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INTRODUCTIE Naasttoeval,gedragenomgevingbepalenerfelijkefactorendelengteenkwaliteitvanhet menselijkleven.Insommigefamiliesbereikenopvallendveelmenseneenhogeleeftijd (‘langlevendheid’)enkinderenvanlanglevendeoudershebbenzelfeengroterekans gezondoudtewordendanhungeneratiegenoten.Kennisoverdeerfelijkefactorendie langlevendheidbeïnvloedenkanbijdragenaanhetontwikkelenvanmethodenvoorhet bereikenvaneenhogeleeftijdingoedegezondheid.Tothedenisonbekendwelkegenen bijdragentotgezondelanglevendheidindemens. Hetgrootstegedeeltevanheterfelijkmateriaalisvooriederindividuhetzelfdeen verklaartdegrotegelijkenistussenmenseninvergelijkingmetanderesoorten.Maar tussenindividuenisongeveer1opde300basenparenverschillend,oftewelpolymorf. Dezepolymorfismenverklarenwaaromindividuenverschillendzijnenkunnenworden gebruiktomdefunctievandeverschillendegenenteachterhalenenhunrolinhet bepalenvanuiterlijkekenmerkenenziekte,maarookvanlevensduurengezondheid. Iedergenisinprincipekandidaatomdelengteenkwaliteitvanleventebeïnvloeden, maarhetbestuderenvanallevijfentwinitigduizendhumanegenenisvooralsnogte tijdrovendenteduur.Identificatievanspecifiekekandidaatgenenisefficiënter. Indiermodellenwordtveelonderzoekgedaannaardebiologischemechanismendie levensduurbepalen.Dezebiologischemechanismenzijngedurendedeevolutie geconserveerdgeblevenenkomenookbijanderesoorten,waaronderdemens,voor.Het doelvanditproefschriftishetidentificerenvanmenselijkekandidaatgenenvoor langlevendheid,doorhetvertalenvanwetenschappelijkeresultatenverkregenin diermodellen.DezekandidaatgenenwerdenvervolgensbestudeerdindeLeiden85plus Studie.AandezestudienamenbijnaalleLeidenarendeeldietussen1997en1999de leeftijdvan85bereikten.Vanhenwerdop85jarigeleeftijdDNAenbloedmonsters afgenomen,endaarnawerdjaarlijksvervolgdmetbetrekkingtothundagelijks functioneren,cognitie,ziekteensterfte. Hetonderzoekbeschreveninditproefschriftwerduitgevoerdinhetkadervaneen InnovativeOrientedResearchProgram(IOP),waarinbiologen,geneticienartsensamen opzoekgingennaarerfelijkefactorendielevensduurbeïnvloeden.Hetonderzoekwerd geiniancierddoorhetMinisterievanEconomischezakeneneenaantalindustriële
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partners,metalsdoelsamenwerkingtebewerkstelligentussenacademieenindustrieen hetgenererenvankennisdieeconomischtegeldekanwordengemaakt. INHOUD DerondwormCenorhabditiseleganswordtveelbestudeerdinhetonderzoeknaar erfelijkedeterminantenvanlanglevendheid.Dewormdoorloopteengoedomschreven ontwikkelingenisuitermatetoegankelijkvoorwetenschappelijkeexperimentenzoalshet stilleggenofmodificerenvancompletegenen,ietsdatbijdemensethischgezien onmogelijkis.Ondernormaleomstandighedenontwikkeltdewormzichviavierlarvale stadiaineenvolwassene.Onderongunstigeomstandigheden(voedseltekort,ongunstige temperatuur)kandewormeenalternatievelarvalevormaannemen,dedauerdiapause, waarindewormnieteet,nauwelijksbeweegt,nietvoortplantenzeerongevoeligisvoor schadelijkefactorenuitdeomgeving.Indezeperiodelijktdewormnietteverouderen, wantalsdeomstandighedenweergunstigwordenhervatdewormzijnnormale ontwikkelingenwordteenvolwassenemeteennormalelevensduurbovenopdeperiode dieinduaerdiapauseisdoorgebracht.InC.eleganszijnveelmutatiesingenen beschrevendiedelevensduurvandevolwassenwormkunnenverlengentotvijfmaalde normalelevensduur,voornamelijkdoorhetbeïnvloedenvandedauerfase(derhalve“daf” genengenaamd). DAF12iseengeninderondwormdatfunctioneertophetkruispuntvanvelesignaal