review article nutrition and healthy ageing: calorie ... · elegans inactivation of the igf/pik/akt...

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2013 Article ID 707421 14 pageshttpdxdoiorg1011552013707421

Review ArticleNutrition and Healthy Ageing Calorie Restriction orPolyphenol-Rich lsquolsquoMediterrAsianrsquorsquo Diet

Kathrin Pallauf Katrin Giller Patricia Huebbe and Gerald Rimbach

Institute of Human Nutrition and Food Science Christian-Albrechts University of Kiel Hermann-Rodewald-Straszlige 624118 Kiel Germany

Correspondence should be addressed to Gerald Rimbach rimbachfoodsciuni-kielde

Received 20 June 2013 Accepted 26 July 2013

Academic Editor David Vauzour

Copyright copy 2013 Kathrin Pallauf et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Diet plays an important role in mammalian health and the prevention of chronic diseases such as cardiovascular disease (CVD)Incidence of CVD is low in many parts of Asia (eg Japan) and the Mediterranean area (eg Italy Spain Greece and Turkey) TheAsian and the Mediterranean diets are rich in fruit and vegetables thereby providing high amounts of plant bioactives includingpolyphenols glucosinolates and antioxidant vitamins Furthermore oily fish which is rich in omega-3 fatty acids is an importantpart of the Asian (eg Japanese) and also of theMediterranean dietsThere are specific plant bioactives which predominantly occurin the Mediterranean (eg resveratrol from red wine hydroxytyrosol and oleuropein from olive oil) and in the Asian diets (egisoflavones from soybean and epigallocatechin gallate from green tea) Interestingly when compared to calorie restriction whichhas been repeatedly shown to increase healthspan these polyphenols activate similar molecular targets such as Sirt1 We suggestthat a so-called ldquoMediterrAsianrdquo diet combining sirtuin-activating foods (= sirtfoods) of the Asian as well as Mediterranean dietmay be a promising dietary strategy in preventing chronic diseases thereby ensuring health and healthy ageing Future (human)studies are needed which take the concept suggested here of the MediterrAsian diet into account

1 Introduction

It has been well established that diet plays a central role inmaintaining health throughout life In the Western worlddiet has significantly changed in recent years Diets thatare rich in saturated fats and cholesterol low in fibre andhigh in sugar and salt may increase the CVD risk [1ndash3] Weare currently facing an increase in the incidence of obesityassociated diseases in general and specifically coronary heartdisease in many parts of the world Contrarily a reductionof food andor calorie intake without malnutrition may beassociated with the prolongation of life- and healthspanThe National Academies Keck Futures Initiative the Futureof Human Healthspan defined healthspan as the time anorganismwas of good healthwith health being the ldquothe abilityof a system to maintain or return to homeostasis in responseto challengesrdquo [4] In mammals including primates calorierestriction (CR) repeatedly delayed disease onset therebyprolonging healthspan [5ndash7] As diet composition also seemsto influence health [8 9] it has been hypothesized that CRand certain dietary factors can prevent age-related diseases

like atherosclerosis and cardiovascular disease (CVD) type2 diabetes mellitus neurodegenerative diseases and cancerDietary factors that decrease CVD risk may be the consump-tion of red wine and olive oil in the Mediterranean area[10] or seaweed in coastal Asia [11] Interestingly polyphenolconsumption and calorie restriction (CR) seem to havesimilar effects on metabolism in humans [12 13] and sup-plementationwith polyphenolsmay attenuate negative effectsfrom a high fat diet in mice [14] Therefore polyphenols arealso referred to as CR mimetics An important mechanismby which polyphenols induce CR-like signalling pathwaysseems to function through sirtuin activation [15] Sirtuins areNAD-dependent deacetylases that were shown to be involvedin the regulation of lifespan and metabolism in differentorganisms [15 16] Further evidence exists supporting a roleof polyphenols in gene regulation via the gamma coactivator1-alpha (PGC-1120572) and transcription factors such as nuclearfactor-erythroid 2 (Nrf2) forkhead box O (FoxO) andnuclear factor kappa B (NF120581B) [17] all of which are alsoimplicated in CR-mediated effects In this review we willdiscuss the literature on CR and foods that induce CR-like

2 Oxidative Medicine and Cellular Longevity

effects with a special focus on sirtuin activators that are foundin the Asian and Mediterranean diets and their potential topromote healthy ageing Because of their sirtuin-activatingproperties we refer to these foodstuffs as rdquosirtfoodsrdquo

2 Signalling Pathways That Are Induced byCalorie Restriction

CR induces body weight loss and has beneficial effects onplasma levels of triglycerides and cholesterol as well as onblood pressure thereby preventing or delaying the onsetof age-related diseases [18] Additionally in response toa reduction of body fat adipose tissue-derived hormonesincluding leptin and adiponectin are modulated These hor-mones are central in the regulation of satiety and appetite inthe hypothalamus [19] As an important regulator of bodyweight [20] circulating leptin levels are directly propor-tional to the total amount of visceral adipose tissue WhileCR decreases leptin levels it increases adiponectin levelsIn contrast to leptin adiponectin exhibits antiatherogenicanti-inflammatory and insulin-sensitizing properties and isassumed to be cardioprotective [21]

21 Insulin-Like Growth Factor and Mammalian Target ofRapamycin Signalling One of the main impacts of dietaryrestriction is the modulation of insulin and insulin-likegrowth factor-1 (IGF-1) signalling [22] Interestingly in miceimpaired IGF-1 signalling leads to a similarly prolongedlifespan as compared to CR [23] and in Caenorhabditiselegans inactivation of the IGFPI3KAkt pathway promotedlongevity [24]

Upon binding to their receptors insulin and IGF-1induce a number of signalling pathways and kinases suchas the phosphatidylinositol 3-kinases class I (PI3KI) theserinethreonine kinase Akt and the mammalian target ofrapamycin (mTOR) mTOR promotes protein synthesis andcellular growth [25] Besides downregulating mTOR vialowering IGFPI3KAkt signalling CR also inhibits mTORthrough activation of the 51015840 adenosine monophosphate-activated protein kinase (AMPK) [26] Inhibition of mTORleads to prolongation of lifespan [27] which is in partmediated by autophagy a lysosomal degradation process thatdegrades no-longer-needed proteins and organelles and alsofunctions as a starvation response [28] Consistent with CRattenuating age-related changes in metabolism and cellularfunctions insulin sensitivity and autophagic activity decreasewith age while being increased by CR [29]

22 Reactive Oxygen Species and the Hormesis Effect Ageingis also characterized by accumulating oxidative damageThere are different mechanisms that lead to this build-up ofdamaged proteins lipids and organelles Damaged macro-molecules may accumulate because of reduced degradationreduced antioxidant capacity or increased reactive oxygenspecies production [30 31]

It was shown that CR can decrease the mitochondrialrelease of reactive oxygen species (ROS) which contributeto this type of damage in ageing organisms [32] However

recent studies have indicated that themetabolic rate increaseswith CR [33] and it has been hypothesized that deleterioussubstances including ROS may have beneficial effects at lowconcentrationsThis concept of a biphasic dose-responsewithlow and high doses of a substance mediating opposite effectsis referred to as hormesis [34] According to this concept lowdoses of a certain substance benefit the organism by inducingadaptive effects In line with the concept of hormesis ROSmay function as essential signalling molecules for exam-ple by regulating redox-sensitive transcription factors [35]Because of a lack of energy supply under CR mitochondrialactivity and as a consequence oxidative phosphorylation inthe respiratory chain could be enhanced leading to increasedROS production [36]

23 The Redox-Regulated Transcription Factors Nrf2 andNF120581B One of the targets of increased ROS production isthe nuclear factor-erythroid 2- (NFE2-) related factor (Nrf2)This CaprsquonrsquoCollar basic leucine zipper transcription factorcontrols the expression of a large number of antioxidant andphase II detoxifying enzymes such as theNAD(P)H dehydro-genase (quinone) 1 (NQO1) the heme oxygenase 1 (HO-1)glutathione S-transferase (GST) the glutathione peroxidase(GPx) and the 120574-glutamylcysteine synthetase (120574GCS) [37ndash39] In CR rodents upregulation and increased activity ofthese gene products have been described repeatedly [40 41]

