the 24-hour rhythms in behavior , physiology and metabolism are known as the circadian rhythms .
it is believed that circadian clocks evolved as an adaptation to periodic light / dark changes caused by the earth s rotation to provide organism s synchronization with the environment and coordination of multiple metabolic processes within the organism .
circadian clocks have been found in different organisms from unicellular to mammals including humans . in mammals , almost all physiological systems such as cardiovascular , nervous
, digestive and urinary systems demonstrate some sort of circadian control and rhythms [ 3 , 4 ] .
the importance of circadian clocks and rhythms for human health has been demonstrated in multiple studies : circadian disruption significantly disturbs homeostasis for many physiological processes and might lead to the development of pathological states .
for example , epidemiological data on shift workers show that the risk of metabolic , cardiovascular diseases and cancer is significantly increased in shift workers in comparison with the general population [ 2 , 5 , 6 ] .
animal models also support the importance of the clock : mice with targeted disruption of clock genes , in addition to the disrupted rhythms in behavior and physiology , demonstrate a predisposition to the development of a variety of pathologies . over the last decade a significant body of evidence accumulated on the interconnections between circadian clocks and aging .
aging causes deterioration of multiple physiological systems and is considered as a single high - risk factor for the development of diseases such as cancer , diabetes , neurodegeneration , osteoporosis and sarcopenia ; interestingly , circadian clock disruption is considered to contribute to the development of these pathologies [ 2 , 1012 ] .
multiple signaling pathways and physiological systems have been proposed as regulators of aging process , but mechanisms of aging are still not quite known .
indeed , data from animal models suggest that circadian disruption through genetic ablation of several circadian clock components results in reduced lifespan and numerous pathological changes . on the other hand ,
studies on alpha mupa transgenic mice revealed that they live longer compared to wild - type mice and show high amplitude circadian rhythms in clock gene expression in the liver and clock - controlled output systems .
synchronization of physiological processes with the environment is also important : indeed , experimental jet lag or exposure of animals to artificially short or long light / dark cycles causes reduction in lifespan [ 8 , 13 ] .
the period of the internal clock rhythms might also be important ; for example , mice with the internal circadian period close to 24 hours live longer than mice whose internal circadian periods are significantly different from 24 hours .
circadian clocks control the oxidative stress , cell cycle , cell death and dna damage response ; all of these systems have been implicated in the control of aging and aging - associated pathologies [ 13 , 15 ] .
there are several excellent reviews on this subject ; therefore , here we will discuss only recently emerged data on how the interplay between dietary regimens , nutrient sensing / response pathways and circadian clocks may affect health and lifespan in different model organisms .
the circadian clocks are entrained by the light and generate daily rhythms in locomotor behavior ; these rhythms persist in constant darkness ( without light cues ) for several months .
the central , or master circadian oscillator is located in the suprachiasmatic nucleus ( scn ) of the anterior hypothalamus .
the scn clock is entrained by the light / dark cycle ( light - entrainable pacemaker ) and is synchronized with the environmental light / dark cycle ( entrainment ) through signals from the retina .
scn ablation results in the disruption of circadian rhythms in locomotion . other organs and tissues
circadian clocks operate literally in every cell , and circadian rhythms can be detected at the level of an individual cell as rhythms in gene expression .
the peripheral clocks generate rhythms in gene expression and different physiological outputs such as body temperature , blood pressure , hormone secretion and metabolic activities [ 2 , 3 , 17 ] .
peripheral clocks are regulated by the scn master clock , but many other cues , including feeding , also affect the clocks and might uncouple the central and peripheral clocks . the circadian clock integrity depends on activities of several genes , the so - called core circadian clock genes , which are expressed in the scn and other peripheral tissues .
these genes and their products form interconnected transcription - translation feedback loops [ 18 , 19 ] ( see fig .  1 ) .