systemenendezeintegreerttoteenbeslissingomaldannietindauerfasetegaan. MenselijkegenendielijkenopDAF12zijndusbelangrijkekandidatenomookindemens levensduurtebeïnvloeden.Inhoofdstuk2identificerenwemenselijkegenendielijkenop DAF12.Hetdaf12gencodeertvooreenNucleaireHormoonReceptor(NHR)enbehoort toteensuperfamilievanNHR’sisdiebijallesoortenvoorkomen,waaronderdemens. DoordevolgordevanaminozurentevergelijkewaaruitdezeNHR’szijnopgebouwd, ontdektenwedatindemensdeLeverXReceptorenalfaenbètahetmeestlijkenopC. elegansDAF12,gevolgddoordePregnaanXReceptor,deVitamineDReceptor,de ConstitutieveAndrostaanReceptorendeFarnesoidXReceptor.Hunbiologischefunctie omvatten,onderandere,detoxificatieenimmunomodulatie.Ditzijnbeidebelangrijke processenbijhetbeschermenvanhetlichaamtegenschadelijkeinvloedenvanbuitenaf. OpvallenderwijshebbenallehumaneNHR’seencholesterolproductalsactivatorof suppressor.DerhalveconcludeerdenwedathetDAF12systeemgedurendedeevolutie ookfunctioneelgeconserveerdlijktendatdehumaneNHR’sbetrokkenzijninkritieke processenvoorhetmenselijklichaam.GenetischevariatieindezeNHR’szijndus belangrijkekandidatenomlanglevendheidtebeïnvloeden.
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DeVitamineDReceptor(VDR)iseenvandemenselijkeiwittendieopDAF12lijken. VitamineDisindemens,onderandere,betrokkenbijhetfunctionerenvanhetbrein.In hoofdstuk3bestudeerdenweofgenetischevariatieindeVDRgeassocieerdismet cognitievefunctieendepressievesymptomenophogeleeftijd.Vijfpolymorfismen,te wetenCdx2,FokI,BsmI,ApaIandTaqI,waarvandelaatstedriesameneen geconserveerderegiomarkeren(eenhaplotypeblok),werdenbepaaldinalledeelnemers vandeLeiden85plusStudie.Hetbleekdatdragersvanhaplotype2eenslechtere cognitievefunctiehadden,terwijlhaplotype1juistassocieerdemeteenbeterecognitieve functieenminderdepressievesymptomen.Dezeassociatieskondennietworden verklaarddoorverschillenincalciumniveausofsterfte,omdatdepolymorfismendaarmee nietassocieerden.DezeresultatenlietenziendatgenetischevariatieindeVDRinvloed heeftopdevatbaarheidvoorleeftijdsafhankelijkeveranderingenzoalscognitief functionerenendepressievesymptomen. Inhoofdstuk4onderzochtenweofgenetischevariatieindeLeverXReceptoralfa(LXRD) associeertmetlanglevendheid.DeLXRDishetmenselijkeeiwitdathetmeestlijktopC. elegansDAF12.IndeelnemersvandeLeiden85plusStudiebepaaldenwevier polymorfismen,diesamenviergangbarehaplotypesmarkeren.Hetbleekdathaplotype2 associeerdemeteen22%verminderdmortaliteitsrisicoindezevenjaarnahetbeginvan destudie.Ditwerdvoornamelijkveroorzaaktdooreen69%verminderdrisicoop overlijdenaaninfectieziekten.Bovendienassocieerdehaplotype2ookmeteenhoger plasmaniveauvanapolipoproteineE,eeneiwitwaarvandeproductiewordtgereguleerd doorLXRD,enhogereniveausvantriglyceriden.Concluderend,genetischevariatieinhet gendatcodeertvoordeLXRDassocieertmetlanglevendheid. EenvandegenenwaarvandefunctiewordtbeïnvloeddoordeLXRDisapolipoproteineE (apoE).DriestructurelevariantenvanapoE(apoE2,E3,andE4)wordengecodeerddoor driegenetischevarianten(resp.2,3en4)enbehorentotdemeestbestudeerde polymorfismenindemens.ApoE4associeertmeteenslechterecognitievefunctieeneen verhoogdekansopcardiovasculairemortaliteit.Opvallendisdater,integenstellingtot overdestructurelevariatie,overdeinvloedvandekwantiteitvanapoEweinigbekendis. Indehoofdstukken5,6en7bestuderenwederolvanplasmaniveausvanapoEin respectievelijkcardiovasculairemortaliteit,cognitieffunctioneren,enhetoptredenvan herseninfarcten.HiertoebepaaldenweinalledeelnemersvandeLeiden85plusStudieop 85jarigeleeftijdhetAPOEgenotype,hetapoEplasmaniveauenvervolgdevervolgensde genoemdeeindpunten.
