The Role of Resveratrol on Aging and Physical Activity...• A wide range of health benefits have...

TheRoleofResveratrolonAgingandPhysicalActivity

RahmiErtanANLIAnkaraUniversityDep.ofFoodEngineering-TURKEY

WhyResveratrol?•  Resveratrol or trans-resveratrol (trans-3,5,4'-trihydroxystilbene) is a natural phytoalexinthatexistsinmanydifferentplants,especiallyingrapes.

•  Phytoalexins are secondary constituents against UVrays,damageandinfectionsinplants.

•  Awiderangeofhealthbenefitshavebeenreportedfor the polyphenol phytoalexin, resveratrol(trans-3,4=,5-trihydroxystilbene), present in grapes,redwine, and several other edible plants (Burns etal.2002;KalantariandDas2010).

SomeproductsareatahighlevelofResveratrol

•  Resveratrol 3,4',5-Trihydroxy-trans-stilbene, 5-[(1E)- 2-(4 Hydroxyphenyl) ethenyl] -1,3-benzenediol

Grape,redwine,peanut,vineleaf,goatearandinblueberries

Biosynthesisoftrans-Resveratrol

•  Trans-resveratrolisproducedinresponsetostressbyplants.

•  Thebiosynthesisoftrans-resveratrolcatalysesbytheenzymestilbenesynthase.

•  Phenylalanine(ammoniumlyaseofthephenylalanine)àcinnamicacid(cinnamate4hydroxylase) àp-coumaricacid(4cumratCoAlyase)P-cumrolCoA+3MalonylCoA(Stilbenesynthase)à RESVERATROL

ThehistoryofResveratrol

Resveratrolwas isolated for the first time in 1940 byJapanese scientist Michio Takaoka from whitehellebore(VeratrumgrandiflorumO.Loes).It has been isolated from Chinese and Japanesemedicine (Polygonum cuspidatum Siebold et Zucc) in1963 and has been used as a health promoting agentforhundredsofyears.However,studiesonpublichealthintheUnitedStatesin1992gainedimportancewiththebeneficialeffectofthe red wine, which is a rich source of resveratrol.Thus, theconceptofFrenchparadox (FrenchParadox)hasemergedintheworld.In the following years, there was a great interest inresveratrolinthehealthfield.

ThehistoryofResveratrolIn1976;ThediscoveryofResveratrolandrelatedinitialstudiesstartedonthegrapeleaf(Vitisvinifera)byresearchersLangcakeandPryce.LaterinJapan,toomuchresveratrolwasfoundintherootsofthemedicalplant(Polygonascapsidatum),alsoknownas'Kojo-kon‘.

•  In1992;SiemannandCreasyhaveshownforthefirsttimethatresveratrolisinwine.

FrenchParadox•  The French paradox is the observation of lowcoronary heart disease (CHD) death rates despitehigh intakeofdietarycholesterolandsaturated fat.1,2 The French paradox concept was formulated byFrench epidemiologists3 in the 1980s. France isactually a country with low CHD incidence andmortality.

•  Sincethen,resveratrolhasbeenbroadlystudiedandshowntohaveantioxidant,anti-inflammatory,anti-proliferative,andanti-angiogeniceffects,withthoseonoxidativestresspossiblybeingmostimportantandunderlyingsomeoftheothers,butmanysignalingpathwaysareamongthemoleculartargetsofresveratrol.

trans-resveratrolandcis-resveratrol

•  InnaturetherearetwoformsofResveratrol:-trans,-cis:-transformismorestableandwidespread,ispreferredinscientificstudies,andithasstrongercardio-protectiveandantioxidantproperties.

•  trans-resveratrolandcis-resveratrol

TheeffectofResveratrolonhumanhealth

ResveratrolandHealth

ResveratrolandExercise

•  Fatigue is usually classified into mental and physicalfatigue. In a fatigued status, subjects find it difficult toinitiate or sustain voluntary activities. Physical fatigue isthought to be accompanied by a deterioration in bodyfunctions[1].