two proteins containing basic helix - loop - helix ( bhlh ) pas ( period , arnt , sim ) domains , brain , and muscle arnt like 1 ( bmal1 ) and circadian locomotor output cycles kaput ( clock ) are the positive regulators of transcription . in some tissues such as forebrain and cardiovascular system the closest homologue of clock npas2 substitutes for clock .
the bmal1:clock or bmal1:npas2 complexes bind to the circadian e - box elements located in the promoter region of various genes and activate expression of circadian clock genes such as the three periods ( per1 , per2 and per3 ) , two cryptochromes ( cry1 and cry2 ) , the nuclear receptors rev - erb and rev - erb , and the retinoid - related orphan receptors ( rors ) .
negative elements of the loop , the per and cry proteins , form complex in the cytoplasm after translation , translocate to the nucleus and act as the negative regulators of the bmal1:clock complex , thus inhibiting their own expression and completing the negative feedback loop .
revs and rors compete for binding to the ror elements in the promoter of bmal1 , with rors being a positive regulator of bmal1 transcription and revs being a negative regulator , and form a second positive - negative feedback loop .
circadian clock proteins undergo multiple posttranslational modifications such as phosphorylation , sumoylation , and acetylation , which provides an additional level of regulation for the core circadian clock gene expression .
the circadian clock controls cellular processes and metabolism through the regulation of the clock - controlled genes ( ccgs ) .
the circadian regulation of ccgs expression occurs via bmal1:clock and revs - dependent mechanisms or through the rhythmic activity of clock - controlled transcriptional factors . in every tested tissue about
the basic - hlh - pas domain containing transcriptional factors bmal1 and clock ( npas2 ) regulate transcription of genes with the circadian e - box elements in the promoter , and represent the positive arm of the transcriptional - translational feedback loop .
cry represent the negative arm of the loop ; they form complexes and inhibit the activity of the bmal1:clock complex and hence their own expression .
rev - erbs and rors represent an additional loop , these transcriptional factors negatively ( rev - erbs ) and positively ( rors ) regulate the expression of bmal1 .
finally , the bmal1:clock complex regulates the expression of circadian clock controlled genes ( ccgs ) , which provide circadian output in physiology .
in addition to the above - described circadian clocks ( the light - entrainable pacemaker in the scn and peripheral circadian clocks ) , the existence of other types of circadian clocks have been proposed .
food - entrainable oscillator ( feo ) produces food anticipatory activity ( faa ) 2 - 3 hours before the scheduled feeding time .
the existence of the food - entrainable peripheral oscillators ( fepos ) , which are situated in the peripheral organs was also suggested , fepos entrain peripheral circadian clocks upon scheduled feeding . despite many studies , anatomical location and the mechanisms of feo and fepo
the result suggested that the scn is not the site , as these rats still possessed the food anticipatory activity .
many other areas of the brain were studied to identify feo , but the location of feo remains unidentified .
( detailed review on studies for the quest of feo ) light- and food - entrainable clocks may interact with each other ; for example , feo may use the scn - based clock as a reference clock , and the light - entrainable pacemaker may control the period of the food - entrainable pacemaker . studies also show that clock genes may play a role in the control of the faa rhythms .
one group reported that the down regulation of bmal1 expression in dorsomedial hypothalamus ( dmh ) affected the formation of faa ; however , several other groups reported normal faa . recently , it was reported that activity of the mechanistic target of rapamycin complex 1 ( mtorc1 )   demonstrates 24-hour rhythms in several tissues in mice .
these rhythms can be observed under both ad libitum and time - restricted feeding conditions , and they might be under the control of a clock - like mechanism .
indeed , when the rhythms were entrained by the feeding , they persisted in fasted animals for at least three cycles , suggesting some internal regulatory mechanism .
importantly , the rhythms of mtorc1 activity were preserved in mice with target disruption of cry genes , and these mice have disrupted circadian rhythms in the scn - controlled behavior ; thus , this clock is not identical with the light - entrainable circadian clock .