The nuclear factor kappa B (NF120581B) is also a redox-sensitive transcription factor that induces the expression ofgenes involved in inflammation and cellular proliferation[42] Although NF120581B is activated by ROS various studieshave reported downregulation of NF120581B by CR [43 44] It hasbeen suggested that CR increases cytoplasmic levels of I120581Bwhich impedes NF120581B translocation into the nucleus Addi-tionally CR may influence NF120581B translocation by decreas-ing nucleophosmin (NPM) expression NPM is a nuclearphosphoprotein that shuttles between the nucleus and thecytoplasm and promotes NF120581B activity [45] Moreover CRmay inhibit the transcription of the NF120581B subunit RelAp65through Sirt1 activation [46] Considering that at a higher ageNF120581B activity and as a consequence inflammation seem toincrease [47] the down-regulation of NF120581B activity by CRmay contribute to the ageing-related health benefits of CR

24 Forkhead Box O Transcription Factors The forkhead boxO (FoxO) transcription factor family activates or repressesgene expression of a wide variety of genes implicated inapoptosis cell cycle and differentiation DNA repair andstress response [48 49] and is also activated by CR [50]Of the four human forkhead genes that have been identifiedso far (FoxO1 FoxO3 FoxO4 and FoxO6) FoxO3 has beenidentified as a longevity-associated gene in centenarians [51]It has been suggested that FoxO transcription factors may beinvolved in longevity because of their ability to detoxify ROSand repair DNA damage

FoxOs can be regulated by various mechanisms suchas phosphorylation acetylation and proteasomal degrada-tion While under nutrient rich conditions insulinIGF-1signalling leads to translocation of FoxO out of the nucleus

Oxidative Medicine and Cellular Longevity 3

Table 1 FoxO regulation by Sirt1

Cell culture Treatment Outcome Reference

HEK 293T Stress conditions (H2O2)uarr Interaction between Sirt1 and FoxO3 [53]

MEF Sirt1minusminusTreatment with LY 294002 (PI3K inhibitor)wild typeSirt1minusminus

uarr Acetylation of FoxO3uarr GADD45 (stress resistance)darr GADD45

HepG2 Serum starvation =gt FoxO translocationinto the nucleus uarr Deacetylation of FoxO1 by Sirt1 [55]

HeLa Sirt1 overexpressiondarr FoxO3 activity(darr FoxO3 target genes Bimp27) [54]

HEK 293T Inhibition of Sirt1darr FoxO4 activitydarrMnSODdarr p27

[58]

Bim Bclminus2 interacting mediator of cell death proapoptotic protein H2O2 hydrogen peroxide HEK-293T human embryonic kidney 293 cells containing theT antigen from simian virus HepG2 human liver carcinoma cell line MEF mouse embryonic fibroblasts MnSOD manganese superoxide dismutase part ofantioxidative defence p27 cyclin-dependent kinase inhibitor controls cell cycle progression PI3K phosphatidylinositol 3-kinase

Table 2 Cellular localization activity and biological function of sirtuins 1ndash7 according to [63]

Sirtuin Localization Activity Biological functionSirt1 Nucleuscytosol Deacetylase Cell survivalmetabolismSirt2 Cytosol Deacetylase Cell cycleSirt3 Mitochondria Deacetylase ThermogenesismetabolismSirt4 Mitochondria ADP-ribosyltransferase Insulin secretionmetabolismSirt5 Mitochondria Deacetylase UnknownSirt6 Nucleus ADP-ribosyltransferase DNA repairSirt7 Nucleolus Unknown rDNA transcriptionADP adenosine diphosphate rDNA ribosomal desoxyribonucleic acid Sirt sirtuin

and subsequent degradation and CR leads to activation ofFoxO-mediated transcription [50] An importantmechanismfor FoxO activation under conditions of limited nutrientsupply is its deacetylation by Sirt1 [52] (see Table 1) It hasbeen shown that Sirt1 leads to a type of FoxO3 activationthat counteracts oxidative stress while suppressing FoxO3-induced apoptosis rather than leading to FoxO3-induced celldeath [53]The finding that Sirt1 can inhibit the transcriptionof one set of genes while switching on the transcription ofanother type of target genes could explain the observationmade by Motta and colleagues [54] who stated that Sirt1-mediated deacetylation of FOXO3 led to its inhibitionHowever in the case of FoxO1 Daitoku and coworkers [55]reported an upregulation via Sirt-mediated deacetylationInterestingly FoxO and the tumour suppressor p53 appear tobe functionally linked as they can alter each otherrsquos functions[56] Both FoxO and p53 are deacetylated by Sirt1 whichthereby controls their activities In addition FoxO inducesgene expression of Sirt1 [57] Therefore it seems plausiblethat CR at least in part leads to lifespan extension throughregulating the insulinIGF1 FoxO and Sirt1 network

3 Sirtuins the Mammalian Homologues ofthe Yeast Longevity Gene SIR2

Sirtuins (Sirt1ndash7) are NAD-dependent histone deacetylases[59] All sirtuins contain a catalytic core domain but differ

in the protein sequences surrounding this domain and theircellular localization [60] They act as protein deacetylasesandor ADP-ribosyltransferases As they require NAD it hasbeen suggested that their activity depends on the metabolicstate of the cell It has been hypothesized that sirtuins maylink energy intake to lifespan [61] An inhibitory mutation ofthe Sirt1 ortholog SIR2 in yeast shortened lifespan whereasoverexpression of SIR2 extended lifespan [62] Their cellularlocalizations activities and biological functions are listed inTable 2

31 Sirt1 and the Control of Metabolism Sirt1 is the beststudied sirtuin to date and is sometimes referred to as aguardian against cellular oxidative stress and DNA damageApart from deacetylating p53 and FoxO transcription factorsit was also shown to interact with NF120581B the peroxisomeproliferator-activated receptor gamma (PPAR120574) and thePPAR120574 coactivator and inducer of mitochondrial biogenesisPGC-1120572 [64 65] (Figure 1) In vivo studies have shown thatCR upregulates themammalian Sirt1 protein levels inmusclebrain fat and kidney (see Table 3) [57 66] In white adiposetissue (WAT) Sirt1 was shown to deacetylate and inhibitPPAR120574 This nuclear receptor which is induced by fatty acidsactivates fat synthesis and adipogenesis Thus inhibition ofPPAR120574 by Sirt1 led to fat loss [64] A decrease in adiposetissue generally lowers the leptinadiponectin ratio therebyfavouring insulin sensitivity and healthy ageing It has also


Table 3 Effects of calorie restriction or starvation on Sirt1 in different tissues in mice and rats

Species Number animals Caloricrestriction Tissue Outcome Reference

Mice(C57BL6) 10 40

Muscle fat

liver

Sirt1 uarr(protein)Sirt1 darr(protein)

[66]

Mice(C57BL6timesC3HHe F1hybrid)

4 15Brain liver

heart muscle

No effect on Sirt1(protein)Sirt1 darr(protein)

[13]

Mice(C57BL6) mdash 24 h starvation Liver

Sirt1 uarr(protein)no effect on mRNA

[65]

Mice(C57BL) mdash 24 h starvation

Brain heartmuscle whiteadipose tissue andkidney


[70]

Mice(C57BLK6timesSV127 F1hybrid)

10 30ndash40 White adipose tissue Sirt1 uarr(protein) [36]

Mice(C57BL6) mdash 40

White adipose tissueliver kidney andbrain

Sirt1 uarr(protein)not significant

[71]

Rats(Fisher 344) mdash 40 Brain fat kidney

and liverSirt1 uarr(protein) [57]

Liver Muscle

Sirt1 Sirt1 Sirt1

UCP2 FoxO

FoxO1FoxO3ATP Stress

120573-cells

PGC-1120572 PGC-1120572resistance uarr

Gluconeogenesis uarrFatty acid oxidation uarr

Insulin secretion uarr Mitochondria uarrMetabolism uarr

Figure 1 Sirt1-mediated regulation of metabolism in differenttissues according to [92] In pancreatic 120573-cells Sirt1 represses theexpression of UCP2 thereby increasing insulin secretion and Sirt 1also regulates FoxOs thereby protecting the120573-cells against oxidativestress In the liver Sirt1 regulates gluconeogenesis by activatingPGC-1120572 In muscle cells Sirt1 activates both PGC-1120572 and FoxOthereby influencing mitochondrial biogenesis respiration and fattyacid oxidation ATP adenosine triphosphate FoxO forkhead boxprotein O PGC-1120572 peroxisome proliferator-activated receptor-120574coactivator 1 alpha UCP uncoupling protein 2

been shown that Sirt1 activation shifts metabolisms awayfrom using glucose as an energy source While Sirt1 led toPPAR120574 inhibition PPAR120572 that transcribes genes involved infatty acid oxidation was activated by Sirt1 localizing to PPARresponse elements upon CR [67] Additionally deacetyla-tion of PGC-1120572 by Sirt1 seems to lead to an activation ofgluconeogenic gene transcription while the expression ofgenes involved in glycolysis decreased [65] With CR PGC-1120572 is also induced on a transcriptional level and activated by