•  Regular exercise training (ET) helps improve humanphysiological performance, and prevent metabolicsyndrome, heart disease, cardiovascular disease (CVD),hypertension,type2diabetes,obesity,andotherdiseasesassociatedwithaging[4–7].

•  On the other hand, the intake of natural antioxidants isassociated with low incidences of cancer, CVD, diabetes,andotherdiseasesassociatedwithaging[8].

Resveratrol-ExerciseandFatigue:InhibitoryEffectsofResveratrolTreatment

ResveratrolandExercise•  Thus, scientists have begun to explore naturalantioxidant products to reduce exercise-inducedoxidativedamageandfightagainstfatigue[9].

•  Many studies showed that resveratrol (RES)possesses various pharmacological effects, such asanti-inflammatoryproperties,antioxidantproperties,cardiovascular protection, chemoprevention ofcancer,andanti-fatigue[10–12].

ThedoseofResveratrol?

•  Theamountofresveratrolfoundinnaturalsourcesisverylow compared to thedoses inmost supplements and thedoses used in animal and human experiments versus in-take of foods naturally rich in resveratrolmay, therefore,nothavethesameeffect.

•  In human studies, doses have ranged from5mg to 5 g ofresveratrol per day,butmost commonly,dosages between30mg and 1 g per day have been used corresponding toaround0.4–14mgkg1day1.[66,67]

•  Due to large variations in design, outcomemeasures andresults from different studies, there is currentlynoconsensus regarding theoptimaldose. For comparison,dosagesofaround150mgkg1day1arecommonlyusedinrodents[68].

Effectsofresveratrolonexercisecapacity•  Based on the findings that resveratrol improvesphysical capacity [138–140] and alleviates the age-relateddecrease inphysicalper- formance[142] inmurine models, it has been hypothesized thatcombining exercise training with resveratrolsupplementation would provide a synergistic effectonphysicalcapacity[163].

•  However,whenexercisetrainingwascombinedwithresveratrolsupplementationtraining-inducedimprovementsinmaximaloxygenuptakewere50%lowercomparedtoexercisetrainingwithplacebo

•  Inaddition,capillarygrowthandVEGFproteinlevelsremainedunchangedinthegroupcombiningexercisewithresveratrolsupplementation(LasseGliemann,MichaelNyberg,YlvaHellsten,2016).

ResveratrolandExercise

•  In a scientific study on the combining Resveratrolsupplementation (RES) with Exercise training (ET) for 4weeks, the muscle strength and endurance performance ofaged mice significantly improved compared to a singleinterventionwitheitherRESorETalone(Nai-WhenKanetal.2016).

•  In this research according to physical, biochemical andpathological examinations, from non-invasive to invasivetests, their findings provide also evidence that supports theeffects of a combination ofRES supplementation andET ontheexerciseperformance(Nai-WhenKanetal.2016).

RESandexerciseperformance(Nai-WhenKanetal.2016)

Theleveloflactate(A),ammonia(B),creatinekinase(C)andglucose(D)withRES

EffectofRESsupplementationonBiochemicalassesments(A:Glukoz,B:Triglyceride,C:Totalprotein,D:Alkalinephophate,

E:bloodureanitrogen,F:creatinin

Inanothersudy:RESandExerciesonskeletalmusclemitochondrialcapacity

•  A total of 16 healthy young adults (9 males, 7 females)volunteeredforthestudy.Participantswereexcludediftheywere currently taking medications other than oralcontraceptivesoranyvitaminsupplements

•  Procedure : This was a longitudinal training study in whichparticipants performed 30 min of supervised forearm wristflexor exercises of the nondominant arm for 3 times perweekover4weeks.

•  Supplementation :Participantswere randomlyassigned inadouble-blind fashion to receive 1 pill containing 500mg ofresveratroland1pillcontaining10mgofpiperine(n=8);or2 identically appearingplacebopillscontaining flour (n=8).Participants were asked to consume the pills upon wakingeachmorning.

•  Mitochondrialcapacitymeasurements;took45minandweremadeatweeks0,2,3,and4.Mitochondrialcapacity,measuredusingnearinfraredspectroscopy(NIRS)(KristineR.Polleyetal.2015).