this hypothetical clock was named namo ( nutrient anticipation metabolic oscillator ) ; the molecular pathways responsible for namo operation are currently unidentified , and it is also not known if any interaction between namo and other circadian clocks exist .
diet affects many physiological systems including the circadian clocks . in nocturnal rodents , time - restricted feeding during the light phase of the day ( unlimited amount of the food provided during the normal rest period ) alters the phase of the circadian clock and clock - controlled genes expression in the peripheral tissues ,
whereas the gene expression in central clock ( scn ) is not affected and still under the control of the light / dark cycle [ 29 , 30 ] .
peripheral clocks adopt to the novel feeding regimens differently : the liver can adapt faster than kidney , lungs or heart . uncoupling
the peripheral and central circadian clocks also cause changes in blood glucose , triglyceride and free fatty acid levels , resembling the state of the metabolic syndrome [ 29 , 30 ] .
all these studies demonstrate that the peripheral clocks can be regulated by the feeding , and support the theory that circadian misalignment has a negative impact on health .
another common dietary paradigm , which models the western diet , is the high fat diet . in rodents ,
demonstrate that the high fat diet also affects the central and peripheral circadian clocks : the major effect was disruption of circadian rhythms in locomotor and feeding behaviors , and significant reduction of the rhythm amplitude of the circadian clock and clock - controlled gene expression in the liver .
the high fat diet causes increased blood glucose level , insulin resistance , and many other metabolic changes ; circadian clock disruption might be one of the contributing factors .
sherman et al . and hatori et al . applied time - restricted feeding to animals on the high fat diet [ 33 , 34 ] , in contrast to above cited studies where the time - restricted feeding was applied during the light / rest phase , here the time - restricted feeding was applied during the night / activity phase ( hatori et al . ) and during light phase ( sherman et  al . ) . in hatori
time - restricted feeding restored liver rhythms in circadian clock gene expressions and , importantly , normalized metabolism and reduced obesity - associated inflammation .
noteworthy , the effect of metabolic improvements was achieved without any reduction in food intake . at the same time , sherman et al .
a pilot study in humans supports the data generated in the experimental system ; as it was reported by panda and colleagues when overweight people restrict their feeding time to day time they show a reduction in body weight . how the time - restricted feeding improve metabolism is unknown , and whether the clock functions are important for metabolic benefits of the time - restricted feeding needs to be studied .
the long - term effects of time - restricted feeding applied during the day / rest period on health and longevity have not been studied , and whether time - restricted feeding applied during the night / activity period without limitation of food intake would have any beneficial effects for animals on the regular diet is not known and needs to be studied .
food is provided , in most cases , as a single meal ; the food is consumed during few hours ; therefore , calorie restriction was frequently used to study food anticipatory activity   and was also called time - restricted feeding in many studies .
calorie restriction is known to have multiple metabolic benefits and most importantly , significantly delays aging , reduces the risk of age - associated diseases and increases longevity in many organisms from yeast to mammals .
calorie restriction affects the expression of the circadian clock genes in flies and in mammals . in katewa
study calorie restriction was applied to drosophila ; the amplitudes of expression of several clock genes were significantly induced by calorie restriction in the head and total body of flies . in patel
study calorie restriction was applied in mice , food for the calorie - restricted group was provided during the dark phase of the day ; therefore , effects on the synchronization of central and peripheral clocks must be minimal .
indeed , as it was expected , no effect on the phase of tested clock gene expression in the liver was detected .
calorie restriction has a significant effect on the amplitude and daily average expression of bmal1 , per1 and per2 genes in the liver .
mendoza et al . studied the effect of calorie restriction on the expression of circadian clock genes in the scn and found that similar to patel et al .
study , calorie restriction significantly affected the expression of several clock genes in the scn .
thus , calorie restriction regulates circadian clock gene expression in different organisms and in different tissues and might affect both central and peripheral clocks .