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Inhoofdstuk5beschrijvenwedatdeelnemersmethogeplasmaapoEniveauseen2.08 maalzohoogsterfterisicohebbendandeelnemersmetlageapoEniveaus.Onderde deelnemersdiehet33genotypedroegen,washetrisicoopcardiovasculairesterfte3.01 maalverhoogd.Anderesterfteoorzakenwarennietverhoogd.HogeapoEniveauswaren geassocieerdmethoogtotaalcholesterol,LDLcholesterolentriglyceridenenmetlage HDLcholesterolniveaus,maardezeassociatiekonhetverbandtussenhogeapoEniveaus encardiovasculairesterftenietverklaren.Hetrisicoopcardiovasculairesterftewashet sterkstindedeelnemersmeteenlaagniveauvanhetCreactiveprotein(CRP),een ontstekingsparameterenbekenderisicoindicatorvanhartenvaatziekten.Bovendien wasindeelnemersmeteenlaagCRPaanhetbeginvandestudie,detoenameinCRP tijdensdefollowuphethoogstindedeelnemersmethogeplasmaapoEniveaus. Concluderend,ophogeleeftijdgaateenhoogapoEniveauvoorafaaneenhoogCRP niveauenassocieertsterkmeteentoegenomenrisicoopcardiovasculairesterfte. Inhoofdstuk6bestudeerdenwevaniederedeelnemervanafdeleeftijdvan85jaaren daarnaiederjaardecognitievefunctie.Ditgebeurdeaandehandvaneen gestandaardiseerdecognitievetestbatterij,waarvandeMiniMentalStateExamination (MMSE)debekendsteis.Onderdragersvanhet33genotypeassocieerdeeenhoog plasmaapoEniveaumeteenslechterecognitieveopalletesten.Klassiekecardiovasculaire risicofactorenkondendezeassociatiesnietverklaren.Eenanderemogelijkeverklaring werdgezochtinhetrisicoophetkrijgenvanherseninfarcten.Inhoofdstuk7 observeerdenwedatdeelnemersmeteenhoogapoEniveaubijaanvangvandestudie een1.47maalhogerekanshaddenophethebbenvaneenherseninfarctinde voorgeschiedenis.GedurendedefollowupwarenhogeplasmaapoEniveausgeassocieerd meteenhogerekansophetkrijgenvaneenherseninfarct.Hetverhoogderisicoop herseninfarctendateveneensgepaardgingmethogeplasmaniveausvanapoEkonde associatiemetlagerecognitienietverklaren. EenandergendatonderinvloedstaatvanLXRDisapolipoproteineCI(apoCI).ApoCI maaktonderdeeluitvanvoornamelijkHDLdeeltjes,eninmuizenbeschermthettegen sterftedoorernstigeontstekingen.Inhoofdstuk8onderzochtenweofhogeplasma niveausvanapoCIookinmensenbeschermendwerkentegensterfteaaninfectieziekten indeLeiden85plusStudie.HetbleekdathethebbenvanhogeplasmaapoCIniveaus associeerdemeteen40%reductieinsterfteaaninfectieziekten,onafhankelijkvanandere lipidenparameters,zoalsHDLcholesterol.Concluderend,hogewaardesvanapoCIlijken ookindemenstebeschermentegensterfteaaninfectieziektenophogeleeftijd.
