Table Of Content

ANNUAL REPORT OF THE OFFICE OF SCIENTIFIC DIRECTOR NATIONAL INSTITUTE ON AGING / Annual Report of the Office of Scientific Director National Institute on Aging TheScientificDirectoroftheNIAisresponsiblefortheoveralldirectionandqualityofresearch conductedbytheIntramuralResearchProgram(IRP) whichincludesninelaboratoriesand branchesinBaltimoreandtheLaboratoryofNeuroscienceslocatedintheNIHClinicalCenterin Bethesda.TheOfficeoftheScientificDirectoroverseesthecentraladministrativeandsupport activitiesnecessaryforthesuccessfuloperationoftheIntra-muralProgram.Theseactivitiesare carriedoutbytheAdministrative,Procurement,andInformationOffices,andtheintramural programPersonnelOffice. FiscalYear1994featuredanumberofchangesinkeystaff.Dr.GuntherL.Eichhom,chief, LaboratoryofCellularandMolecularBiologyretiredafteradistinguishedcareerspanning39 years,includingservingasNIAactingscientificdirectorin 1988. Anotherkeyplayersupportingresearch,Mr.PhillipThorne,chiefoftheResearchResources Branch,retiredalsoalongwithtwootherimportantbranchstaff,Thesedepartureshave necessitatedanevaluationoftheresourcesavailableandfuturedirectionsforthisimportantIRP supportunit. Ms. BerthaVoelker,administrativeofficer,withover30yearsofadministrativeexperienceatthe Center,retiredinDecember 1993.Afteranextensivesearch,Ms. EliseKreisswas selectedtofill thispositionandjoinedtheIRPinAugustof1994. Ms.KreissbringsimpressiveNIH administrativeandbudgetaryexperiencetohernewposition. Intheresearcharena,theyearprovedaproductiveonefortheIntramuralResearchProgram. Selectedhighlightsfromthelaboratoriesandbranchesfollow. Basic Sciences • GADD153 Activation Pathway ScientistsintheGeneExpressionandAgingSectionareusingthegrowtharrestandDNA induciblegene,GADD153,toinvestigatesignaltransductionpathwaysoperatingtoregulategene expressionfollowingDNAdamage.Evidencehasbeenfoundinthislaboratoryindicatingthat GADD153isactivatedthroughap53-independentpathwaywhichdoesnotrequireactivationof tyrosinekinasesandisindependentofc-rasandc-rafactivation.However,otherrecentstudies suggestthatanalternativepathwaydependentonp53alsocouldcontributetoGADD153induction DNA inresponseto damage. • DNA Repair in Cancer and Aging DifferentmodelsystemsandapproacheshavebeenusedtoexplainDNArepairchangesthat occurincancerandsenescence.OnesystemusedbyLaboratoryofMolecularGenetics(LMG) scientistsisthatoftelomericDNA.Telomeresaretheendregionsofchromosomesandarecritical forthemaintenanceofgenomicstability. Itappearsthattelomeresdecreasewithaging.Thisyeara protocolwasdevelopedtomeasureDNAdamageandrepairintelomeres.Thereislessrepairin DNA oldthaninyoungtelomeres.Persistenceoftelomeric couldbeanalternativeexplanationfor telomericshortening. • Cardiovascular Gene Therapy Genetherapyhasgreatpotentialforitspossibleclinicalapplicationsandasatooltolearnmore aboutbasicbiologicalevents.Adenovirusvectorshavebeenusedsuccessfullyforgenetransferin vivoandlookpromisingfortreatingcardiovasculardisorders. ResearchersintheLaboratoryof CardiovascularSciencehaveengineeredreplication-deficientrecombinantadenovirusvectors carryingthecDNAforVascularEndothelialGrowthFactor(VEGF),foracidicFibroblastGrowth Factor(aFGF),andforarecombinantformofaFGFmodifiedbytheadditionofthesignal sequenceforsecretionfromFGF-4.Theseviralvectorscauseendothelialcellproliferation, modulateendothelialcellproliferationintocapillary-likestructuresinvitro, andinduce angiogenesisinamousemodelinvivo.Thescientistsnextplantoengineeradditionaladenovirus vectorswhichmaycauseangiogenesisandinhibitrestenosisaftervascularinjury. • Degenerative Cartilage Disease Therapies Osteoarthritis(OA)andAlzheimer'sdisease(AD)aredegenerativediseasesafflictingmillions ofolderpeople. Bothdiseasesinvolvelossofcellsrequiredforthemaintenanceandfunctionof tissuestheyareassociatedwith,cartilageandthecentralnervoussystem,respectively.Cell BiologyUnitresearchersaretestingthehypothesisthatthiscelllossisduetoprogrammedcell death(apoptosis).Thisyear,theyusedtheTUNELtechniquetolabelnucleicontainingfragmented DNAandfoundthatthelevelofapoptosisinADbrainswaselevatedincomparisontoage- matchedcontrolbrains.ThiswasmostpronouncedintheCA-1 regionofthehippocampus. Evidencealsohasbeenobtainedshowingthat,atleastinvitro,chondrocytesdiebyapoptosisin responsetoconflictinggrowthsignals. Researchersarenowtestingaratmodelofage-associated cartilagedegenerationtodeterminetheincidenceofapoptosisinthistissuewithageanddisease. • Oxidative DNA Damage and Repair OxidativeDNAdamageisveryrelevanttoagingsinceitisamainproductofmetabolic processesincells,andthisdamagedoesaccumulatewithaging.Thisaccumulationismost