular metabolic homeostasis. Situations which impact the clock, such as shift-work, disturbance in the nutritional cues of even mutations in certain clock genes result in circadian desynchrony impairing the organisms ability to predict/react to changing demands of physiology which unbalances cellular homeostasis by metabolic dysregulation, reactive oxygen species (ROS) generation, affecting repair mechanisms leading to damage accumulation and apoptosis. This results in accelerated aging and propensity for age-related pathologies.
Ijms 14 03026f1 1024
Ijms 14 03026f2 200
Figure 2. A representation of SIRT1- mediated regulation of the circadian clock and metabolism impacting aging. SIRT1 interacts with CLOCK, which heterodimerizes with BMAL1. BMAL1 is deacetylated by SIRT1 in a circadian manner and promotes expression of clock genes. Additionally, SIRT1 interacts with and deacetylates PER2 (in mammals) which heterodimerizes with CRY proteins to inhibit CLOCK-BMAL1 function and promotes its degradation. NAD+ from AMPK and NAMPT is a key regulator for SIRT1 function. Synchronous expression of clock genes results in regulation of clock controlled genes (CCGs) which impact metabolism and hence aging.

Click here to enlarge figure

Figure 2. A representation of SIRT1- mediated regulation of the circadian clock and metabolism impacting aging. SIRT1 interacts with CLOCK, which heterodimerizes with BMAL1. BMAL1 is deacetylated by SIRT1 in a circadian manner and promotes expression of clock genes. Additionally, SIRT1 interacts with and deacetylates PER2 (in mammals) which heterodimerizes with CRY proteins to inhibit CLOCK-BMAL1 function and promotes its degradation. NAD+ from AMPK and NAMPT is a key regulator for SIRT1 function. Synchronous expression of clock genes results in regulation of clock controlled genes (CCGs) which impact metabolism and hence aging.
Ijms 14 03026f2 1024
Ijms 14 03026f3 200
Figure 3. Regulation of PGC-1α—this schematic represents the relationship between nutrition, circadian clock and other regulatory factors involved in post-translational modification of PGC-1α and its consequent impact on metabolic genes and aging. Nutritional availability impacts the circadian clock - when energy is replete, TOR results in transcriptional regulation of PGC-1α through transcription factor YY1 (see text for details). The serine threonine kinase AKT (a key component of insulin signaling pathway) has an inhibitory effect (negative regulator) on PGC-1α. In energy deficient situations, AMPK has an inhibitory effect on TOR thus inducing PGC-1α and increased mitochondrial biogenesis. SIRT1 has a stimulatory deacetylation effect on PGC-1α under conditions of fasting and oxidative stress and helps accumulate it in the nucleus. Both TOR and AKT feed-back on the circadian clock and regulate it as a pacemaker. The nutrient sensitive kinase GSK3β targets PGC-1α for proteasomal mediated degradation and is a function of oxidative stress response. PGC-1α by its transcriptional activity plays an important role in the expression and activity of many metabolic genes which impact longevity.

Click here to enlarge figure

Figure 3. Regulation of PGC-1α—this schematic represents the relationship between nutrition, circadian clock and other regulatory factors involved in post-translational modification of PGC-1α and its consequent impact on metabolic genes and aging. Nutritional availability impacts the circadian clock - when energy is replete, TOR results in transcriptional regulation of PGC-1α through transcription factor YY1 (see text for details). The serine threonine kinase AKT (a key component of insulin signaling pathway) has an inhibitory effect (negative regulator) on PGC-1α. In energy deficient situations, AMPK has an inhibitory effect on TOR thus inducing PGC-1α and increased mitochondrial biogenesis. SIRT1 has a stimulatory deacetylation effect on PGC-1α under conditions of fasting and oxidative stress and helps accumulate it in the nucleus. Both TOR and AKT feed-back on the circadian clock and regulate it as a pacemaker. The nutrient sensitive kinase GSK3β targets PGC-1α for proteasomal mediated degradation and is a function of oxidative stress response. PGC-1α by its transcriptional activity plays an important role in the expression and activity of many metabolic genes which impact longevity.
Ijms 14 03026f3 1024
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert