AgeingVulnerability:CausesandInterventions:NovartisFoundationSymposium235.Volume235 EditedbyGregoryBockandJamieA.Goode Copyright(cid:182)NovartisFoundation2001.ISBN:0-471-49438-0 AGEING VULNERABILITY: CAUSES AND INTERVENTIONS TheNovartisFoundationisaninternationalscienti¢candeducational charity(UKRegisteredCharityNo.313574).KnownuntilSeptember1997 astheCibaFoundation,itwasestablishedin1947bytheCIBAcompany ofBasle,whichmergedwithSandozin1996,toformNovartis.The FoundationoperatesindependentlyinLondonunderEnglishtrust law.Itwasformallyopenedon22June1949. TheFoundationpromotesthestudyandgeneralknowledgeof scienceandinparticularencouragesinternationalco-operationin scienti¢cresearch.Tothisend,itorganizesinternationally acclaimedmeetings(typicallyeightsymposiaandalliedopen meetingsand15^20discussionmeetingseachyear)andpublishes eightbooksperyearfeaturingthepresentedpapersanddiscussions fromthesymposia.Althoughprimarilyanoperationalratherthan agrant-makingfoundation,itawardsbursariestoyoungscientists toattendthesymposiaandafterwardsworkwithoneoftheother participants. TheFoundation’sheadquartersat41PortlandPlace,LondonW1B1BN, providelibraryfacilities,opentograduatesinscienceandallieddisciplines. Mediarelationsarefosteredbyregularpressconferencesandbyarticles preparedbytheFoundation’sScienceWriterinResidence.TheFoundation o¡ersaccommodationandmeetingfacilitiestovisitingscientistsandtheir societies. InformationonallFoundationactivitiescanbefoundat http://www.novartisfound.org.uk Novartis Foundation Symposium 235 AGEING VULNERABILITY: CAUSES AND INTERVENTIONS 2001 JOHN WILEY & SONS, LTD Chichester · New York · Weinheim · Brisbane · Singapore · Toronto Copyright&NovartisFoundation2001 Publishedin2001byJohnWiley&SonsLtd, Ba⁄nsLane,Chichester, WestSussexPO191UD,England National 01243779777 International(+44)1243779777 e-mail(forordersandcustomerserviceenquiries):[email protected] VisitourHomePageonhttp://www.wiley.co.uk orhttp://www.wiley.com AllRightsReserved.Nopartofthisbookmaybereproduced,storedinaretrieval system,ortransmitted,inanyformorbyanymeans,electronic,mechanical,photocopying, recording,scanningorotherwise,exceptunderthetermsoftheCopyright,Designsand PatentsAct1988orunderthetermsofalicenceissuedbytheCopyrightLicensingAgency, 90TottenhamCourtRoad,London,W1P9HE,UK,withoutthepermissioninwriting ofthepublisher. OtherWileyEditorialO⁄ces JohnWiley&Sons,Inc.,605ThirdAvenue, NewYork,NY10158-0012,USA WILEY-VCHVerlagGmbH,Pappelallee3, D-69469Weinheim,Germany JohnWiley&SonsAustralia,Ltd,33ParkRoad, Milton,Queensland4064,Australia JohnWiley&Sons(Asia)PteLtd,2ClementiLoop#02-01, JinXingDistripark,Singapore129809 JohnWiley&Sons(Canada)Ltd,22WorcesterRoad, Rexdale,OntarioM9W1L1,Canada NovartisFoundationSymposium235 ix+282pages,38¢gures,10tables LibraryofCongressCataloging-in-PublicationData Ageingvulnerability:causesandinterventions. p.;cm.^(NovartisFoundationsymposium;235) Editors,GregoryBockandJamieA.Goode. Includesbibliographicalreferencesandindexes. ISBN0-471-49438-0(alk.paper) 1.Aging^Molecularaspects^Congresses. 2.Degeneration(Pathology)^Molecular aspects^Congresses. I.Bock,Gregory. II.Goode,Jamie. III.Series. 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Contents SymposiumonAgeingvulnerability:causesandinterventions,heldattheNovartisFoundation, London,29February^3March2000 Editors:GregoryBock(Organizer)andJamieA.Goode ThissymposiumisbasedonaproposalmadebyGaryAndrews.Itwasorganizedasakeycomponent andinsupportoftheUnitedNationsProject‘AResearchAgendaonAgeingforthe21st Century’ ThomasB.L.Kirkwood Introduction 1 GaryR.Andrews Thepriorityofbasicresearchonageingvulnerabilityina comprehensiveresearchagendaonageingforthe21stcentury 4 Discussion 9 JulieK.Andersen Doalterationsinglutathioneandironlevelscontributeto pathologyassociatedwithParkinson’sdisease? 