Effect of feeding regimens on circadian rhythms: Implications for agingand longevity

II. The circadian clock

A. The location of the mammalian circadian clock. In mammals, the central circadian clock is located in the suprachiasmatic nuclei (SCN), a distinct bilateral group of cells located in the anterior hypothalamus in the brain. Similar clock oscillators have been found in many peripheral tissues, such as the liver, intestine, heart, adipose tissue, retina and in various regions of the brain [2,22-24]. The SCN clock is composed of multiple, intracellular circadian oscillators, which, when synchronized, generate coordinated circadian outputs that regulate overt rhythms [25-28]. SCN oscillation is not exactly 24 h and it is necessaryto entrain the circadian pacemaker each day to the external light-dark cycle to prevent drifting (or free-running) out of phase. Light perceived primarily by melanopsin-expressing retinal ganglion cells transmit signals to the SCN via the retinohypothalamic tract (RHT) [2,29,30]. As a result, vasoactive intestinal polypeptide (VIP), an intrinsic SCN factor, acutely activates and synchronizes SCN neurons [31,32]. Synchronization among SCN neurons leads to the sending of signals to peripheral oscillators to prevent the dampening of circadian rhythms in these tissues. The SCN accomplishes this task via neuronal connections or circulating humoral factors [33] although the mechanisms are not fully understood (Figure 1). Several humoral factors expressed cyclically by the SCN, such as transforming growth factor α (TGFα) [34], prokineticin 2 (PK2) [35], and cardiotrophin-like cytokine (CLC) [36], have been shown to affect peripheral clocks. Their intracerebroventricular injection inhibits nocturnal locomotor activity, an SCN output. Complete electrical destruction of SCN neurons abolishes overall circadian rhythmicity in SCN-controlled tissues, because of the loss of synchrony among individual cells in the periphery and damping of the rhythm at the population level [37]. However, at the cellular level each cell oscillates, but with a different phase [37,38]. The fraction of cyclically expressed transcripts in each peripheral tissue ranges between 5-20% of the total population and the vast majority of these genes are tissue-specific [24,39-47]. These findings emphasize the circadian control over a large portion of the transcriptomes in peripheral tissues. Considering the circadian gene expression in peripheral tissues, it is difficult to determine whether the SCN clock drives these rhythmic patterns directly or indirectly by driving rhythmic feeding, activity, and/or body temperature, which, in turn, contribute to rhythms in gene expression in the periphery. It has been shown that for a peripheral tissue, such as the liver, signals both from the SCN clock or the local endogenous clock may control rhythmic gene expression [48,49].

B. The biological clock at the molecular level. Genetic analysis of mutations affecting the clock in Neurospora, Drosophila, Cyanobacteria, Arabidopsis, and, recently, the mouse have paved the way for the identification of clock genes. In mammals, the clock is an intracellular mechanism sharing the same molecular components in SCN neurons and peripheral cells [3]. Generation of circadian rhythms is dependent on the concerted co-expression of specific clock genes. Transcriptional-translational feedback loops lie at the very heart of the core clock mechanism. Many clock gene products function as transcription factors, which possess PAS (PER, ARNT, SIM) and basic helix-loop-helix (bHLH) domains involved in protein-protein and protein-DNA interactions, respectively. These factors ultimately activate or repress their own expression and, thus, constitute self-sustained transcriptional feedback loops. Changes in concentration, subcellular localization, post-transcriptional microRNA regulation, posttranslational modifications (phosphorylation, acetylation, deacetylation, SUMOylation), and delays between transcription and translation are crucial in order to achieve a 24-h cycle [1,2,50-52].

Figure 1. Resetting signals of the central and peripheral clocks. The SCN resets peripheral oscillators via humoral factors or autonomic innervation leading to circadian hormone expression and secretion and rhythmic activity of metabolic pathways. In addition, the SCN dictates rhythms of locomotor activity, sleep-wake cycle, blood pressure, and body temperature. Light, food, and feeding regimens affect either the central clock in the SCN or peripheral clocks. Input to central or peripheral clocks are in blue. Outputs from the central clock to the periphery are in green.