establishedformitochondrialDNA.TheDNAdamagethatmayaccumulatesinregionssuchas mitochondrialDNAmayleadtoariseinmutationsgeneinactivation,ortodeletionscommonly foundincancerandaging.LaboratoryofMolecularGeneticsresearchershavedevelopeda techniquewhichallowsthemtomeasuretheformationofanimportantoxidativeDNAlesion,8- OHguanosine,atthelevelofindividualgenes.Efficientrepairofthislesionwasfoundinboth nuclearandmitochondrialDNA.ltwaspreviouslythoughtnoDNArepairtookplacein mitochondria,butthisfindingopensamultitudeofperspectives.Nextthesescientistswill determinewhetherthemechanismofrepairinmitochondriadiffersfromthatinthenucleus, whethermitochondrialDNArepairdeclineswithage,andiflocalDNArepairdefectsin DNA mitochondriamightleadto deletions. • Caloric Restriction and Primate Aging ResearchersintheMolecularPhysiologyandGeneticsSectionfoundthatbothfastinglevels andpeakglucoselevelsinaglucosetolerancetestarereducedincaloricrestrictedrhesusmonkeys. Thus,withthedelayedmaturationandreducedbodysizereportedpreviously,itseemsthatcaloric restrictionexertsmanyeffectsinprimateswhichparallelthoseseeninrodents. Othereffectsseen whichagreewiththosenotedinrodentsareadecreaseinIGF-1 levelsandapossiblereductionin thenormalage-associatedincreaseintheskincollagenpentosidine,anindexofglycation. Pentosidineaccumulationappearstobeproportionaltothemaximallifespanofthespecies examined.Itoccurstwiceasfastinsquirrelmonkeysasintherhesus. Othercaloricrestriction effectsincludeincreasedactivitylevelsofyoungrhesusduringdaylighthoursandapossible decreaseinfibroblastclonalefficiency. • Enhancing Memory for Maze Learning IncollaborationwithanNIDAscientist,LaboratoryofCellularandMolecularBiologystaff NMDA foundthatthepolyamine,spermidine,potentiatestheantagonisticeffectsofthe channel blocker,dizocilpine,onthemazelearningperformanceofyoungratswhenbothweregiven NMDA systematically.Thisdemonstratesthatsignaltransductionthroughthe receptorcanbe augmentedbydrugsactingatthepolyaminesite. Studiesarenowunderwaytoevaluatewhether spermidinetreatmentscanimprovelearningperformanceinagedrats,but notablesideeffects requireasubstantialdosagereduction. Clinical Studies • Arecoline Improves Memory in DAT Patients Ninepatientswithmild-to-moderateDATreceivedarecolinebycontinuous,escalating intravenousinfusionforabouttwoweeksinaLaboratoryofNeurosciencesstudy.Anoptimal dosewasthengivencontinuouslyforfivedaysusingaplacebo-controlled,randomized,double- blind,crossoverdesign.Theresearchersfoundthatlong-termrecallincreasedduringdose-finding acrosssubjects,withaU-shapedrelationtodose. MeasurementsweremadeusingtheBuschke SelectingRemindingtest.Long-termrecallimprovedforfiveofsixinitialresponders(mean increasesixwords)duringre-infusionatanoptimaldose. Nosideeffectswerenoted.Thus, duringreinfusionofarecoline,withindividualdoseoptimization,verbalmemoryisselectively improvedinthemajorityofpatientswithmildtomoderateAlzheimersdisease. • Brain Aging and Disease LaboratoryofNeurosciencesresearchersusedanextractofnormalhumanentorhinalcortexto generateantibodieswhichstainedaxonal/synapticelementsandneurofibrillarytanglesinthe temporallobeofAlzheimersbrain,andelementsofthelimbicsysteminratbrain.Theydeveloped aselectivemethodtoidentifysuchantibodies(SOFISTIC).Thisantibodymayhelpdeterminewhy thehumanentorhinalcortexisvulnerabletoAlzheimer'spathology. • Heart Performance and Exercise Agingisoftenaccompaniedbyadecreaseinphysicalactivityandbyareductioninmaximal exercisecapacityandcardiacperformance.LaboratoryofCardiovascularScienceresearchershave shownthatolderendurancetrainedmenhavebettercardiacpumpingcapacityduringexhaustive bicycleexercisethantheiruntrainedagepeers.Olderathletes(meanage63years)achieved35 percenthigherpeakworkratesandpumped23percentmorebloodatexhaustionthanuntrained men.Infact,theyachievedlevelssimilartothoseinyoungermen.Theseresultssuggestthat lifestylefsctorsmayaccountformuchoftheage-associateddeclineinmaximalcardiovascular performance,andthatregularvigorousexercisemayhelpattenuatethisdecline. • Exercise Lessens GI Bleeding AstudybyinvestigatorsintheEpidemiology,DemographyandBiometryBranchsuggested thatolderpeoplewhoexercisedatleastthreetimesaweek,evenifonlywalkingorgardening, were30percentlesslikelytosuffersevereorfatalgastrointestinalhemorrhages. Regularwalking reducedtheriskofinternalbleedingbyabout50percent. Morethan6000deathsand542,000 hospitalizationswerelinkedtothisproblemin 1991.Thisresearchinvolved8205people68years ofageandolderwhoparticipateintheNLA'sEstablishedPopulationsforEpidemiologicStudiesof theElderly(EPESE).