AMPK-mediated phosphorylation [68] Activated PGC-1120572increases mitochondrial biogenesis by expressing severalcomponents of the respiratory chain Moreover PGC-1120572contributes to the metabolic shift away from glycolysisunder conditions of limited nutrient supply by promotingmitochondrial fatty acid oxidation and gluconeogenesis inthe liver [69]

However while various reports find increased Sirt1 pro-tein levels in the muscle and WAT of CR animals there iscontradicting data as to whether liver Sirt1 changes uponCR (see Table 3) Chen and colleagues [66] even stated thathepatic Sirt1 levels were decreased by CR This may berelated to tissue-specific functions of Sirt1 (Figure 1) In thestudy by Chen and colleagues the repression of hepatic Sirt1by CR resulted in decreased hepatic fat synthesis and fataccumulation Consistent with this finding mice with a liver-specific knockout of Sirt1 fed a Western diet showed lowerbody weight gain than wild typemice A possible explanationfor this lowered fat accumulation in the livermay be a reducedcoactivation of liver X receptor (LXR) resulting in decreasedactivation of the cholesterol transporter ABCA1 and the fatsynthesis regulator SREBP1c [66] However in another studyalso using Sirt1 LKO contrary observations were made anda weight gain in the LKO mice higher than in the wild typecontrols was reported [67] As pointed out by Haigis andSinclair [72] this may have resulted from the different typesof diets used in these two studies with the diet from thesecond trial containing more fat Of interest transgenic Sirt1mice were protected against fatty liver when fed a high fatdiet Moreover these mice showed lower NF120581B activationand consistently lower levels of proinflammatory cytokines


Glutamate dehydrogenase

Glutamate

Sirt4

ADP-ribosylation

120572-Ketoglutarate

Amino acidmetabolism darr

ASSIS darr

Figure 2 Sirt4 mediated amino acid metabolism according to [92] ASSIS amino acid-stimulated insulin secretion

as well as lower glucose levels when compared to their wildtype controls [73] Thus the authors hypothesize that Sirt1protects from damage induced by a high fat diet

32 Cardiovascular Disease and Sirt1 CVD is the primarycause of death in most countries and is characterized by ele-vated levels of low density lipoprotein cholesterol oxidativedamage to proteins and lipids and chronic inflammationThis environment promotes atherosclerotic plaque formationand a deteriorated endothelial function Apart from geneticfactors a high fat diet and ageing are the main risk factorsfor developing this type of disease Sirt1 induction by CR orby the ldquosirtfoodrdquo- constituent resveratrol has been shown tocounteract elevated levels of inflammation and might lowercholesterol and triglyceride synthesis [74] An importantfactor that contributes to the protective role of Sirt1 in CVDseems to be its function as a suppressor of the proinflamma-tory transcription factor NF120581B Sirt1 inhibits NF120581B-mediatedtranscription by deacetylating its subunit RelAp65 and as aconsequence lowering its DNA-binding ability [46] Variousreports have shown that Sirt1 activation in vitro decreasedthe levels of proinflammatory mediators such as the tumournecrosis factor 120572 interleukins 1 and 6 intercellular adhesionmolecule 1 and inducible nitric oxide synthase (NOS) [72] Ina mouse model for CVD an apolipoprotein E double knock-out and endothelial Sirt1 overexpression lowered the forma-tion of atherosclerotic plaques [75] In mouse liver it couldbe shown that Sirt1 interacts with the nuclear factor LXR andactivates this transcription factor through its deacetylationLXR induces reverse cholesterol transport by activating thetranscription of the cholesterol efflux transporter ABCA1thereby lowering peripheral cholesterol levels and promotingcholesterol excretion [76] In contrast to inducible NOSwhich is found in macrophages and produces NO that harmsmicroorganisms endothelial NOS (eNOS) protects arteriesInterestingly it was shown that Sirt1 activates eNOS and thusleads to endothelium-dependent vasodilatation

33 Sirt1 Interaction with AMPK and Importance forAutophagy Activation of the energy sensing kinase AMPKhas shown similar effects on metabolism energy expenditureas compared to sirtuin signalling on various occasions [77]This can be explained by the findings that Sirt1 activatesAMPK [78] and vice versa [79] Additionally these reportspoint to the notion that both enzymes are needed toorchestrate the organismrsquos response to limited nutrientsupply or elevated energy demand during exercise A partof the organismrsquos response to such catabolic metabolicstates is the lysosomal degradation pathway autophagyInterestingly autophagy was shown to be induced via Sirt1

and AMPK [80 81] In Caenorhabditis elegans autophagyinduction is necessary for and contributes to the lifespanprolonging effect of CR and its mimetic resveratrol [82] Inanother experimentmeasuring lifespan extension autophagydeficient worms did not benefit from caloric restriction tothe same extent as wild type C elegans [83] Similarly to theactivation of sirtuins autophagy induction leads to lifespanextension in Drosophila and other organisms [84 85] Inaddition sirtuins and autophagy are induced by CR [29]Therefore part of the ageing-related benefits from Sirt1activation by CR or polyphenolic CR mimetics seems tobe caused by autophagy [86] In the case of the secondaryplant metabolite resveratrol this connection could alreadybe shown By inducing autophagy via Sirt1 activationresveratrol promoted longevity in worms and flies [87]Interestingly other polyphenolic Sirt1 inducers such asquercetin also promoted autophagic degradation [15 88]Considering that autophagy is a starvation and especiallyin higher eukaryotes a stress response the activation ofthis lysosomal degradation pathway might be one the mainmechanisms by which Sirt1 protects the organism fromstressors (and thereby contributes to longevity)

34 The Mammalian Sirtuins 2ndash6 Apart from Sirt1 bothSirt3 and Sirt4 play important metabolic roles during foodlimitation Additionally in a study by Kawahara and cowork-ers [89] Sirt6-induced histone deacetylation led to prolonga-tion of lifespan

Sirt3 is mainly expressed in the liver kidney brain andbrown adipose tissue [90] A high expression of Sirt3 inbrown adipose tissue during CR induces the expression ofPGC-1120572 and the uncoupling protein-1 (UCP-1) which isimportant for thermogenesis Downregulation of Sirt4 by CRseems to affect amino acid metabolism and insulin secre-tion Decreased Sirt4 levels lead to a higher conversion ofglutamate to 120572-ketoglutarate by the glutamate dehydrogenaseGDH [91] thereby promoting the use of amino acids as ATPsource under CR Contrarily under nutrient-rich conditionsSirt4 ADP-ribosylates GDH which attenuates GDH activity[91] Furthermore CR-mediated Sirt4 decrease and GDHactivity induce the amino acid-stimulated insulin secretion(AASIS) resulting in increased insulin secretion in responseto CR [92] (Figure 2)

4 Potential Health Benefits ofa MediterrAsian Diet

As in the Western world the prevalence of obesity and age-associated diseases such as type 2 diabetes mellitus cancerAlzheimerrsquos and atherosclerosis is increasing and in order to


benefit from CR a lifelong restriction seems to be necessary[41] interest in dietary restriction mimetics has been rising(see Table 4)

However although substances such as metformin can beused as an antidiabetic drug [97] most of the pharmacologi-cal CR mimetics have severe side effects Therefore the con-sumption of secondary plant bioactives such as polyphenolswith the normal diet appears to be a safer strategy to benefitfrom potentially healthspan-improving CR mimetics

Although further studies are needed to prove thatthese foods promote health in humans through their CR-mimicking secondary plant metabolite content we hypoth-esize that the concept of combining foods from Asian andMediterranean diets could possibly improve health statusin an ageing population Unfortunately it can be difficultto study how dietary components influence health becauseof the low doses of bioactives found in diets when com-pared to the doses fed in some animal studies or thedoses applied in most cell culture models Additionallybioactives are metabolised before and after adsorption fromthe gastrointestinal tract and could work synergistically orantagonistically with each other and other components inthe diet These factors make it complicated to extrapolatefindings from in vitro and in vivo experiments to humansFurthermore when carrying out human studies dietaryeffects tend to be smaller than in many pharmacologicalintervention studies and therefore require a higher number ofparticipants to obtain measurable results However it seemsthat diets rich in saturated fats and cholesterol low in fibreand high in sugar and salt may increase CVD risk [1ndash3]and dietary factors such as olive oil consumption in theMediterranean area [10] or seaweed in coastal Asia [11] maydecrease CVD risk Therefore we believe that combiningAsian andMediterranean foods in aMediterrAsian diet couldbe a promising approach for improving human health