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Inhoofdstuk9beschouwenwedegenendieevolutionairgeconserveerdzijnendie betrokkenzijninderegulatievanlanglevendheidindiermodellenenbestudeerdzijninde mens.Biologischemechanismendietotdusverzijngeïdentificeerdspeleneenrolin stofwisselingeninonderhoudenreparatiemechanismen,diedeleeftijdsgerelateerde ophopingvanschadebeperken.Deliteratuurbeschouwendkangeconcludeerdworden datmethetcomplexerwordenvandesoorteninhetverloopvandeevolutie,ookhet genetischmateriaalcomplexerisgeworden.Waarbijvoorbeeldindewormslechtseen geneenbepaaldefunctievervult,zijndaterindemenssomsvier.Ditresulteerterindat genetischevariatieineenvandieviergenenmindergroteinvloedenzalhebbenop langlevendheiddangenetischevariatieinhetoorspronkelijkegen.Eenanderefactordie hetvertalenvanresultatenvandiernaarmensbemoeilijktisdeomgeving.Defunctievan hetgenoomiskritischafhankelijkvandeomgevingwaarinhetzichbevindt.Deomgeving waarinsommigevanonzevoorouderszijngeselecteerdistotaalandersdanonzehuidige omgeving.Enzelfsonzeomgevingvannuisnietdezelfdeals100jaargeleden.Ditzorgt ervoordatresultatenverkregenindiermodellenonderlaboratoriumomstandighedenniet altijdhetzelfderesultaatopleverenalsdeobservationelestudieindemens.Tenslotte,de methodendieonsterbeschikkingstaanomgenetischevariatietebestuderenindemens zijnvooralsnogbeperkt,duurentijdrovend.Concluderendkangezegdwordendat, hoewelhetbestuderenvandiermodelleneenaantalmogelijkekandidaatgenenheeft opgeleverd,hetonduidelijkblijftinwelkematezijlanglevendheidindemenselijke populatiebepalen.
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SCIENTIFICPUBLICATIONS BosmaGP,HuizingaTW,MooijaartSP,vanBuchemMA.Abnormalbraindiffusivityin patientswithneuropsychiatricsystemiclupuserythematosus. AJNRAmJNeuroradiol.2003;24:850854. MooijaartSP,vanHeemstD,SchreuderJ,vanGerwenS,BeekmanM,BrandtBW, SlagboomPE,WestendorpRG;LongLifestudygroup.VariationintheSHC1geneand longevityinhumans. ExpGerontol.2004;39:263268. vanHeemstD,MooijaartSP,BeekmanM,SchreuderJ,deCraenAJ,BrandtBW,Slagboom PE,WestendorpRG;LongLifestudygroup.VariationinthehumanTP53geneaffectsold agesurvivalandcancermortality. ExpGerontol.2005;40:1115. vanHeemstD,BeekmanM,MooijaartSP,HeijmansBT,BrandtBW,ZwaanBJ,Slagboom PE,WestendorpRG.Reducedinsulin/IGF1signalingandhumanlongevity. AgingCell.2005;4:7985. MooijaartSP,BrandtBW,BaldalEA,PijpeJ,KuningasM,BeekmanM,ZwaanBJ,Slagboom PE,WestendorpRG,vanHeemstD.C.elegansDAF12,NuclearHormoneReceptorsand humanlongevityanddiseaseatoldage. AgeingResRev.2005;4:351371. MooijaartSP,GusseklooJ,FrolichM,JollesJ,StottDJ,WestendorpRG,deCraenAJ. Homocysteine,vitaminB12,andfolicacidandtheriskofcognitivedeclineinoldage:the Leiden85PlusStudy. AmJClinNutr.2005Oct;82(4):86671. KuningasM,MooijaartSP,SlagboomPE,WestendorpRG,vanHeemstD.Geneticvariants intheglucocorticoidreceptorgene(NR3C1)andcardiovasculardiseaserisk.TheLeiden 85plusStudy. Biogerontology.2006May5 MooijaartSP,BerbeeJF,vanHeemstD,HavekesLM,deCraenAJ,SlagboomPE,Rensen PC,WestendorpRG.ApoEPlasmaLevelsandRiskofCardiovascularMortalityinOldAge. PLoSMed.2006May9;3(6):e176 MooijaartSP,KuningasM,WestendorpRG,HouwingDuistermaatJJ,SlagboomPE, RensenPC,vanHeemstD.LiverXreceptoralphaassociateswithhumanlifespan. JGerontolABiolSciMedSci.2007Apr;62(4):3439
