Frailty in Older Adults: Evidence for a Phenotype

Results. Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past ... SkiptoMainContent Advertisement SearchMenu Menu NavbarSearchFilter ThisissueAllTheJournalsofGerontology:SeriesA AllGSAJournalsAllJournals MobileMicrositeSearchTerm Search SignIn Issues TheJournalsofGerontology,SeriesA(1995-present) JournalofGerontology(1946-1994) MoreContent AdvanceArticles Editor'sChoice Translationalarticles Blogs Submit CallsforPapers AuthorGuidelines BiologicalSciencesSubmissionSite MedicalSciencesSubmissionSite Purchase Advertise AdvertisingandCorporateServices Advertising Mediakit ReprintsandePrints SponsoredSupplements JournalsCareerNetwork About AboutTheJournalsofGerontology,SeriesA AboutTheGerontologicalSocietyofAmerica EditorialBoard-BiologicalSciences EditorialBoard-MedicalSciences Alerts Self-ArchivingPolicy DispatchDates TermsandConditions ContactUs GSAJournals Issues TheJournalsofGerontology,SeriesA(1995-present) JournalofGerontology(1946-1994) MoreContent AdvanceArticles Editor'sChoice Translationalarticles Blogs Submit CallsforPapers AuthorGuidelines BiologicalSciencesSubmissionSite MedicalSciencesSubmissionSite Purchase Advertise AdvertisingandCorporateServices Advertising Mediakit ReprintsandePrints SponsoredSupplements JournalsCareerNetwork About AboutTheJournalsofGerontology,SeriesA AboutTheGerontologicalSocietyofAmerica EditorialBoard-BiologicalSciences EditorialBoard-MedicalSciences Alerts Self-ArchivingPolicy DispatchDates TermsandConditions ContactUs GSAJournals Close searchfilter Thisissue AllTheJournalsofGerontology:SeriesA AllGSAJournals AllJournals searchinput Search AdvancedSearch SearchMenu ArticleNavigation Closemobilesearchnavigation ArticleNavigation Volume56 Issue3 1March2001 ArticleContents Abstract Methods Results Discussion References ArticleNavigation ArticleNavigation FrailtyinOlderAdults:EvidenceforaPhenotype LindaP.Fried, LindaP.Fried LindaP.Fried,Director,CenteronAgingandHealth,TheJohnsHopkinsMedicalInstitutions,2024EastMonumentStreet,Suite2-700,Baltimore,MD21205E-mail:[email protected]. Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar CatherineM.Tangen, CatherineM.Tangen Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar JeremyWalston, JeremyWalston Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar AnneB.Newman, AnneB.Newman Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar CalvinHirsch, CalvinHirsch Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar JohnGottdiener, JohnGottdiener Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar TeresaSeeman, TeresaSeeman Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar RussellTracy, RussellTracy Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar WillemJ.Kop, WillemJ.Kop Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar GregoryBurke, GregoryBurke Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar ...Showmore MaryAnnMcBurnie MaryAnnMcBurnie fortheCardiovascularHealthStudyCollaborativeResearchGroup Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar TheJournalsofGerontology:SeriesA,Volume56,Issue3,1March2001,PagesM146–M157,https://doi.org/10.1093/gerona/56.3.M146 Published: 01March2001 Articlehistory Received: 30June2000 Accepted: 19September2000 Published: 01March2001 PDF SplitView Views Articlecontents Figures&tables Video Audio SupplementaryData Cite Cite LindaP.Fried,CatherineM.Tangen,JeremyWalston,AnneB.Newman,CalvinHirsch,JohnGottdiener,TeresaSeeman,RussellTracy,WillemJ.Kop,GregoryBurke,MaryAnnMcBurnie,FrailtyinOlderAdults:EvidenceforaPhenotype,TheJournalsofGerontology:SeriesA,Volume56,Issue3,1March2001,PagesM146–M157,https://doi.org/10.1093/gerona/56.3.M146 SelectFormat Selectformat .ris(Mendeley,Papers,Zotero) .enw(EndNote) .bibtex(BibTex) .txt(Medlars,RefWorks) Downloadcitation Close PermissionsIcon Permissions Share Email Twitter Facebook More NavbarSearchFilter ThisissueAllTheJournalsofGerontology:SeriesA AllGSAJournalsAllJournals MobileMicrositeSearchTerm Search SignIn