41 Components of Mediterranean Diets From a nutritionalpoint of view there is a substantial overlap between theAsian and Mediterranean diets These diets are rich in fruitand especially vegetables which are both important sourcesof dietary polyphenols glucosinolates and vitamin C (seeFigure 3) Furthermore for some parts of Asia and theMediterranean a high consumption of oily fish rich in omega3 fatty acids has been reported Consistent with the lowincidence of CVD in populations consuming such diets inAsia and the Mediterranean area it has been suggested thatfoods with a high content of polyphenols glucosinolates andomega 3 fatty acids reduce the CVD risk

In addition there are also specific foods which arepredominantly consumed in the Mediterranean area suchas red wine The same is true for olive oil which is alsoconsumed to a higher extent in Southern as opposed toNorthern Europe Studies in model organisms (eg Celegans D melanogaster) and laboratory rodents suggestthat red wine constituents (eg resveratrol) may positivelyaffect both health and lifespan [14 16] Our own datademonstrate that mice consuming diets rich in olive oilphenolics (eg hydroxytyrosol) exhibit decreased oxidative

damage markers (eg lipid peroxides protein carbonyls)and improved expression of Nrf2-dependent genes encodingantioxidant (120574GCS NQO1) and cardioprotective (paraox-onase) proteins We have also shown that olive oil phenolicsmay induce proteasomal activity and Sirt1 signalling [98]Recently another group also observed Sirt1 induction by oliveoil phenolics [99] and further evidence exists supportinga role of polyphenols in gene regulation via sirtuins andtranscription factors such as Nrf2 and NF120581B [17] Resvera-trol activated Nrf2 and attenuated oxidative stress therebyprotecting the endothelium in a mouse model [100] andinhibited inflammation in macrophages via downregulationof the proinflammatory NF120581B [101] Resveratrol has beenrepeatedly shown to induce Sirt1 [15 82 102] and thereforeit seems possible that the endothelium protection and NF120581Binhibition may also be connected to Sirt1 induction Thepolyphenol quercetin found in onions could also induce Sirt1[15] In Table 5 we have listed polyphenols that were shownto induce sirtuins and the type of foods they are found inGiven the fact that Sirt1 activation appears to benefit healthbymimicking CR these ldquosirtfoodsrdquomay contribute to healthyageing

42 Components of Asian Diets The Asian diet is rich insoy and turmeric Curcuma longa is a significant source ofcurcumin [111] and soy contains considerable amounts ofisoflavones [112 113] Similar to resveratrol and quercetincurcumin has also been shown to induce Nrf2 [114] andother transcription factors [115] and inhibit NF120581B-mediatedinflammation [116 117] In contrast to the Asian diet theMediterranean diet is almost devoid of both isoflavones andcurcuminWe and others have shown that soy isoflavones andcurcuminmediates cardioprotective activity including reduc-tion of LDL oxidation inhibition of platelet aggregation andimprovement in vascular reactivity [118ndash120] Interestinglyisoflavones such as daidzein were also shown to induce Sirt1and PGC-1120572 [103] Further constituents of the Asian diet thatcontain possible health-promoting bioactives are green teaand seaweed Tea polyphenols seem to inhibit the proinflam-matory transcription factor NF120581B [121] while seaweed is asource of antioxidant vitamins and polyunsaturated omega 3fatty acids [122] which may also prevent CVD [123 124]

43 Human Intervention Studies on Secondary Plant Metabo-lites Found in theMediterrAsianDiet Most of the in vitro andin vivo research and various human intervention studies withbioactives from the Mediterranean and Asian diets foundpromising results regarding possible health-promoting ben-efits [125 126] However some studies reported controversialdata For example red wine has been stated to decrease lowdensity lipoprotein (LDL) peroxidation in humans whichwould be beneficial for CVD prevention [127] In contrastred or white wine with a reduced alcohol content did notdecrease (LDL) peroxidation in human volunteers [128] andone group of researchers showed that although moderatered wine consumption could lower LDL oxidation the othertested alcoholic beverages also did [129] On the other handin one study only red wine as compared to white wine


Table4Dietary

restric

tionmim

eticsmechanism

sand

sidee

ffects

Nam

eofcom

poun

dStructureo

fcom

poun

dMechanism

ofactio

nSide

effects

References

Rapamycinsiro

limus

O

O

ON O

OH

O

H

O

O

O

OH

HO OH

O

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

H3C

H3C

Inhibitio

nof

mTo

rindu

ctionof

autoph

agy

Immun

osup

pressio

n[93]

2-Deoxy-D

-glucose

O

OH

HH

OH

OH

H

H

OH

Inhibitio

nof

glucosem

etabolism

Cardiotoxicity

[94]

Metform

inN

HN

NH

NH

NH

2

CH3

H3C

Inhibitio

nof

glucon

eogenesis

stim

ulationof

glucoseu

ptake

inhibitio

nof

AMPK

and

improvem

ento

finsulin

sensitivity

Gastro

intestinal

complaints

[95ndash97]


Table5Sirt1-ind

ucingplantb

ioactiv

esandtheldquosir

tfood

srdquothey

arefou

ndin

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Daidzein

O O

OH

OH

Soybeantofuand

othersoy

prod

ucts

[103104]

Fisetin

O O

OH

OH

OH

OH

Strawberriesapples

persim

mon

sgrapes

[15105]

Form

onon

etin

O O

OH

O

H3C

Soybean

[103]

Isoliquiritigenin

OH O

OH

OH

Soybean

shallots

andlicorice

[15106107]

Hydroxytyrosolloz

OH

OHO

H

Oliveo

il[9899]


Table5Con

tinued

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Kaem

pferol

O O

OH

OH

OH

OH

Cabb

agekale

parsleydifferent

typeso

fbeansC

orchorus

olito

riuslowastand

cruciferous

vegetables

[105108]

Piceatanno

l

OH

OHO

H

OH

Redwinegrapesand

Rhodom

yrtustom

entosa

[15109110

]

Quercetin

O O

OH

OH

OH

OH

OH

Onion

sapplesw

hitewine

capersand

Corchoruso

litoriuslowast

[15105]

Resveratrol

OH

OH

OH

Redwineredgrapes

[15109]

lowastCon

sumed

inJapanas

ldquoMolok

hekardquo

ediblep

lant

nativ

etoAsia

lozandpo

ssiblyotherp

heno

liccompo

unds

foun

din

oliveo

il


Mediterranean diet Asian diet

Curcuma longa (curcumin)Soy (isoflavones)Green tea (catechins)Seaweed (omega-3 fatty acids)

Red wine (resveratrol)Olives (oleic acid

hydroxytyrosol and oleuropein)

Fruit and vegetables(polyphenolsglucosinolates

antioxidant vitamins)

Oily fish

MediterrAsian diet

MediterrAsian diet

(omega-3 fatty acids)

Figure 3 Important food items and their corresponding constituents in the Mediterranean Asian and so-called MediterrAsian diet

lowered LDL oxidation in healthy humans thereby pointingto the notion that certain components found in red but notwhite wine are responsible for this effect [130] Similarlyconflicting results were reported for the influence of fruit-derived polyphenols on blood pressure While Aviram andcolleagues observed that pomegranate juice reduced bloodpressure in humans [131] in the study by Sumner andcolleagues blood pressure did not change after administeringpomegranate juice to the patients [132] In the context ofcancer prevention by soy-containing diets a meta-analysison the influence of isoflavones on a breast cancer biomarkerfound only a small positive effect that might or might notbe clinically relevant [133] In the case of curcumin datafrom cell models and animal studies made this polyphenolappear an efficient treatment for dementia [134] Howeverin clinical trials curcumin did not improve the symptoms ofAlzheimer patients [135] There are various factors that maycontribute or explain these controversial findings includingthe differences in the health status of the patients differentdoses and dosage forms or different parameters measured(eg lipid peroxidation in plasma versus blood pressure forCVD) However these conflicting results demonstrate thatfurther research is needed to better understand the effect ofdietary components on sirtuin activation and healthy ageing