patel et al . and katewa et al . also investigated if circadian clocks play any role in the calorie restriction effects on metabolism and longevity [ 38 , 39 ] .
both in drosophila and mice , disruption of the circadian clock through the knockout of the core clock genes ( per and tim in drosophila and bmal1 in mice ) significantly compromised the beneficial effects of calorie restriction including the effect on longevity . in flies ,
the circadian clocks are important for calorie restriction - mediated increase in fat turn over . in mammals ,
calorie restriction mediates reduction in blood igf-1 level and this effect was compromised in mice deficient for the circadian transcriptional factor bmal1 .
thus , these studies established that calorie restriction and circadian clock mechanisms are interlinked , and raised many important questions that need to be studied : how does calorie restriction affect the clock mechanisms ? how does the clock contribute to the beneficial metabolic effects of calorie restriction ?
do other lifespan - extending interventions such as treatment with rapamycin , or genetic models of extreme longevity such as ames dwarf mice , require the clock ? is it possible to extend the lifespan by targeting the clock ?
oscillation of gene daily expression is regulated by interplay between the circadian clocks and feeding cycles at both transcriptional and translational levels .
the feeding / fasting cycle causes multiple changes : concentrations of nutrients and microelements in blood and tissues are changed , different hormones are released ; below we will discuss the effect of hormones and nutrients on the central and peripheral circadian clocks .
feeding results in the release of insulin into the bloodstream ; insulin affects many organs and tissues : the liver , skeletal muscles , adipose tissue , and brain are major targets .
insulin was proposed as a candidate mediator that resets peripheral clocks in response to feeding cues .
insulin induces a rapid response in cultured rat hepatocytes , affecting the expression of per1 , per2 , and dec1 genes .
the mapk and pi3k inhibitors are found to block the induction of clock genes , suggesting that mapk and pi3k are involved in resetting clocks downstream of insulin signaling .
cell culture studies are in agreement with in vivo studies : an injection of insulin elicits a rapid change in per2 and rev - erb expression and shifts the phase of liver clocks .
clock gene expression is rapidly induced by insulin injection in other insulin - sensitive tissues , such as the muscle and adipose tissues , but not in insulin - insensitive tissues , such as the lungs .
thus , the effect of insulin on the peripheral clocks is tissue - specific ; it is still unknown if insulin can regulate central clock in the brain .
glucose is a well - documented circadian clock regulator . in fibroblasts exposed to high glucose concentration the expression of per1 and per2 genes
is down regulated . in cell culture experiments , the phase and period of the circadian rhythms in expression of clock genes such as per2 depends on glucose concentration in the media . in vivo glucose
glucose infusion during the daytime strongly induces expression of per2 in the scn and suppresses per2 expression in the liver ; thus , the effects of glucose are also tissue - specific .
insulin and glucose mutually regulate levels of each other , and some of the in vivo effects of glucose might be the effects of insulin and vice versa ; however , cell culture data strongly argue that glucose and insulin have independent effects on the clocks .
glucose availability indirectly regulates adenosine monophosphate - dependent protein kinase ( ampk ) , which phosphorylates and controls stability of the cry proteins .
transforming growth factor b - inducible early gene ( tieg1 ) and vitamin d3 upregulated protein ( vdup1 ) are glucose responsive immediate early genes and upregulation of tieg1 and vdup1 contributes to glucose - dependent clock gene expression .
glucose may also regulate cellular clocks through hexosamine / o - glcnac pathway ; o - glcnacylation of bmal1 and clock inhibits their ubiquitination and degradation regulating the amplitude and phase of clock oscillation .
several nuclear receptors are potential regulators of the circadian clock by lipids ( reviewed in ) .
the nuclear receptors are transcription factors regulated by hydrophobic molecules such as steroids , vitamins , and fatty acids .
many nuclear receptor genes are expressed in the liver in a circadian manner including three ppar and two rev - erb isoforms and two ror isoforms .
