Ageing Vulnerability: Causes and Interventions: Novartis Foundation Symposium 235

291 Pages·2001·3.033 MB·English

by  Novartis Foundation(eds.)

AgeingVulnerability:CausesandInterventions:NovartisFoundationSymposium235.Volume235
EditedbyGregoryBockandJamieA.Goode
Copyright(cid:182)NovartisFoundation2001.ISBN:0-471-49438-0
AGEING
VULNERABILITY:
CAUSES AND
INTERVENTIONS
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Novartis Foundation Symposium 235
AGEING
VULNERABILITY:
CAUSES AND
INTERVENTIONS
2001
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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.
[DNLM:1.Aging^pathology^Congresses.WT104A26562001]
QP86.A3562001
616.07^dc21 00-068655
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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