11 Discussion 20 AshleyI.BushandLeeE.Goldstein Speci¢cmetal-catalysedproteinoxidation reactionsinchronicdegenerativedisordersofageing:focusonAlzheimer’sdisease andage-relatedcataracts 26 Discussion 38 GeneraldiscussionI Theroleofglialcellsintheageingbrain 44 R.N.Kalaria,C.G.Ballard,P.G.Ince,R.A.Kenny,I.G.McKeith,C.M.Morris, J.T.O’Brien,E.K.Perry,R.H.PerryandJ.A.Edwardson Multiplesubstrates oflate-onsetdementia:implicationsforbrainprotection 49 Discussion 60 C.S.Potten,K.MartinandT.B.L.Kirkwood Ageingofmurinesmallintestinal stemcells 66 Discussion 79 AmielaGloberson Haematopoieticstemcellageing 85 Discussion 96 GeneraldiscussionII 101 v vi CONTENTS JamesK.LeungandOliviaM.Pereira-Smith Identi¢cationofgenes involvedincellsenescenceandimmortalization:potentialimplicationsfor tissueageing 105 Discussion 110 JerryW.ShayandWoodringE.Wright Ageingandcancer:thetelomereand telomeraseconnection 116 Discussion 125 RitaB.E¡ros Ageingandtheimmunesystem 130 Discussion 139 GeneraldiscussionIII 146 LisMosekilde Mechanismsofage-relatedboneloss 150 Discussion 166 EdwardG.Lakatta,StevenJ.SollottandSalvatorePepe Theoldheart: operatingontheedge 172 Discussion 196 AnthonyCeramiandPeterUlrich Pharmaceuticalinterventionofadvanced glycationendproducts 202 Discussion 212 GeneraldiscussionIV 217 HollyVanRemmen,ZhongmaoGuoandArlanRichardson Theanti-ageing actionofdietaryrestriction 221 Discussion 230 D.A.Cottrell,E.L.Blakely,M.A.Johnson,G.M.Borthwick,P.I.Inceand D.M.Turnbull MitochondrialDNAmutationsindiseaseandageing 234 Discussion 243 DouglasC.Wallace Amitochondrialparadigmfordegenerativediseasesand ageing 247 Discussion 263 Finaldiscussion 267 Indexofcontributors 273 Subjectindex 275 Participants JulieAndersen BuckInstituteforAgeResearch,8001RedwoodBlvd.,Novato, CA94948,USA GaryAndrews CentreforAgeingStudies,FlindersUniversityofSouth Australia,SciencePark,BedfordPark,SA5042,Australia AlexanderBu« rkle InstituteforHealthoftheElderly,UniversityofNewcastle uponTyne,WolfsonResearchCentre,NewcastleGeneralHospital,Westgate Road,NewcastleuponTyneNE46BE,UK AshleyBush GeneticsandAgingUnit,MassachusettsGeneralHospitalEast, Building149,13thStreet,Charlestown,MA02129,USA JudithCampisi LawrenceBerkeleyNationalLaboratory,1CyclotronRoad, Mailstop84-144,Berkeley,CA94720,USA AnthonyCerami TheKennethS.WarrenLaboratories,765OldSawMillRiver Road,Tarrytown,NY10591,USA DavidCottrell DepartmentofNeurology,TheMedicalSchool,Framlington Place,UniversityofNewcastleuponTyne,NewcastleuponTyneNE24HH,UK RitaE¡ros DepartmentofPathologyandLaboratoryMedicine,UCLASchool ofMedicine,10833LeConteAvenue,LosAngeles,CA90095-1732,USA AmielaGloberson DepartmentofImmunology,WeizmannInstituteof Science,76100Rehovot,Israel JohnGrimleyEvans UniversityofOxford,DepartmentofClinical Geratology,Radcli¡eIn¢rmary,OxfordOX26HE,UK BarryHalliwell DepartmentofBiochemistry,NationalUniversityof Singapore,KentRidgeCrescent,Singapore119260 vii viii PARTICIPANTS TamaraHarris NIHNationalInstituteonAging,Suite3C309,Gateway,7201 WisconsinAvenue,Bethesda,MD20892-9205,USA OliverF.W.James TheMedicalSchool,FramlingtonPlace,Universityof NewcastleuponTyne,NewcastleuponTyne,NE24HH,UK RajKalaria MRC^NewcastleUniversityCentreDevelopmentinClinicalBrian Ageing,WolfsonResearchCentre,InstituteforHealthoftheElderly,Newcastle GeneralHospital,WestgateRoad,NewcastleuponTyneNE46BE,UK ThomasB.L.Kirkwood(Chair) InstituteforHealthoftheElderly,University ofNewcastleuponTyne,WolfsonResearchCentre,NewcastleGeneralHospital, WestgateRoad,NewcastleuponTyneNE46BE,UK EdwardLakatta NationalInstituteonAging,GerontologyResearchCenter, 5600NathanShockDrive,Baltimore,MD21224-6825,USA