In the mouse, the first clock gene identified, encodes the transcription factor CLOCK (Circadian Locomotor Output Cycles Kaput) [53], which dimerizes with BMAL1 (brain and muscle ARNT-like protein 1) to activate transcription. CLOCK and BMAL1, two bHLH-PAS transcription factors, are capable of activating transcription upon binding to E-box (5'- CACGTG -3') and E-box-like promoter sequences [2]. BMAL1 can also dimerize with other CLOCK homologs, such as neuronal PAS domain protein 2 (NPAS2), to activate transcription and sustain rhythmicity [54,55]. Amongst the regulatory targets of CLOCK:BMAL1 are the three Period genes (Per1, Per2, and Per3), which encode PAS domain factors, and two Cryptochrome genes (Cry1 and Cry2). PERs and CRYs function as negative regulators, blocking CLOCK:BMAL1-mediated transcriptional activation [2,56] (Figure 2A).Thus, CLOCK:BMAL1 heterodimers bind to E-box sequences and mediate transcription of a large number of genes including those of the negative feedback loop Pers and Crys. When PERs and CRYs are produced in the cytoplasm, they oligomerize after reaching an appropriate concentrationand translocate to the nucleus to inhibit CLOCK:BMAL1-mediated transcription. All the aforementioned clock genes exhibit a 24-h oscillation in SCN cells and peripheral tissues, except for Clock that has been shown not to oscillate in the SCN [50]. Recent studies have demonstrated that CLOCK has intrinsic histone acetyltransferase activity, suggesting that rhythmic activation of chromatin remodeling may underlie the clock transcriptional network [57,58]. Indeed, cyclic histone acetylation and methylation have been observed on the promoters of several clock genes [58-63]. In addition, CLOCK also acetylates several proteins of the core clock apparatus, thus, enabling cycles of acetylation and deacetylation, the latter activity involving SIRT1 will be discussed below (Figure 2).

Figure 2. The core mechanism of the mammalian circadian clock and its link to energy metabolism. (A) High NAD(P)H levels promote CLOCK:BMAL1 binding to E-box sequences leading to the acetylation of BMAL1 and expression of Pers, Crys, and other clock-controlled genes. The negative feedback loop, PERs:CRYs, binds to CLOCK:BMAL1 and consequently PERs are acetylated. Activated AMPK leads to a rise in NAD+ levels, phosphorylation of CRYs, and phosphorylation of CKI?, which then phosphorylates the PERs. As a result of increased NAD+ levels, SIRT1 deacetylates PERs and BMAL1. This and the destabilization of phosphorylated PERs and CRYs relieves PERs:CRYs repression and another cycle starts. (B) Expression of Bmal1 and Rev-erbα genes are controlled by PPARα and binding of RORs to RORE sequences. RORs need a co-activator, PGC-1α, which is phosphorylated by activated AMPK. In parallel, AMPK activation leads to an increase in NAD+ levels, which, in turn activate SIRT1. SIRT1 activation leads to PGC-1α deacetylation and activation. Acetyl adenosine diphosphate ribose (Ac-ADP-r) and nicotinamide (NAM) are released after deacetylation by SIRT1.

Several other players appear to be important to sustain clock function. Casein kinase I epsilon (CKIε) phosphorylates the PER proteins and, thereby, enhances their instability and degradation [50,64-66]. CKIε also phosphorylates and partially activates the transcription factor BMAL1 [67]. Bmal1 expression is nega�tively regulated by the transcription factor reverse erythroblastosis virus α (REV-ERBα) [68], which recruits histone deacetylase (HDAC) complexes [69]. Bmal1 expression is positively regulated by retinoic acid receptor-related orphan receptor α (RORα) and RORγ [70]via the ROR response element (RORE) [71]. Thus, Bmal1 oscillation is driven by a rhythmic change in RORE occupancy by RORs and REV-ERBα. This alternating occupancy occurs due to the robust rhythmic levels of REV-ERBα, a result of direct transcriptional activation of the Rev-erbα gene by the heterodimer CLOCK:BMAL1 [68]. Indeed, mice deficient in RORα or REV-ERBα have impaired circadian rhythms of locomotor activity and clock gene expression [68,70] (Figure 2B).