rev - erbs and rors are components of the circadian molecular oscillator and ppars can modulate the expression of clock genes , therefore , dietary lipids and their metabolic derivatives can signal to the clock through regulation of the nuclear receptor transcriptional activity . as it was discussed above , the high fat diet disrupts the circadian rhythms in behavior and gene expression , therefore affecting both central and peripheral clocks . how the high fat diet signals to the clocks is unknown ;
releasing some gastrointestinal tract - derived peptides or bile in response to fat and/or deregulation of ppar alpha signaling in the liver and other tissues can be one of the mechanisms .
the regulation of the clock by amino acids have not been demonstrated in direct experiments ; however , it is possible that the total amino acid level or some specific amino acids affect the clock .
s6 kinase is a downstream target of mtorc1 , and mtorc1 activity is regulated by growth factors , including insulin , and by amino acid availability ; therefore , the above - discussed rhythms in mtorc1 activity could be a consequence of rhythms in amino acid concentration .
thus , hypothetically , rhythms in amino acids concentration may cause rhythms in mtorc1 activity followed by rhythms in s6 kinase , and through bmal1 phosphorylation may also contribute to clock resetting .
importantly , a combination of the nutrients might influence the clocks in different ways than treatment with individual nutrients .
the rapid phase - shift in the liver clocks is induced by a combination of carbohydrate and protein , whereas the application of only proteins , sugar , or oil is insufficient .
the liver clocks can be reset by injection of glucose combined with amino acids , but not by either of the nutrients alone .
circadian clock gene expression responds to feeding rapidly ; indeed , the expressions of per2 and dec1 genes have been induced in the liver of fasted rat just thirty minutes after re - feeding . similarly , in mice
re - feeding affects the per1 , per2 , dec1 and rev - erb expression in the liver within one hour .
these findings indicate that nutrients containing glucose and amino acids induce rapid changes in the expression of clock genes , especially per2 and rev - erb , resulting in a phase - shift .
interestingly , the dose of caffeine required to affect circadian rhythms is only 0.05% , which is equivalent to the dose contained in a coffee drink . it is observed that coffee prolongs circadian activity rhythms in mice under constant darkness .
resveratrol , a polyphenol found in red wine and dietary polyamines , also affect clock gene expression .
studies revealed that consumption of a diet containing 4% nacl for more than two weeks induces phase - advances of clock and clock - controlled genes in peripheral tissues , whereas locomotor activity rhythms , including feeding and drinking behaviors are not affected .
gastrointestinal tract - derived hormones and bile acids can also be involved in clock resetting ( reviewed by ) .
placed ppar alpha , rev - erb alpha , and creb as central players for the shift of peripheral clocks upon time restricted feeding .
fasting induced by rf causes reduction in insulin level , release of glucagon and increased blood concentration of free fatty acids .
free fatty acids affect ppar alpha , and reduced insulin causes gsk3 beta activation , which in turn cause changes in the expression and activity of rev - erb alpha .
rev - erb alpha affects the expression of bmal1 and , in turn , the shifted bmal1 expression results in shifted peripheral circadian clocks .
creb - dependent regulation of adrenal corticosterone production affects the shift of peripheral clocks in the muscles and heart .
regulation of the circadian clocks and rhythms by diet and nutrients is summarized in fig . 
feeding causes changes in blood and tissue concentrations of hormones such as insulin and various nutrients such as glucose , lipids and amino acids .
hormones and nutrients activate different signaling pathways and change gene expression through indicated signaling pathways and transcriptional factors , which in turn affects the circadian clocks in the brain and peripheral tissues .
calorie restriction leads to several metabolic changes in animals : reduced circulating glucose and insulin levels , increased insulin sensitivity , increased fat turn over , reduced igf-1 level , decreased activity of mtorc1 signaling pathway , increased activity of sirtuins and increased resistance to various stresses [ 6063 ] .