5 Conclusion

A high content of fruit vegetables and oily fish in thediets of Mediterranean and certain Asian populations islikely to cause the improved health status observed in theMediterrAsian area

However we suggest that plant bioactives antioxidantvitamins and omega-3 fatty acids do not work in isola-tion Rather they may act synergistically thereby preventing

chronic diseasesThus it is possible that the complexmixtureof diet-derived plant bioactives antioxidatives and omega-3 fatty acids cannot be substituted by a single purifiedcompound [136]

Instead we propose combining healthy foodstuffs ofthe Asian and the Mediterranean diets especially rich inldquosirtfoodsrdquo in order to prevent chronic diseases and ensurehealthy ageing

We would like to encourage future studies in culturedcells model organisms laboratory rodents and ultimatelyhumans to unravel and evaluate potential health benefitsof the MediterrAsian diet from a molecular to the systembiology level

References

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[2] W C Willett ldquoDietary fats and coronary heart diseaserdquo Journalof Internal Medicine vol 272 no 1 pp 13ndash24 2012

[3] F J Sanchez-Muniz ldquoDietary fibre and cardiovascular healthrdquoNutricion Hospitalaria vol 27 no 1 pp 31ndash45 2012

[4] M Kon and A M Cuervo ldquoChaperone-mediated autophagy inhealth and diseaserdquo FEBS Letters vol 584 no 7 pp 1399ndash14042010

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[6] R Weindruch and R L Walford ldquoDietary restriction in micebeginning at 1 year of age effect on life-span and spontaneouscancer incidencerdquo Science vol 215 no 4538 pp 1415ndash1418 1982


[7] J A Mattison G S Roth T M Beasley et al ldquoImpact of caloricrestriction on health and survival in rhesus monkeys from theNIA studyrdquo Nature vol 489 no 7415 pp 318ndash321 2012

[8] D Vauzour A Rodriguez-Mateos G Corona M J Oruna-Concha and J P E Spencer ldquoPolyphenols and human healthprevention of disease andmechanisms of actionrdquoNutrients vol2 no 11 pp 1106ndash1131 2010

[9] D Vauzour ldquoDietary polyphenols as modulators of brainfunctions biological actions andmolecularmechanisms under-pinning their beneficial effectsrdquoOxidativeMedicine andCellularLongevity vol 2012 Article ID 914273 16 pages 2012

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[94] D K Ingram and G S Roth ldquoGlycolytic inhibition as a strat-egy for developing calorie restriction mimeticsrdquo ExperimentalGerontology vol 46 no 2-3 pp 148ndash154 2011

[95] I B Sahra Y L Marchand-Brustel J Tanti and F BostldquoMetformin in cancer therapy a new perspective for an oldantidiabetic drugrdquo Molecular Cancer Therapeutics vol 9 no5 pp 1092ndash1099 2010

[96] H K Park ldquoMetformin and cancer in type 2 diabetesrdquoDiabetesamp Metabolism Journal vol 37 no 2 pp 113ndash116 2013

[97] C Bouza T Lopez-Cuadrado L F Gutierrez-Torres and JAmate ldquoEfficacy and safety of metformin for treatment ofoverweight and obesity in adolescents an updated systematicreview and meta-analysisrdquo Obesity Facts vol 5 no 5 pp 753ndash765 2012

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[100] Z Ungvari Z Bagi A Feher et al ldquoResveratrol confersendothelial protection via activation of the antioxidant tran-scription factor Nrf2rdquo American Journal of Physiology vol 299no 1 pp H18ndashH24 2010

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[103] K A Rasbach and R G Schnellmann ldquoIsoflavones promotemitochondrial biogenesisrdquo Journal of Pharmacology and Exper-imental Therapeutics vol 325 no 2 pp 536ndash543 2008

[104] T Song K Barua G Buseman and P A Murphy ldquoSoyisoflavone analysis quality control and a new internal standardrdquoAmerican Journal of Clinical Nutrition vol 68 supplement 6pp 1474Sndash1479S 1998

[105] Y Arai S Watanabe M Kimira K Shimoi R Mochizukiand N Kinae ldquoDietary intakes of flavonols flavones andisoflavones by Japanese women and the inverse correlationbetween quercetin intake and plasma LDL cholesterol concen-trationrdquo Journal of Nutrition vol 130 no 9 pp 2243ndash22502000

[106] R Kape M Parniske S Brandt and D Werner ldquoIsoliquirit-igenin a strong nod gene- and glyceollin resistance-inducingflavonoid from soybean root exudaterdquoApplied andEnvironmen-tal Microbiology vol 58 no 5 pp 1705ndash1710 1992

[107] Y Hsu C Chia P Chen S Huang S Huang and P KuoldquoShallot and licorice constituent isoliquiritigenin arrests cellcycle progression and induces apoptosis through the inductionof ATMp53 and initiation of the mitochondrial system inhuman cervical carcinomaHeLa cellsrdquoMolecular Nutrition andFood Research vol 53 no 7 pp 826ndash835 2009

[108] W S Da-Silva J W Harney B W Kim et al ldquoThe smallpolyphenolic molecule kaempferol increases cellular energyexpenditure and thyroid hormone activationrdquoDiabetes vol 56no 3 pp 767ndash776 2007


[109] R F Guerrero B Puertas M I Fernandez M Palma andE Cantos-Villar ldquoInduction of stilbenes in grapes by UV-Ccomparison of different subspecies of Vitisrdquo Innovative FoodScience and Emerging Technologies vol 11 no 1 pp 231ndash2382010

[110] TNH LaiMHerent -F JQuetin-Leclercq et al ldquoPiceatannola potent bioactive stilbene as major phenolic component inRhodomyrtus tomentosardquo Food Chemistry vol 138 no 2-3 pp1421ndash1430 2013

[111] A Goel and B B Aggarwal ldquoCurcumin the golden spicefrom Indian saffron is a chemosensitizer and radiosensitizerfor tumors and chemoprotector and radioprotector for normalorgansrdquo Nutrition and Cancer vol 62 no 7 pp 919ndash930 2010

[112] G Rimbach C Boesch-Saadatmandi J Frank et al ldquoDietaryisoflavones in the prevention of cardiovascular diseasemdashamolecular perspectiverdquo Food and Chemical Toxicology vol 46no 4 pp 1308ndash1319 2008

[113] A Mortensen S E Kulling H Schwartz et al ldquoAnalyticaland compositional aspects of isoflavones in food and theirbiological effectsrdquo Molecular Nutrition and Food Research vol53 supplement 2 pp S266ndashS309 2009

[114] E Balogun M Hoque P Gong et al ldquoCurcumin activatesthe haem oxygenase-1 gene via regulation of Nrf2 and theantioxidant-responsive elementrdquo Biochemical Journal vol 371part 3 pp 887ndash895 2003

[115] S Shishodia ldquoMolecular mechanisms of curcumin action geneexpressionrdquo Biofactors vol 39 no 1 pp 37ndash55 2013

[116] C Yeh T Chen Y Wu Y Lin and P Jing Lin ldquoInhibition ofNF120581B activation with curcumin attenuates plasma inflamma-tory cytokines surge and cardiomyocytic apoptosis followingcardiac ischemiareperfusionrdquo Journal of Surgical Research vol125 no 1 pp 109ndash116 2005

[117] J H Kim S C Gupta B Park V R Yadav and B BAggarwal ldquoTurmeric (Curcuma longa) inhibits inflammatorynuclear factor (NF)-120581B and NF-120581B-regulated gene productsand induces death receptors leading to suppressed proliferationinduced chemosensitization and suppressed osteoclastogene-sisrdquo Molecular Nutrition and Food Research vol 56 no 3 pp454ndash465 2012

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[119] R Turner T Baron S Wolffram et al ldquoEffect of circulatingforms of soy isoflavones on the oxidation of low densitylipoproteinrdquo Free Radical Research vol 38 no 2 pp 209ndash2162004

[120] W L Hall G Rimbach and C M Williams ldquoIsoflavones andendothelial functionrdquo Nutrition Research Reviews vol 18 no 1pp 130ndash144 2005

[121] M Pan S Lin-Shiau C Ho J Lin and J Lin ldquoSuppres-sion of lipopolysaccharide-induced nuclear factor-120581B activityby theaflavin-33rsquo-digallate from black tea and other poly-phenols through down-regulation of I120581B kinase activity inmacrophagesrdquo Biochemical Pharmacology vol 59 no 4 pp357ndash367 2000

[122] N Rajapakse and S Kim ldquoNutritional and digestive healthbenefits of seaweedrdquo Advances in Food and Nutrition Researchvol 64 pp 17ndash28 2011