Researchresults:•  Allparticipantscompletedthesupplementation,exercisetraining,andtestingwithoutanyadverseevents.

•  Whencomparingtheresveratrol+piperine-trainedarmwiththeplacebo-trainedarm,thechangefrombaselinetopost-testingindicatedsignificantdifferencesbetweenthe2groups(p=0.02);theresveratrol+piperinegroupincreasedabout40%frombaseline(k=0.58),wheretheplacebogroupincreasedabout10%frombaseline(k=0.13).

•  Increasingthedosageofresveratrolgiveninthisstudyto500mg insteadof the250mggiven in thepreviousstudiesmayhave been important in inducing beneficial adaptations andincreasingmitochondrialcapacity.

Influenceofexercisetrainingwithresveratrolsupplementationonskeletalmusclemitochondrialcapacity(KristineR.Polleyetal.2015)

Resveratrolandaerobiccapacitiy(Lagougeetal.,2006)

Experimentalanimalstudy,withinvivoandex-vivoanalysis,4to8weekmaleC57B1/6Jmice,Supplementation:Intervention : Resveratrol was mixed either with powdered

choworhighfatdietComparator:HighfatdietwithoutresveratrolMeasurements : Body composition by DEXA indirect

calorimetry,locomotorfunctionbyrotarod,stringandgriptest, glucose sensitivity, endurance test by variable speedbelt treadmill and incremental speed protocol, O2consumption, histological and biochemicalanalysis,includingcitratesynthaseactivityingastrocnemiusmuscle,DNARNAanalysis,clinicalgeneticstudy

Resultsofthestudy:•  Treatment ofmicewith Resveratrol increased theiraerobic capacity, evidenced by increased runningtime and consumption of oxygen in muscle fibres,increasedPGC-1αactivity,

•  Resveratrol treatment protected mice against diet-induced-obesity and insulin resistance, SIRT1as keyregulatorofenergyandmetabolichomeostasis.

Resveratrolandaerobiccapacity

Therearealsosomestudiesindicatedthatitisineffective!

•  Scribbans, et al 2014 ; “Resveratrol supplementation doesnotaugmentperformanceadaptationsorfibre-type–specificresponsestohigh-intensityintervaltraininginhumans”

•  In this study, it was shown that combining 4weeks of highintensity interval trainingwith resveratrol (150mgday1) inyoung healthy subjects had no positive effect on traininginducedimprovementsonexercisecapacity.

•  Moreover,peakaerobicpowerwasimprovedinthegroup supplemented with placebo but not in thegroupreceivingresveratrol.Itmaybesuggestedthatresveratrol does not augment exercise traininginduced improvements in exercise endurance ormaximal aerobic capacity in healthy young or agedsubjects

ResveratrolandAging

•  Aging is closely associated with microvascular andmacro-vascular impairmentsand isaccordinglyoneofthestrongestpredictorsofcardiovasculardisease(Windeckeretal2014).

•  Amajor cause of the impaired vascular function isdysfunction of the endothelium with a consequentalteration in the formation of nitric oxide (NO) andother important vasoactive compoundsaswell as areduction in skeletalmuscle capillarization (El Assaretal2013).

•  Chronologicalageis notthesameasbiologicalage,as biological age is strongly influenced by physicalactivity and other lifestyle factors (Santos-Parker etal2014)

ResveratrolandAging

Resveratrol+ExerciseanAging??

Effectsofexercisetrainingandresveratrolonvascularhealthinaging

•  Inagedmen,8weeksofexercisetraining improvedmaximal oxygen uptake and skeletal musclecapillarisation in concurrence with increased VEGFproteinexpression(Gilemannetal.2013)

•  However,whenexercisetrainingwascombinedwithresveratrol supplementation training-inducedimprovements inmaximaloxygenuptakewere50%lower compared to exercise training with placebo(Gilemannetal.2014).

•  Inaddition,capillarygrowthandVEGFproteinlevelsremained unchanged in the group combiningexercisewithresveratrolsupplementation(Gilemannetal.2014).