below we will discuss how the circadian clocks might contribute to all these changes ( illustrated in fig . 
circadian clocks regulate expression and activity of the rate - limiting enzymes in multiple signaling pathways . through these regulations
calorie restriction recruits the circadian clocks , this recruitment leads to optimization of metabolic processes and increases the organism s fitness , which contributes to calorie restriction - mediated longevity benefits .
the role of the circadian clocks in glucose homeostasis is well documented and have been extensively reviewed ; therefore , we only briefly describe it here .
both central and peripheral clocks are involved in the control of glucose homeostasis , and disruption of synchronization between them has a negative effect on glucose metabolism .
blood glucose homeostasis is regulated through external glucose supply ( from the digested food ) , tissue glucose uptake and utilization and gluconeogenesis .
insulin is the main regulator of glucose uptake and utilization in insulin - responsive tissues .
insulin production and secretion is regulated by the pancreatic clock ; disruption of the clock through clock or bmal1 knock out compromises the functions of pancreatic islets , which leads to reduced insulin secretion and increased blood glucose level . at the same time , knock out of crys or pers leads to increased insulin level [ 66 , 67 ] .
insulin sensitivity is also under the control of the circadian clocks , however , the effect of clock disruption on the insulin sensitivity is complicated .
while it was proposed that circadian disruption contributes to a reduced insulin sensitivity upon the high fat diet , many circadian clock mutants demonstrate increased insulin sensitivity [ 58 , 68 ] .
thus , the effect of the clock on insulin and insulin signaling pathways might be tissue- , time- and gene - dependent , which warrant further study .
1 ) cry 1 and cry 2 proteins decrease gluconeogenesis by regulating glucagon signaling and creb phosphorylation , and also through regulation of the phosphoenolpyruvate carboxykinase 1 transcription in a glucocorticoid - dependent manner .
another element of the negative loop per2 also decreases gluconeogenesis and promotes glycogen storage by decreasing the activity of glycogen phosphorylase .
the clock transcriptional factor rev - erb alpha downregulates the expression of many genes important for hepatic gluconeogenesis . on the other side ,
therefore , similarly to the role of the clocks in the insulin signaling , the effect of the clock on gluconeogenesis is tissue- and clock gene - dependent ; some mutants have increased and others decreased gluconeogenesis .
the circadian clocks play an important role in regulation of adipose tissue functions and fat turn over .
circadian clock - regulated lipid metabolism pathways in mammals have been revealed by the large - scale profiling , the regulatory circuits involved in fatty acid metabolism have been identified in the adipose tissue , liver , and muscle [ 72 , 73 ] .
circadian clock disruption results in abnormal fat storage , lipid transport , triglyceride levels , and a decrease in absorption of dietary lipids .
mechanistically , the core components of the molecular clock , rev - erbs and peroxisome proliferator - activated receptors ( ppars ) , provide a basis for circadian regulation of lipid metabolism via cyclic transcriptional repression of multiple genes , including the mrna expression for several rate - limiting lipolytic enzymes [ 72 , 73 ] .
circadian regulation of adipocyte differentiation occurs through bmal1 controlled mechanisms and is wnt signaling - dependent [ 74 , 75 ] .
clock - controlled deadenylase nocturnin is central for the circadian dietary fat uptake . in agreement with that ,
clock mutant mice show altered absorption and transport of diurnal transcription of genes in the small intestine . finally , adipose tissue - derived hormones including the appetite - suppressant leptin show circadian rhythms .
thus , multiple studies establish a key role of the molecular circadian clock in regulating lipid homeostasis , this regulation is complicated and how it might contribute to the increased fat turn over upon cr needs to be studied .
nad+ production in cells are regulated by several pathways : the rate limiting enzyme in nad+ production through salvage pathways is nampt , whose expression is under the control of the bmal1/clock transcriptional complex ; the rhythmic nampt expression contributes to the daily oscillation of nad+ concentration [ 78 , 79 ] . in turn ,
sirt1 deacetylates per and bmal1 proteins , providing feedback regulation to the clock [ 80 , 81 ] .