[123] D Mozaffarian and J H Y Wu ldquo(n-3) Fatty acids and car-diovascular health are effects of EPA and DHA shared or

complementaryrdquo Journal of Nutrition vol 142 no 3 pp 614Sndash625S 2012

[124] P Saravanan N C Davidson E B Schmidt and P C CalderldquoCardiovascular effects of marine omega-3 fatty acidsrdquo TheLancet vol 376 no 9740 pp 540ndash550 2010

[125] M F-F Chong R MacDonald and J A Lovegrove ldquoFruitpolyphenols and CVD risk a review of human interventionstudiesrdquo British Journal of Nutrition vol 104 supplement 3 ppS28ndashS39 2010

[126] D Del Rio A Rodriguez-Mateos J P Spencer M TognoliniG Borges and A Crozier ldquoDietary (poly)phenolics in humanhealth structures bioavailability and evidence of protectiveeffects against chronic diseasesrdquo Antioxidants amp Redox Signal-ing vol 18 no 14 pp 1818ndash1892 2013

[127] EN Frankel J Kanner J BGerman E Parks and J E KinsellaldquoInhibition of oxidation of human low-density lipoprotein byphenolic substances in red winerdquoThe Lancet vol 341 no 8843pp 454ndash457 1993

[128] Y B De Rijke P N M Demacker N A Assen L M SlootsM B Katan and A F H Stalenhoef ldquoRed wine consumptiondoes not affect oxidizability of low-density lipoproteins involunteersrdquo American Journal of Clinical Nutrition vol 63 no3 pp 329ndash334 1996

[129] M S Van Der Gaag A Van Tol L M Scheek et al ldquoDailymoderate alcohol consumption increases serum paraoxonaseactivity a diet-controlled randomised intervention study inmiddle-aged menrdquo Atherosclerosis vol 147 no 2 pp 405ndash4101999

[130] B Fuhrman A Lavy and M Aviram ldquoConsumption of redwine with meals reduces the susceptibility of human plasmaand low-density lipoprotein to lipid peroxidationrdquo AmericanJournal of Clinical Nutrition vol 61 no 3 pp 549ndash554 1995

[131] M Aviram M Rosenblat D Gaitini et al ldquoPomegranate juiceconsumption for 3 years by patients with carotid artery stenosisreduces common carotid intima-media thickness blood pres-sure and LDL oxidationrdquo Clinical Nutrition vol 23 no 3 pp423ndash433 2004

[132] M D Sumner M Elliott-Eller G Weidner et al ldquoEffectsof pomegranate juice consumption on myocardial perfusionin patients with coronary heart diseaserdquo American Journal ofCardiology vol 96 no 6 pp 810ndash814 2005

[133] LHooper GMadhavan J A Tice S J Leinster andACassidyldquoEffects of isoflavones on breast density in pre-and post-menopausal women a systematic review and meta-analysis ofrandomized controlled trialsrdquo Human Reproduction Updatevol 16 no 6 Article ID dmq011 pp 745ndash760 2010

[134] T Jayasena A Poljak G Smythe N Braidy G Munch and PSachdev ldquoThe role of polyphenols in the modulation of sirtuinsand other pathways involved in Alzheimerrsquos diseaserdquo AgeingResearch Reviews 2013

[135] JM Ringman S A Frautschy E Teng et al ldquoOral curcumin forAlzheimerrsquos disease tolerability and efficacy in a 24-week ran-domized double blind placebo-controlled studyrdquo AlzheimerrsquosResearch ampTherapy vol 4 no 5 p 43 2012

[136] S Egert and G Rimbach ldquoWhich sources of flavonoids com-plex diets or dietary supplementsrdquo Advances in Nutrition vol2 no 1 pp 8ndash14 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


effects with a special focus on sirtuin activators that are foundin the Asian and Mediterranean diets and their potential topromote healthy ageing Because of their sirtuin-activatingproperties we refer to these foodstuffs as rdquosirtfoodsrdquo

2 Signalling Pathways That Are Induced byCalorie Restriction

CR induces body weight loss and has beneficial effects onplasma levels of triglycerides and cholesterol as well as onblood pressure thereby preventing or delaying the onsetof age-related diseases [18] Additionally in response toa reduction of body fat adipose tissue-derived hormonesincluding leptin and adiponectin are modulated These hor-mones are central in the regulation of satiety and appetite inthe hypothalamus [19] As an important regulator of bodyweight [20] circulating leptin levels are directly propor-tional to the total amount of visceral adipose tissue WhileCR decreases leptin levels it increases adiponectin levelsIn contrast to leptin adiponectin exhibits antiatherogenicanti-inflammatory and insulin-sensitizing properties and isassumed to be cardioprotective [21]

21 Insulin-Like Growth Factor and Mammalian Target ofRapamycin Signalling One of the main impacts of dietaryrestriction is the modulation of insulin and insulin-likegrowth factor-1 (IGF-1) signalling [22] Interestingly in miceimpaired IGF-1 signalling leads to a similarly prolongedlifespan as compared to CR [23] and in Caenorhabditiselegans inactivation of the IGFPI3KAkt pathway promotedlongevity [24]

Upon binding to their receptors insulin and IGF-1induce a number of signalling pathways and kinases suchas the phosphatidylinositol 3-kinases class I (PI3KI) theserinethreonine kinase Akt and the mammalian target ofrapamycin (mTOR) mTOR promotes protein synthesis andcellular growth [25] Besides downregulating mTOR vialowering IGFPI3KAkt signalling CR also inhibits mTORthrough activation of the 51015840 adenosine monophosphate-activated protein kinase (AMPK) [26] Inhibition of mTORleads to prolongation of lifespan [27] which is in partmediated by autophagy a lysosomal degradation process thatdegrades no-longer-needed proteins and organelles and alsofunctions as a starvation response [28] Consistent with CRattenuating age-related changes in metabolism and cellularfunctions insulin sensitivity and autophagic activity decreasewith age while being increased by CR [29]

22 Reactive Oxygen Species and the Hormesis Effect Ageingis also characterized by accumulating oxidative damageThere are different mechanisms that lead to this build-up ofdamaged proteins lipids and organelles Damaged macro-molecules may accumulate because of reduced degradationreduced antioxidant capacity or increased reactive oxygenspecies production [30 31]

It was shown that CR can decrease the mitochondrialrelease of reactive oxygen species (ROS) which contributeto this type of damage in ageing organisms [32] However

recent studies have indicated that themetabolic rate increaseswith CR [33] and it has been hypothesized that deleterioussubstances including ROS may have beneficial effects at lowconcentrationsThis concept of a biphasic dose-responsewithlow and high doses of a substance mediating opposite effectsis referred to as hormesis [34] According to this concept lowdoses of a certain substance benefit the organism by inducingadaptive effects In line with the concept of hormesis ROSmay function as essential signalling molecules for exam-ple by regulating redox-sensitive transcription factors [35]Because of a lack of energy supply under CR mitochondrialactivity and as a consequence oxidative phosphorylation inthe respiratory chain could be enhanced leading to increasedROS production [36]

23 The Redox-Regulated Transcription Factors Nrf2 andNF120581B One of the targets of increased ROS production isthe nuclear factor-erythroid 2- (NFE2-) related factor (Nrf2)This CaprsquonrsquoCollar basic leucine zipper transcription factorcontrols the expression of a large number of antioxidant andphase II detoxifying enzymes such as theNAD(P)H dehydro-genase (quinone) 1 (NQO1) the heme oxygenase 1 (HO-1)glutathione S-transferase (GST) the glutathione peroxidase(GPx) and the 120574-glutamylcysteine synthetase (120574GCS) [37ndash39] In CR rodents upregulation and increased activity ofthese gene products have been described repeatedly [40 41]

The nuclear factor kappa B (NF120581B) is also a redox-sensitive transcription factor that induces the expression ofgenes involved in inflammation and cellular proliferation[42] Although NF120581B is activated by ROS various studieshave reported downregulation of NF120581B by CR [43 44] It hasbeen suggested that CR increases cytoplasmic levels of I120581Bwhich impedes NF120581B translocation into the nucleus Addi-tionally CR may influence NF120581B translocation by decreas-ing nucleophosmin (NPM) expression NPM is a nuclearphosphoprotein that shuttles between the nucleus and thecytoplasm and promotes NF120581B activity [45] Moreover CRmay inhibit the transcription of the NF120581B subunit RelAp65through Sirt1 activation [46] Considering that at a higher ageNF120581B activity and as a consequence inflammation seem toincrease [47] the down-regulation of NF120581B activity by CRmay contribute to the ageing-related health benefits of CR