Conclusion-11-A general common finding after a period ofexercise training is a reduction in plasmacholesterol and triglycerides, strong indicators ofatherosclerosisandvascularhealth.2-Animal studies so far have shown benefits ofResveratrol intake to enhance enduranceperformance in mice and suppressing the agingrelateddeclineinphysicalperformance.

3-Basic research on the metabolic level shows thatResveratrolonitsownandinconjunctionwithexercisehavea positive influence on changes associated with longerlifespanandinchronicmedicalconditions.4-However,insomestudiesonhumanhaveshownthatwhenexerciese training in aged and young subjects is combinedwith resveratrol supplementation, the lowering of plasmalipidlevelsisabrogated.5-Insomestudies,Resveratrolsupplementationalonehasnoapparent effect on total cholesterol, low density lipoproteinsortriglyceridesasevidencedinameta-analysis.

Conclusion-2

•  6-InsomeresearchesshowthatSupplementationwiththepolyphenolresveratrolhasnotbeenfoundtohavebeneficialeffectsoncardiovascularhealthfactorsinagedhumans.

•  7-Instead, resveratrol in take may,similarly toantioxidant supple-mentation, interferewith redoxdependent signaling, counter acting severalpathwaysofadaptiveresponsestoexercisetraining.

•  8-Thesereportscontradictfindingsinrodentswhereithasbeenshownthatacombinationofexerciseandresveratrolimprovestheplasmalipidprofileinagedratscomparedtoexercisealone.

THANKYOUFORYOURATTENTION

ReferencesAbdEl-MohsenM.,BayeleH.,KuhnleG.,GibsonG.,DebnamE.,KailaS.S.,Rice-EvansC.,SpencerJ.P.(2006).Distributionof[3H]trans-resveratrolinrattissuesfollowingoraladministration.Br.J.Nutr.96,62–7010.1079/BJN20061810[PubMed][CrossRef]AgoT.,MatsushimaS.,KurodaJ.,ZablockiD.,KitazonoT.,SadoshimaJ.(2010).TheNADPHoxidaseNox4andagingintheheart.Aging(AlbanyNY)2,1012–1016[PMCfreearticle][PubMed]AhmadA.,SyedF.A.,SinghS.,HadiS.M.(2005).Prooxidantactivityofresveratrolinthepresenceofcopperions:mutagenicityinplasmidDNA.Toxicol.Lett.159,1–1210.1016/j.toxlet.2005.04.001[PubMed][CrossRef]AhmadK.A.,ClementM.V.,PervaizS.(2003).Pro-oxidantactivityoflowdosesofresveratrolinhibitshydrogenperoxide-inducedapoptosis.Ann.N.Y.Acad.Sci.1010,365–37310.1196/annals.1299.067[PubMed][CrossRef]AlmeidaL.,Vaz-da-SilvaM.,FalcaoA.,SoaresE.,CostaR.,LoureiroA.I.,Fernandes-LopesC.,RochaJ.F.,NunesT.,WrightL.,Soares-da-SilvaP.(2009).Pharmacokineticandsafetyprofileoftrans-resveratrolinarisingmultiple-dosestudyinhealthyvolunteers.Mol.Nutr.FoodRes.

M.G.Novelle,D.Wahl,C.Diéguez,M.Bernier,R.deCabo,Resveratrolsup-plementation:wherearewenowandwhereshouldwego?AgeingRes.Rev.21(2015)1–15,http://dx.doi.org/10.1016/j.arr.2015.01.002.M.M.Poulsen,J.O.L.Jørgensen,N.Jessen,B.Richelsen,S.B.Pedersen,Re-sveratrolinmetabolichealth:anoverviewofthecurrentevidenceandperspectives,Ann.N.Y.Acad.Sci.1290(2013)74–82,http://dx.doi.org/10.1111/nyas.12141.O.Vang,N.Ahmad,C.A.Baile,J.A.Baur,K.Brown,A.Csiszar,etal.,Whatisnewforanoldmolecule?Systematicreviewandrecommendationsontheuseofresveratrol,PLoSOne6(2011)e19881,http://dx.doi.org/10.1371/journal.pone.0019881.