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vanVlietP,MooijaartSP,deCraenAJ,RensenPC,vanHeemstD,WestendorpRG.Plasma levelsofapolipoproteinEandriskofstrokeinoldage. AnnNYAcadSci.2007Apr;1100:1407 MooijaartSP*,vanVlietP*,vanHeemstD,RensenPC,BerbeeJF,JollesJ,deCraenAJ, WestendorpRG.PlasmalevelsofapolipoproteinEandcognitivefunctioninoldage. AnnNYAcadSci.2007Apr;1100:14861 *theseauthorscontributedequallytothiswork MooijaartSP.Gunstigercardiovasculairrisicoprofielbijkinderenvanlanglevendeouders. NedTijdschrGeneeskd.200729september;151(39) MooijaartSP,KoeijvoetsKMC,SijbrandsEJG,DahaMR;WestendorpRGJ.Complement FactorHpolymorphismY402Hassociateswithvisualacuityandcardiovascularmortalityin theelderlypopulationatlarge. ExperimentalGerontology,42 (2007) 1116–1122 KuningasM,MooijaartSP,JollesJ,SlagboomPE,WestendorpRGJ,vanHeemstD.VDR genevariantsassociatewithcognitivefunctionanddepressivesymptomsinoldage. NeurobiologyofAgeing,inpress,doi:10.1016/j.neurobiolaging.2007.07.001 BerbeeJFP,MooijaartSP,deCraenAJM,HavekesLM,vanHeemstD,RensenPCN,and WestendorpRGJ.PlasmaApolipoproteinCIProtectsagainstMortalityfromInfectionin OldAge. JGerontolABiolSciMedSci.,inpress OTHERPUBLICATIONS MooijaartS.Scientistsandsocieties.Younggenomicistsgetconnected. Nature.2004;429:226
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DANKWOORD Onderzoekisnietmogelijkzondermensendiezichlatenonderzoeken.Mijndankgaatdus ineersteinstantieuitnaardedeelnemersvandeLeiden85plusStudie.Eendeelvanhen hebikmogenontmoetenenonderzoekenendezeontmoetingenhebbenvoormijkleur gegevenaanhetonderzoekenmijwarmgemaaktvoorhetvakOuderengeneeskunde. VelemensenwarenbetrokkenbijdeopzetenuitvoeringvandeLeiden85plusStudie, ookvoormijnkomstnaardeafdeling.Henbenikzeerdankbaar. Mijncollega’sopdeafdelingOuderengeneeskundeendaarbuitendankikvoordeplezierig werkomgevingeninspirerendesamenwerking. HetonderzoekinditproefschriftwerduitgevoerdonderdevlagvanhetIOPproject “geneticdeterminantsoflongevityanddiseaseatoldage”.Hierinwerktenbiologen, geneticiendokterssamenomhetgeheimvaneengezondeoudedagteontrafelenin fruitvlieg,vlinderenmens.Eeninteressantemixvanmensenuitverschillende wetenschappelijkewereldenmetveleinteressantediscussiesensamenwerkingenals gevolg.Iedereendiedaaraanbijdroegwilikhartelijkdanken.
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CVOFTHEAUTHOR TheauthorwasborninOegstgeestonJanuary13th1974.In1992hegraduatedfromthe StedelijkGymnasiuminLeiden.IntheseyearshestudiedMedicineattheRijksUniversitair CentrumAntwerpen(RUCA),inAntwerpenBelgiumandBiomedicalSciencesattheLeiden UniversityMedicalCenter(LUMC).In1994hestartedhisMedicaleducationattheLUMC, duringwhichhewasactivelyinvolvedintheorganizationoftheeducationalsystem.In 1997hepostponedhisstudyforayeartobethe"studentassessor"totheboardof directorsoftheLeidenUniversityMedicalCenter.InApril2002hereceivedhisMD degree. InthesameyearhegotapositionasaPhDattheDepartmentofGerontologyand GeriatricsattheLUMC(head:Prof.dr.R.G.J.Westendorp).Thepositionwasembedded withinanInnovationOrientedResearchProgram(IOP)entitled"Thegenetic determinationoflongevityanddiseaseatoldage"inwhichbiologists,geneticistsand physicianscollaborated.Thepresentthesisfocusesonthehumanbranchofthisproject. DuringthisperiodtheauthorwascofounderandchairmanoftheGenomicsNetworkfor YoungScientists(GeNeYouS). SinceMay2006theauthorisintrainingtobecomeaspecialistinInternalMedicineinthe LUMC(Prof.dr.J.A.Romijn).ThetrainingstartedintheRijnlandZiekenhuis,Leiderdorp (Dr.F.H.M.Cluitmans).InSeptember2008,hewillreturntotheLUMCtocontinuehis education. TheauthorlivestogetherwithhisgirlfriendFemkePetersandtheirsonsKasper(2003) andWiebe(2007).