B. Calorie restriction (CR)

CR, sometimes denoted dietary restriction (DR), refers to a dietary regimen low in calories without malnutrition, that restricts the daily amount of calories derived from carbohydrates, fats, or proteins usually to 60-75% of ad libitum-fed animals. CR extends the life span of diverse species, such as C. elegans, Drososphila, rodents [125,173,174], and recently monkeys [175]. CR in mice, rats, and monkeys prevents or delays the onset of major age-related diseases, such as cancer, diabetes, kidney disease, and cataracts [173,176]. In humans, long-termed CR results in sustained beneficial effects on major risk factors for atherosclerosis, type 2 diabetes, and inflammation [177]. The reduction of energy intake is considered to be the critical beneficial factor in the CR regimen [173]. Theories on how CR modulates aging and longevity abound, but the exact mechanism is still unclear [178]. For a longtime, the most prevalent explanation was related to the widely acceptable theory on aging, the Free Radical Theory. This theory attributes the aging process to the continuousaccumulation of oxidative damage in macromolecules generated by reactive oxygen species (ROS) produced in the mitochondria [179]. A later variation of this theory, the Oxidative Stress Theory, attributes the oxidative damage to the imbalance between preoxidant and antioxidant components, and CR was suggested to increase the resistance to oxidative stress [180]. Recently, this explanation was put into question, at least for rodents, as increasing oxidative stress by several genetic alterations increased aging-related diseases, such as cancer, but did not diminish life span [181-183]. ROS, primarily H₂O₂, have recently been suggested to promote aging as activators of the TOR (target of rapamycin) pathway [184]. This signaling pathway acts as a sensor of the nutritional and energetic state in the cell and transmits anabolic signals to regulate cell size, growth, and metabolism. Mammalian TOR (mTOR) could play an important role in the regulation of life span, as indicated by findings showing that CR attenuated mTOR signaling in several tissues in mice [185], and mice deficient of ribosomal protein S61 kinase 1, a central component in mTOR signaling, or mice treated with rapamycin, an inhibitor of the mTORC1 component, exhibited increased life span [186,187]. Interestingly, mTOR has also been recently linked to the circadian clock as a light-activated signaling cascade in the SCN of mice [188].

Figure 3. Effect of night vs. day RF and night vs. day IF on clock gene expression. Expression of a representative clock gene mCry1 was measured in the liver of C57BL mice during ad libitum (AL), day and night RF, and day and night IF.Total RNA extracted from liver tissue collected every 3 h around the circadian cycle (mean ± SEM; n=3 for each time-point and each mouse group) was reverse transcribed and analyzed by quantitative real time PCR. Clock gene levels were normalized using Gapdh as the reference gene. The grey and black bars designate the subjective light and dark cycles, respectively.

CR-fed animals resemble RF-treated animals, as they usually consume all or most of their food within a short period of time. While anticipating for food, calorically restricted animals show a rise in body temperature [189]. Thus, due to the temporal component of food intake, it is possible that CR, similarly to RF, synchronizes peripheral clocks and influences clock-controlled output systems, such as the anticipatory behavior and body temperature. As opposed to RF, CR entrains the clock in the SCN [190-192]. Under light-dark conditions and daytime feeding, calorically restricted mice showed strong FAA but with a phase advance of the nocturnal pattern of activity, a direct output of the SCN clock. When mice were transferred to dark-dark conditions, i.e. under free-running conditions, and fed ad libitum, the onset of the nocturnal period of locomotor activity occurred significantly earlier (1.3 h) in the calorically restricted than in ad libitum-fed animals, indicating an SCN effect. The period, however, did not differ between calorically restricted and ad libitum-fed mice [190]. Also, when SCN clock gene expression was tested, slight changes in gene expression were observed [191,192]. Overall, these results suggest that CR during the daytime affects the temporal organization of the SCN clockwork and circadian outputs in mice under light-dark cycle. In addition, CR affects photic responses of the circadian system, as measured by light pulses, suggesting that energy metabolism modulates gating of photic inputs in mammals [192]. It is noteworthy that microarray data comparing gene expression in seven different tissues under CR identified circadian rhythms among the three most over-expressed biological processes, with Per2 being the most up-regulated gene [193]. Collectively, these findings suggest that synchronization of peripheral oscillators during CR could be achieved directly due to the temporal feeding, as has been reported for RF [143,152,153], or by synchronizing the SCN [190-192], which, in turn, sends humoral or neuronal signals to entrain the peripheral tissues [194,195]. It is not known whether there is dominancy or harmony between the central pacemaker and peripheral oscillators under CR.