D.Taubert,R.Berkels,UpregulationandactivationofeNOSbyresveratrol,Circulation107(2003)e78–e79.M.Lagouge,C.Argmann,Z.Gerhart-Hines,H.Meziane,C.Lerin,F.Daussin,etal.,ResveratrolimprovesmitochondrialfunctionandprotectsagainstmetabolicdiseasebyactivatingSIRT1andPGC-1α,Cell127(2006)1109–1122,http://dx.doi.org/10.1016/j.cell.2006.11.013.V.W.Dolinsky,K.E.Jones,R.S.Sidhu,M.Haykowsky,M.P.Czubryt,T.Gordon,etal.,Improvementsinskeletalmusclestrengthandcardiacfunctionin-ducedbyresveratrolduringexercisetrainingcontributetoenhancedex-erciseperformanceinrats,J.Physiol.590(2012)2783–2799,http://dx.doi.org/10.1113/jphysiol.2012.230490.R.S.Matos,L.A.V.Baroncini,L.B.Précoma,G.Winter,P.H.Lambach,E.Y.Caron,etal.,Resveratrolcausesantiatherogeniceffectsinananimalmodelofatherosclerosis,Arq.Bras.Cardiol.98(2012)136–142.

Kuo,S.M.Dietaryflavonoidandcancerprevention:Evidenceandpotentialmechanism.Crit.Rev.Oncog.1997,8,47–69.Huang,C.C.;Hsu,M.C.;Huang,W.C.;Yang,H.R.;Hou,C.C.Triterpenoid-richextractfromAntrodiacamphorataimprovesphysicalfatigueandexerciseperformanceinmice.Evid.BasedComplement.Altern.Med.2012Olas,B.;Wachowicz,B.ResveratrolandvitaminCasantioxidantsinbloodplatelets.Thromb.Res.2002,106,143–148.Liu,J.C.;Chen,J.J.;Chan,P.;Cheng,C.F.;Cheng,T.H.Inhibitionofcyclicstrain-inducedendothelin-1geneexpressionbyresveratrol.Hypertension2003,42,1198–1205.Wu,R.E.;Huang,W.C.;Liao,C.C.;Chang,Y.K.;Kan,N.W.;Huang,C.C.Resveratrolprotectsagainstphysicalfatigueandimprovesexerciseperformanceinmice.Molecules2013,18,4689–4702.

S.Windecker,F.Alfonso,J.-P.Collet,J.Cremer,V.Falk,G.Filippatos,etal.,ESC/EACTSGuidelinesonmyocardialrevascularization:theTaskForceonMyocardialRevascularizationoftheEuropeanSocietyofCardiology(ESC)andtheEuropeanAssociationforCardio-ThoracicSurgery(EACTS).Devel-opedwiththespecialcontributionoftheEuropeanAssociationofPercuta-neousCardiovascularInterventions(EAPCI),Eur.J.Cardiothorac.Surg.46(2014)(2014)517–592,http://dx.doi.org/10.1093/ejcts/ezu366.

M.ElAssar,J.Angulo,L.Rodríguez-Mañas,Oxidativestressandvascularinflammationinaging,FreeRadic.Biol.Med.65(2013)380–401,http://dx.doi.org/10.1016/j.freeradbiomed.2013.07.003.J.R.Santos-Parker,T.J.LaRocca,D.R.Seals,Aerobicexerciseandotherhealthylifestylefactorsthatinfluencevascularaging,Adv.Physiol.Educ.38(2014)296–307,http://dx.doi.org/10.1152/advan.00088.2014.

L.Gliemann,J.F.Schmidt,J.Olesen,R.S.Biensø,S.L.Peronard,S.U.Grandjean,etal.,Resveratrolbluntsthepositiveeffectsofexercisetrainingoncardio-vascularhealthinagedmen,J.Physiol.591(2013)5047–5059.L.Gliemann,J.Olesen,R.S.Biensø,R.S.Biensø,J.Schmidt,J.F.Schmidt,etal.,Resveratrolmodulatestheangiogenicresponsetoexercisetraininginske-letalmusclesofagedmen,Am.J.Physiol.HeartCirc.Physiol.307(2014)