whether the circadian clock contributes to known induction of nad+ level upon cr needs to be studied .
several groups have recently reported circadian regulation of the mtor signaling pathway [ 28 , 82 , 83 ] . rhythms in mtorc1 activity were observed in the scn and in metabolic tissues such as the liver .
these rhythms may contribute to the rhythms in protein biosynthesis , temperature regulation or organism response to infection .
bmal1 was reported as a negative regulator of mtorc1 activity ; therefore , one might expect that increased bmal1 activity may contribute to the reduction of mtorc1 activity upon calorie restriction , however , it was never formally studied . finally , calorie restriction increases cell resistance to various stress including oxidative stress .
circadian clock has been established as an important regulator of ros homeostasis [ 85 , 86 ] .
concentrations of ros and many products of oxidation display circadian rhythms in blood and tissues in vivo .
circadian clock mutants have increased level of ros and oxidative damage , supporting the importance of clock mechanisms in the oxidative stress response [ 85 , 86 ] .
circadian clock - controlled hormone melatonin is a well - known antioxidant ; the master regulator of oxidative stress response transcriptional factor nrf2 is under the direct circadian clock transcriptional control through bmal1 .
calorie restriction requires a significant level of optimization ; indeed , an organism has to adapt to reduced level of resources . in order to maintain homeostasis
, tissues also need to synchronize their metabolic activity and produce enzymes necessary for metabolic reaction in a timely manner .
as it was discussed above , the clocks control the expression and activity of many rate - limited enzymes ; therefore , the clocks guarantee that metabolic reaction will go with an appropriate rate at the appropriate time .
the circadian clocks enable anticipation of daily events and also confer the considerable advantage by the efficient use ofenergy .
aging of the world population opens novel challenges for the modern biomedical science : how to improve the quality of life for aged populations , how to reduce the rate of age - associated diseases and ultimately increase longevity .
dietary paradigms have been known as modulators of aging for a long period of time .
there is evidence that some of the dietary paradigms such as calorie restriction extend longevity in many organisms .
multiple signaling pathways are proposed as mediators of the beneficial effects of diets on health , and recent data suggest that circadian clocks can be among the important players .
the importance of the interplay between the feeding cycles and clocks in humans is an emerging field .
multiple studies on experimental or work - related circadian misalignment provide data on metabolic and health effects .
restoration of the rhythms ( pharmacologically , through the light therapy or the timed feeding ) may be beneficial in the clinical setting and for the treatment of mood - related disorders [ 88 , 89 ] .
thus , targeting the circadian clocks through feeding or pharmacological intervention opens a novel direction in anti - aging therapy and warrants further study on the interplay between the diets , the clocks , and longevity .
 diets and feeding regimens affect many physiological systems in the organism and may contribute to the development or prevention of various pathologies including cardiovascular diseases or metabolic syndromes . 
 some of the dietary paradigms , such as calorie restriction , have many well - documented positive metabolic effects as well as the potential to extend longevity in different organisms . 
 recently , the circadian clocks were put forward as integral components of the calorie restriction mechanisms . 
 the circadian clocks generate the circadian rhythms in behavior , physiology , and metabolism ; circadian disruption is associated with reduced fitness and decreased longevity . here 
 we focus on recent advances in the interplay between the circadian clocks and dietary paradigms . 
 we discuss how the regulation of the circadian clocks by feeding / nutrients and regulation of nutrient signaling pathways by the clocks may contribute to the beneficial effects of calorie restriction on metabolism and longevity , and whether the circadian system can be engaged for future medical applications . 
Introduction
The circadian clocks
Clocks, dietary paradigms and longevity
How the diet affects the circadian clocks?
How the circadian clocks may act as a part of calorie restriction mechanisms
Conclusions