24 Forkhead Box O Transcription Factors The forkhead boxO (FoxO) transcription factor family activates or repressesgene expression of a wide variety of genes implicated inapoptosis cell cycle and differentiation DNA repair andstress response [48 49] and is also activated by CR [50]Of the four human forkhead genes that have been identifiedso far (FoxO1 FoxO3 FoxO4 and FoxO6) FoxO3 has beenidentified as a longevity-associated gene in centenarians [51]It has been suggested that FoxO transcription factors may beinvolved in longevity because of their ability to detoxify ROSand repair DNA damage

FoxOs can be regulated by various mechanisms suchas phosphorylation acetylation and proteasomal degrada-tion While under nutrient rich conditions insulinIGF-1signalling leads to translocation of FoxO out of the nucleus










[58]












Mice(C57BL6) 10 40

Muscle fat

liver


[66]


4 15Brain liver

heart muscle


[13]



[65]




[70]






[71]



Liver Muscle

Sirt1 Sirt1 Sirt1

UCP2 FoxO


120573-cells










Glutamate

Sirt4

ADP-ribosylation



ASSIS darr




















Table4Dietary

restric

tionmim

eticsmechanism

sand

sidee

ffects

Nam

eofcom

poun

dStructureo

fcom

poun

dMechanism

ofactio

nSide

effects

References

Rapamycinsiro

limus

O

O

ON O

OH

O

H

O

O

O

OH

HO OH

O

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

H3C

H3C

Inhibitio

nof

mTo

rindu

ctionof

autoph

agy

Immun

osup

pressio

n[93]

2-Deoxy-D

-glucose

O

OH

HH

OH

OH

H

H

OH

Inhibitio

nof

glucosem

etabolism

Cardiotoxicity

[94]

Metform

inN

HN

NH

NH

NH

2

CH3

H3C

Inhibitio

nof

glucon

eogenesis

stim

ulationof

glucoseu

ptake

inhibitio

nof

AMPK

and

improvem

ento

finsulin

sensitivity

Gastro

intestinal

complaints

[95ndash97]


Table5Sirt1-ind

ucingplantb

ioactiv

esandtheldquosir

tfood

srdquothey

arefou

ndin

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Daidzein

O O

OH

OH

Soybeantofuand

othersoy

prod

ucts

[103104]

Fisetin

O O

OH

OH

OH

OH

Strawberriesapples

persim

mon

sgrapes

[15105]

Form

onon

etin

O O

OH

O

H3C

Soybean

[103]

Isoliquiritigenin

OH O

OH

OH

Soybean

shallots

andlicorice

[15106107]

Hydroxytyrosolloz

OH

OHO

H

Oliveo

il[9899]


Table5Con

tinued

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Kaem

pferol

O O

OH

OH

OH

OH

Cabb

agekale

parsleydifferent

typeso

fbeansC

orchorus

olito

riuslowastand

cruciferous

vegetables

[105108]

Piceatanno

l

OH

OHO

H

OH

Redwinegrapesand

Rhodom

yrtustom

entosa

[15109110

]

Quercetin

O O

OH

OH

OH

OH

OH

Onion

sapplesw

hitewine

capersand

Corchoruso

litoriuslowast

[15105]

Resveratrol

OH

OH

OH

Redwineredgrapes

[15109]

lowastCon

sumed

inJapanas

ldquoMolok

hekardquo

ediblep

lant

nativ

etoAsia

lozandpo

ssiblyotherp

heno

liccompo

unds

foun

din

oliveo

il








Oily fish

MediterrAsian diet

MediterrAsian diet




5 Conclusion






References



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























[58]












Mice(C57BL6) 10 40

Muscle fat

liver


[66]


4 15Brain liver

heart muscle


[13]



[65]




[70]






[71]



Liver Muscle

Sirt1 Sirt1 Sirt1

UCP2 FoxO


120573-cells










Glutamate

Sirt4

ADP-ribosylation



ASSIS darr




















Table4Dietary

restric

tionmim

eticsmechanism

sand

sidee

ffects

Nam

eofcom

poun

dStructureo

fcom

poun

dMechanism

ofactio

nSide

effects

References

Rapamycinsiro

limus

O

O

ON O

OH

O

H

O

O

O

OH

HO OH

O

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

H3C

H3C

Inhibitio

nof

mTo

rindu

ctionof

autoph

agy

Immun

osup

pressio

n[93]

2-Deoxy-D

-glucose

O

OH

HH

OH

OH

H

H

OH

Inhibitio

nof

glucosem

etabolism

Cardiotoxicity

[94]

Metform

inN

HN

NH

NH

NH

2

CH3

H3C

Inhibitio

nof

glucon

eogenesis

stim

ulationof

glucoseu

ptake

inhibitio

nof

AMPK

and

improvem

ento

finsulin

sensitivity

Gastro

intestinal

complaints

[95ndash97]


Table5Sirt1-ind

ucingplantb

ioactiv

esandtheldquosir

tfood

srdquothey

arefou

ndin

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Daidzein

O O

OH

OH

Soybeantofuand

othersoy

prod

ucts

[103104]

Fisetin

O O

OH

OH

OH

OH

Strawberriesapples

persim

mon

sgrapes

[15105]

Form

onon

etin

O O

OH

O

H3C

Soybean

[103]

Isoliquiritigenin

OH O

OH

OH

Soybean

shallots

andlicorice

[15106107]

Hydroxytyrosolloz

OH

OHO

H

Oliveo

il[9899]


Table5Con

tinued

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Kaem

pferol

O O

OH

OH

OH

OH

Cabb

agekale

parsleydifferent

typeso

fbeansC

orchorus

olito

riuslowastand

cruciferous

vegetables

[105108]

Piceatanno

l

OH

OHO

H

OH

Redwinegrapesand

Rhodom

yrtustom

entosa

[15109110

]

Quercetin

O O

OH

OH

OH

OH

OH

Onion

sapplesw

hitewine

capersand

Corchoruso

litoriuslowast

[15105]

Resveratrol

OH

OH

OH

Redwineredgrapes

[15109]

lowastCon

sumed

inJapanas

ldquoMolok

hekardquo

ediblep

lant

nativ

etoAsia

lozandpo

ssiblyotherp

heno

liccompo

unds

foun

din

oliveo

il








Oily fish

MediterrAsian diet

MediterrAsian diet




5 Conclusion






References



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Mice(C57BL6) 10 40

Muscle fat

liver


[66]


4 15Brain liver

heart muscle


[13]



[65]




[70]






[71]



Liver Muscle

Sirt1 Sirt1 Sirt1

UCP2 FoxO


120573-cells










Glutamate

Sirt4

ADP-ribosylation



ASSIS darr




















Table4Dietary

restric

tionmim

eticsmechanism

sand

sidee

ffects

Nam

eofcom

poun

dStructureo

fcom

poun

dMechanism

ofactio

nSide

effects

References

Rapamycinsiro

limus

O

O

ON O

OH

O

H

O

O

O

OH

HO OH

O

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

H3C

H3C

Inhibitio

nof

mTo

rindu

ctionof

autoph

agy

Immun

osup

pressio

n[93]

2-Deoxy-D

-glucose

O

OH

HH

OH

OH

H

H

OH

Inhibitio

nof

glucosem

etabolism

Cardiotoxicity

[94]

Metform

inN

HN

NH

NH

NH

2

CH3

H3C

Inhibitio

nof

glucon

eogenesis

stim

ulationof

glucoseu

ptake

inhibitio

nof

AMPK

and

improvem

ento

finsulin

sensitivity

Gastro

intestinal

complaints

[95ndash97]


Table5Sirt1-ind

ucingplantb

ioactiv

esandtheldquosir

tfood

srdquothey

arefou

ndin

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Daidzein

O O

OH

OH

Soybeantofuand

othersoy

prod

ucts

[103104]

Fisetin

O O

OH

OH

OH

OH

Strawberriesapples

persim

mon

sgrapes

[15105]

Form

onon

etin

O O

OH

O

H3C

Soybean

[103]

Isoliquiritigenin

OH O

OH

OH

Soybean

shallots

andlicorice

[15106107]

Hydroxytyrosolloz

OH

OHO

H

Oliveo

il[9899]