B. αMUPA mice, circadian rhythms, and aging

Recent data show that αMUPA mice exhibit higher amplitude in the circadian expression of several clock genes in the liver compared with FVB/N WT mice. This change coincides with higher amplitude rhythms of food intake and body temperature [194]. Since circadian patterns of food intake and body temperature constituteclock-controlled output systems, it is conceivable that their alteration in the transgenic mice stems from the higher amplitude of clock gene expression in the periphery, and possibly also in the central biological clock in the SCN. Higher amplitude of circadian rhythms have been previously associated with young age [15] and extended life span [19]. Support for a linkage between circadian rhythms and attenuation of aging in αMUPA mice is provided by comparing young vs. old mice. When tested for circadian food intake, an SCN output system, 18-month-old WT control mice exhibit a 4-6-h shift in circadian food intake compared to 5-month-old mice [195]. This behaviour is consistent with literature data showing that aging can alter the amplitude and/or phase of circadian rhythms [15,16,18]. In contrast to WT mice, adult and young αMUPA mice show similar circadian food intake, indicating that at least some aspects of circadian behavior maintain a youthful pattern at an old age in these mice. At an old age, αMUPA mice maintain a young and healthier appearance, they look lean, and their fur is shiny, whereas WT mice are sluggish and they look old (Figure 4). In addition, αMUPA mice do not become obese throughout their life-time, whereas about one third of the WT mice show severe obesity (Figure 4). The major difference in body weight between αMUPA and WT mice stems from the fact that the quantitative difference in food intake between αMUPA and WT mice is maintained at the old age.

Figure 4. 18-month-old αMUPA and FVB/N WT mice. αMUPA mice maintain a youthful and healthy appearance, whereas WT mice look old.

C. αMUPA mice reveal effectsof feeding regimens on circadian rhythms

It is difficult to eliminate the effect of temporal food consumption in calorically restricted animals, as mice consume their food within a few hours. αMUPA mice spontaneously consume reduced calories (20-30% reduction) compared with WT mice under different feeding regimens, i.e. AL, RF and IF, suggesting that these mice can be utilized as a model for CR in the absence of the imposed temporal food consumption under ad libitum feeding, and a model for imposed temporal CR under RF or IF conditions. Therefore, the transgenic mouse model αMUPA [225] has recently been used to investigate the contribution of calorie reduction per se vs. timed feeding to clock adaptation [49]. Under light-dark conditions and ad libitum feeding, αMUPA mice show high amplitude, appropriately reset circadian rhythms in peripheral clock genes [194] (Figure 5). This finding could reflect the effect of the reduced calorie intake on the SCN in αMUPA mice, as has been previously reported for calorically restricted animals [190-192].

Figure 5. Clock gene expression in the liver under various feeding and lighting conditions in αMUPA (M) and WT mice. Expression levels of the following clock genes are presented under light-dark or disruptive light conditions:mPer2during ad libitum (AL) feeding, mCry1 under RF, and Bmal1 under IF.Total RNA extracted from liver tissue collected every 3 h around the circadian cycle (mean ± SEM; n=3 for each time-point and each mouse group) was reverse transcribed and analyzed by quantitative real time PCR. Clock gene levels were normalized using Gapdh as the reference gene.

Under light-dark conditions, RF advanced the expression phase of all clock genes in the liver in a similar manner in both WT mice and αMUPA mice, and in some cases increased the amplitude [49](Figure 5). These findings were in concert with previous results in the literature, as is mentioned above. Nevertheless, an effect of the SCN on clock-controlled output systems under RF could be seen when the phases of peripheral clock gene expression in WT mice vs. αMUPA mice were compared under arrhythmicity imposed by disruptive light. Whereas the pattern of clock gene expression did not change in WT mice, a phase shift was seen in several genes in αMUPA mice (Figure 5), suggesting an SCN effect. Again, this effect of the SCN could be attributed to the reduced calorie intake of αMUPA mice. Altogether, these findings suggest that both the reduced calories and the light-dark cycle work in synchrony on the central biological clock of αMUPA mice to generate rhythms in the periphery. However, it seems that in WT mice, as has been found for other mouse strains, RF is dominant over the SCN in dictating rhythms in the periphery regardless of the lighting conditions. In αMUPA mice, RF dictates the phase of clock gene expression under light-dark; but under disruptive light conditions, as the SCN is under the influence of calorie restriction, it becomes dominant in dictating the phase of clock gene expression.