GeorgeMMartin DepartmentofPathology,Box357470,Universityof Washington,1959NEPaci¢cAvenue,HealthSciencesBuildingK-543,Seattle, WA98195-7470,USA LisMosekilde TheInstituteofAnatomy,Wilh.MeyersAlle¤,bygn.233/234, Universitetsparken,DK-8000—rhusC,Denmark OliviaMPereira-Smith Hu⁄ngtonCenteronAging,BaylorCollegeof Medicine,M320,1BaylorPlaza,AlkekTower,RoomN803,Houston,TX77030, USA ChrisPotten EpithelialBiologyDepartment,ChristieHospitalNHSTrust, WilmslowRoad,ManchesterM204BX,UK ArlanRichardson DepartmentofPhysiology,TheUniversityofTexasHealth ScienceCenteratSanAntonio,703FloydCurlDrive,SanAntonio, TX78229-3900,USA LeslieRobert Faculte¤ deMe¤decineBroussaisHo“telDieu,EscalierB3,6e'me e¤tage,1PlaceduParisNotre-Dame,F-75181ParisCedex04,France PARTICIPANTS ix JerryW.Shay TheUniversityofTexasSouthwesternMedicalCenteratDallas, DepartmentofCellBiology,5323HarryHinesBlvd,Dallas,Texas75390-9039, USA DouglasC.Wallace CenterforMolecularMedicine,EmoryUniversitySchool ofMedicine,1462CliftonRoad,NE,Suite420,Atlanta,Georgia30322,USA HuberR.Warner NIHNationalInstituteonAging,GatewayBuilding,Suite 2C231,7201WisconsinAvenue,Bethseda,MD20892-9205,USA AgeingVulnerability:CausesandInterventions:NovartisFoundationSymposium235.Volume235 EditedbyGregoryBockandJamieA.Goode Copyright(cid:182)NovartisFoundation2001.ISBN:0-471-49438-0 Introduction ThomasB.L.Kirkwood Institute for Health for the Elderly, University of Newcastle upon Tyne, Wolfson Research Centre,NewcastleGeneralHospital,WestgateRoad,NewcastleuponTyne,NE46BE,UK Itisparticularlyappropriatetoholdthismeetingon‘Ageingvulnerability’atthe NovartisFoundation,previouslytheCibaFoundation,becausethiswasthesitein the1950sofahighlydistinguishedseriesofcolloquiaonageing.Thesemeetings wereremarkablyfarsightedintheirscopeandintheimportancethattheyattached toageingresearchatthattime,whenthesubjectwasverymuchinitsinfancy.The CibaColloquiaonAgeingcontainsomerealgems,eventhoughmanyofthepapers have now been superseded by other developments. There was also a Ciba Foundation symposium on ‘Research and the ageing population’ in 1986, held on the National Institutes of Health campus in Bethesda. This was another milestone,andattemptedabroadcompass.Itisthusvery¢ttingtobehereatthe NovartisFoundationaddressingatopicthatisastimelyandimportantinitsscope asageingvulnerability. Whenweconsiderpatternsofageandsex-speci¢cmortalityastheyoccurinthe developed countries of the world the most striking feature is the remorseless increase with age. A blip occurs in early adulthood, greater among males than females, re£ecting the toll chie£y of accidents from risk-prone behaviours like drinking and driving. When we take this away, the increase in the risk of mortality with advancing age is steadily exponential. This in a very real sense is what this meeting is all about: increasing vulnerability with age. We might also ask why males are more vulnerable than females across all ages, something to bear in mind as we discuss the wider aspects of ageing. The minimum point in themortalitycurveoccursveryearlyinlife. Theage-associatedincreaseinmortality,indicatinganincreaseinvulnerability, startsinourteens.Thisisimportantwhenweexamineinmechanistictermswhatthe ageing process actually does to us. A useful consensus of the kinds of processes which we believe contribute to intrinsic ageing is that as we live our lives, we accumulate within the cells and tissues of our bodies a great variety of di¡erent kindsoffaultordamage.Thisisaninsidiousprocessthatmaybeginevenbefore weareborn.Inthecourseofthismeetingwewillhearagreatdealaboutthedi¡erent kindsofdefectsthatariseduringageing.Intime,thisaccumulationoffaultsleadsto theovertsignsofageing,theage-associateddiseasesandgeneralfrailty. 1