Table5Con

tinued

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Kaem

pferol

O O

OH

OH

OH

OH

Cabb

agekale

parsleydifferent

typeso

fbeansC

orchorus

olito

riuslowastand

cruciferous

vegetables

[105108]

Piceatanno

l

OH

OHO

H

OH

Redwinegrapesand

Rhodom

yrtustom

entosa

[15109110

]

Quercetin

O O

OH

OH

OH

OH

OH

Onion

sapplesw

hitewine

capersand

Corchoruso

litoriuslowast

[15105]

Resveratrol

OH

OH

OH

Redwineredgrapes

[15109]

lowastCon

sumed

inJapanas

ldquoMolok

hekardquo

ediblep

lant

nativ

etoAsia

lozandpo

ssiblyotherp

heno

liccompo

unds

foun

din

oliveo

il








Oily fish

MediterrAsian diet

MediterrAsian diet




5 Conclusion






References



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Glutamate

Sirt4

ADP-ribosylation



ASSIS darr




















Table4Dietary

restric

tionmim

eticsmechanism

sand

sidee

ffects

Nam

eofcom

poun

dStructureo

fcom

poun

dMechanism

ofactio

nSide

effects

References

Rapamycinsiro

limus

O

O

ON O

OH

O

H

O

O

O

OH

HO OH

O

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

H3C

H3C

Inhibitio

nof

mTo

rindu

ctionof

autoph

agy

Immun

osup

pressio

n[93]

2-Deoxy-D

-glucose

O

OH

HH

OH

OH

H

H

OH

Inhibitio

nof

glucosem

etabolism

Cardiotoxicity

[94]

Metform

inN

HN

NH

NH

NH

2

CH3

H3C

Inhibitio

nof

glucon

eogenesis

stim

ulationof

glucoseu

ptake

inhibitio

nof

AMPK

and

improvem

ento

finsulin

sensitivity

Gastro

intestinal

complaints

[95ndash97]


Table5Sirt1-ind

ucingplantb

ioactiv

esandtheldquosir

tfood

srdquothey

arefou

ndin

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Daidzein

O O

OH

OH

Soybeantofuand

othersoy

prod

ucts

[103104]

Fisetin

O O

OH

OH

OH

OH

Strawberriesapples

persim

mon

sgrapes

[15105]

Form

onon

etin

O O

OH

O

H3C

Soybean

[103]

Isoliquiritigenin

OH O

OH

OH

Soybean

shallots

andlicorice

[15106107]

Hydroxytyrosolloz

OH

OHO

H

Oliveo

il[9899]


Table5Con

tinued

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Kaem

pferol

O O

OH

OH

OH

OH

Cabb

agekale

parsleydifferent

typeso

fbeansC

orchorus

olito

riuslowastand

cruciferous

vegetables

[105108]

Piceatanno

l

OH

OHO

H

OH

Redwinegrapesand

Rhodom

yrtustom

entosa

[15109110

]

Quercetin

O O

OH

OH

OH

OH

OH

Onion

sapplesw

hitewine

capersand

Corchoruso

litoriuslowast

[15105]

Resveratrol

OH

OH

OH

Redwineredgrapes

[15109]

lowastCon

sumed

inJapanas

ldquoMolok

hekardquo

ediblep

lant

nativ

etoAsia

lozandpo

ssiblyotherp

heno

liccompo

unds

foun

din

oliveo

il








Oily fish

MediterrAsian diet

MediterrAsian diet




5 Conclusion






References



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























Table4Dietary

restric

tionmim

eticsmechanism

sand

sidee

ffects

Nam

eofcom

poun

dStructureo

fcom

poun

dMechanism

ofactio

nSide

effects

References

Rapamycinsiro

limus

O

O

ON O

OH

O

H

O

O

O

OH

HO OH

O

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

H3C

H3C

Inhibitio

nof

mTo

rindu

ctionof

autoph

agy

Immun

osup

pressio

n[93]

2-Deoxy-D

-glucose

O

OH

HH

OH

OH

H

H

OH

Inhibitio

nof

glucosem

etabolism

Cardiotoxicity

[94]

Metform

inN

HN

NH

NH

NH

2

CH3

H3C

Inhibitio

nof

glucon

eogenesis

stim

ulationof

glucoseu

ptake

inhibitio

nof

AMPK

and

improvem

ento

finsulin

sensitivity

Gastro

intestinal

complaints

[95ndash97]


Table5Sirt1-ind

ucingplantb

ioactiv

esandtheldquosir

tfood

srdquothey

arefou

ndin

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Daidzein

O O

OH

OH

Soybeantofuand

othersoy

prod

ucts

[103104]

Fisetin

O O

OH

OH

OH

OH

Strawberriesapples

persim

mon

sgrapes

[15105]

Form

onon

etin

O O

OH

O

H3C

Soybean

[103]

Isoliquiritigenin

OH O

OH

OH

Soybean

shallots

andlicorice

[15106107]

Hydroxytyrosolloz

OH

OHO

H

Oliveo

il[9899]


Table5Con

tinued

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Kaem

pferol

O O

OH

OH

OH

OH

Cabb

agekale

parsleydifferent

typeso

fbeansC

orchorus

olito

riuslowastand

cruciferous

vegetables

[105108]

Piceatanno

l

OH

OHO

H

OH

Redwinegrapesand

Rhodom

yrtustom

entosa

[15109110

]

Quercetin

O O

OH

OH

OH

OH

OH

Onion

sapplesw

hitewine

capersand

Corchoruso

litoriuslowast

[15105]

Resveratrol

OH

OH

OH

Redwineredgrapes

[15109]

lowastCon

sumed

inJapanas

ldquoMolok

hekardquo

ediblep

lant

nativ

etoAsia

lozandpo

ssiblyotherp

heno

liccompo

unds

foun

din

oliveo

il








Oily fish

MediterrAsian diet

MediterrAsian diet




5 Conclusion






References



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table5Sirt1-ind

ucingplantb

ioactiv

esandtheldquosir

tfood

srdquothey

arefou

ndin

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Daidzein

O O

OH

OH

Soybeantofuand

othersoy

prod

ucts

[103104]

Fisetin

O O

OH

OH

OH

OH

Strawberriesapples

persim

mon

sgrapes

[15105]

Form

onon

etin

O O

OH

O

H3C

Soybean

[103]

Isoliquiritigenin

OH O

OH

OH

Soybean

shallots

andlicorice

[15106107]

Hydroxytyrosolloz

OH

OHO

H

Oliveo

il[9899]


Table5Con

tinued

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Kaem

pferol

O O

OH

OH

OH

OH

Cabb

agekale

parsleydifferent

typeso

fbeansC

orchorus

olito

riuslowastand

cruciferous

vegetables

[105108]

Piceatanno

l

OH

OHO

H

OH

Redwinegrapesand

Rhodom

yrtustom

entosa

[15109110

]

Quercetin

O O

OH

OH

OH

OH

OH

Onion

sapplesw

hitewine

capersand

Corchoruso

litoriuslowast

[15105]

Resveratrol

OH

OH

OH

Redwineredgrapes

[15109]

lowastCon

sumed

inJapanas

ldquoMolok

hekardquo

ediblep

lant

nativ

etoAsia

lozandpo

ssiblyotherp

heno

liccompo

unds

foun

din

oliveo

il








Oily fish

MediterrAsian diet

MediterrAsian diet




5 Conclusion






References



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table5Con

tinued

Nam

eofcom

poun

dStructureo

fcom

poun

dldquoSirtfood

srdquofoun

din

References

Kaem

pferol

O O

OH

OH

OH

OH

Cabb

agekale

parsleydifferent

typeso

fbeansC

orchorus

olito

riuslowastand

cruciferous

vegetables

[105108]

Piceatanno

l

OH

OHO

H

OH

Redwinegrapesand

Rhodom

yrtustom

entosa

[15109110

]

Quercetin

O O

OH

OH

OH

OH

OH

Onion

sapplesw

hitewine

capersand

Corchoruso

litoriuslowast

[15105]

Resveratrol

OH

OH

OH

Redwineredgrapes

[15109]

lowastCon

sumed

inJapanas

ldquoMolok

hekardquo

ediblep

lant

nativ

etoAsia

lozandpo

ssiblyotherp

heno

liccompo

unds

foun

din

oliveo

il








Oily fish

MediterrAsian diet

MediterrAsian diet




5 Conclusion






References



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Oily fish

MediterrAsian diet

MediterrAsian diet




5 Conclusion






References



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article nutrition and healthy ageing: calorie ... · elegans inactivation of the igf/pik/akt...

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