Unlike RF, the effect of IF on circadian rhythms in αMUPA mice was similar to that of WT mice under light-dark or disruptive light conditions, and it resembled also that on C57BL mice (Figure 3, Figure 5). Thus, in all mice tested, daytime IF caused arrhythmia in clock gene expression in the liver under light-dark, whereas rhythmicity was restored under disruptive light [198] (Figure 3). These observations suggest that IF, similarly to CR, may affect the SCN clock. This effect could possibly be mediated through a metabolic state generated by the day of fast during IF regardless of the calories consumed, as discussed earlier.

Altogether, the findings in αMUPA mice suggest that reduced calories affect the SCN so it becomes dominant over RF in the periphery only under disruptive light conditions. In addition, IF affects peripheral rhythms depending on the timing of food availability and light conditions, but regardless of the total daily calorie consumption, suggesting that this regimen induces a metabolic state that affects the SCN.

E. Differences between αMUPA mice and calorically restricted rodents

Although αMUPA mice exhibit reduced calorie intake and body fat, they show remarkable differences in energy metabolism compared with CR-treated animals. In particular, calorically restricted animals exhibit high levels of ghrelin [238,239], but low levels of leptin [240,241]and insulin [173], indicating an overall state of hunger. It is noteworthy that leptin-deficient animals are long-lived under CR feeding regimen, suggesting that leptin is not necessary for the CR-mediated benefits [242,243]. In addition, CR-treated mice exhibit high expression levels of PGC-1α and no change in PPARγ levels in the liver [244,245]. All these findings are in sharp contrast with those found in αMUPA mice that have low levels of ghrelin and high levels of leptin and insulin, suggesting that αMUPA mice eat less because their metabolism is of satiated rather than hungry animals (unpublished data). Nevertheless, one aspect found to be common to both αMUPA mice and calorically restricted animals are the low SIRT1 expression levels in the liver [246] and high levels in the brain [247]. It is noteworthy that the information regarding SIRT1 levels in the hypothalamus of calorically restricted animals is still lacking, and data for peripheral tissues is sometimes contradictory [124,246]. Results obtained with SIRT1-null micehave recently suggested that this enzyme could be required for the in vivo response to CR [248], and transgenic mice over-expressing SIRT1 show a phenotype resembling calorically restricted animals [249]. We assume that, in calorically restricted mice, SIRT1 activity could be elevated in the brain, possibly in the hypothalamus and SCN, through AMPK activation, as AMPK can be activated in the hypothalamus under starvation conditions and high ghrelin [112,121]. In αMUPA mice, that show low AMPK levels in the hypothalamus, the high leptin levels could lead to SIRT1 elevation, as leptin is required for the increase in SIRT1 protein levels in the hypothalamus under starvation [250]. Thus, although stimulated through different pathways in αMUPA and calorically restricted mice, SIRT1 could act as a common factor modulating the SCN clock and, as a result, longevity.

αMUPA mice share also some similarities with those of Lou/C rats, both obesity-resistant long-lived rodents.

Figure 6. A schematic model describing the effect of feeding regimens on longevity through peripheral and SCN clock resetting. CR and IF reset circadian rhythms in the periphery and the SCN. The synchronized, robust circadian rhythms could be the mediator though which these feeding regimens lead to aging attenuation and life span extension. RF resets circadian rhythms only in the periphery, but its effect on life span is not known.

However, there are some fundamental differences in Lou/C rats compared with αMUPA mice, such as increased levels of PGC-1α and SIRT1 in the liver, increased levels of ghrelin, and reduced levels of leptin and insulin in the serum, although with some improved sensitivity for the latter two hormones [251,252].Overall, it seems that αMUPA mice are metabolically different from Lou/C rats.

Conflicts of Interest

The authors of this manuscript have no conflict of interest to declare.

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