Close searchfilter Thisissue AllTheJournalsofGerontology:SeriesA AllGSAJournals AllJournals searchinput Search AdvancedSearch SearchMenu Abstract Background.Frailtyisconsideredhighlyprevalentinoldageandtoconferhighriskforfalls,disability,hospitalization,andmortality.Frailtyhasbeenconsideredsynonymouswithdisability,comorbidity,andothercharacteristics,butitisrecognizedthatitmayhaveabiologicbasisandbeadistinctclinicalsyndrome.Astandardizeddefinitionhasnotyetbeenestablished.Methods.Todevelopandoperationalizeaphenotypeoffrailtyinolderadultsandassessconcurrentandpredictivevalidity,thestudyuseddatafromtheCardiovascularHealthStudy.Participantswere5,317menandwomen65yearsandolder(4,735fromanoriginalcohortrecruitedin1989–90and582fromanAfricanAmericancohortrecruitedin1992–93).Bothcohortsreceivedalmostidenticalbaselineevaluationsand7and4yearsoffollow-up,respectively,withannualexaminationsandsurveillanceforoutcomesincludingincidentdisease,hospitalization,falls,disability,andmortality.Results.Frailtywasdefinedasaclinicalsyndromeinwhichthreeormoreofthefollowingcriteriawerepresent:unintentionalweightloss(10lbsinpastyear),self-reportedexhaustion,weakness(gripstrength),slowwalkingspeed,andlowphysicalactivity.Theoverallprevalenceoffrailtyinthiscommunity-dwellingpopulationwas6.9%;itincreasedwithageandwasgreaterinwomenthanmen.Four-yearincidencewas7.2%.FrailtywasassociatedwithbeingAfricanAmerican,havinglowereducationandincome,poorerhealth,andhavinghigherratesofcomorbidchronicdiseasesanddisability.Therewasoverlap,butnotconcordance,inthecooccurrenceoffrailty,comorbidity,anddisability.Thisfrailtyphenotypewasindependentlypredictive(over3years)ofincidentfalls,worseningmobilityorADLdisability,hospitalization,anddeath,withhazardratiosrangingfrom1.82to4.46,unadjusted,and1.29–2.24,adjustedforanumberofhealth,disease,andsocialcharacteristicspredictiveof5-yearmortality.Intermediatefrailtystatus,asindicatedbythepresenceofoneortwocriteria,showedintermediateriskoftheseoutcomesaswellasincreasedriskofbecomingfrailover3–4yearsoffollow-up(oddsratiosforincidentfrailty=4.51unadjustedand2.63adjustedforcovariates,comparedtothosewithnofrailtycriteriaatbaseline).Conclusions.Thisstudyprovidesapotentialstandardizeddefinitionforfrailtyincommunity-dwellingolderadultsandoffersconcurrentandpredictivevalidityforthedefinition.Italsofindsthatthereisanintermediatestageidentifyingthoseathighriskoffrailty.Finally,itprovidesevidencethatfrailtyisnotsynonymouswitheithercomorbidityordisability,butcomorbidityisanetiologicriskfactorfor,anddisabilityisanoutcomeof,frailty.Thisprovidesapotentialbasisforclinicalassessmentforthosewhoarefrailoratrisk,andforfutureresearchtodevelopinterventionsforfrailtybasedonastandardizedascertainmentoffrailty. DecisionEditor:JohnE.Morley,MB,BChFRAILTYisconsideredtobehighlyprevalentwithincreasingageandtoconferhighriskforadversehealthoutcomes,includingmortality,institutionalization,falls,andhospitalization(1)(2)(3).Numerousgeriatricinterventionshavebeendevelopedtoimproveclinicaloutcomesforfrailolderadults(3)(4)(5)(6)(7).Amajorobstacletothesuccessofsuchinterventionshasbeentheabsenceofastandardizedandvalidmethodforscreeningofthosewhoaretrulyfrailsoastoeffectivelytargetcare(1)(3).Potentialdefinitionsoffrailtyabound,definingfrailtyassynonymouswithdisability(1)(8)(9),comorbidity(8),oradvancedoldage(3).Increasingly,geriatriciansdefinefrailtyasabiologicsyndromeofdecreasedreserveandresistancetostressors,resultingfromcumulativedeclinesacrossmultiplephysiologicsystems,andcausingvulnerabilitytoadverseoutcomes(9)(10)(11)(12)(13).Thisconceptdistinguishesfrailtyfromdisability(9)(10)(14)(15).Thereisagrowingconsensusthatmarkersoffrailtyincludeage-associateddeclinesinleanbodymass,strength,endurance,balance,walkingperformance,andlowactivity(9)(10)(14)(15)(16)(17),andthatmultiplecomponentsmustbepresentclinicallytoconstitutefrailty(9)(14).Manyofthesefactorsarerelated(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)andcanbeunified,theoretically,intoacycleoffrailtyassociatedwithdecliningenergeticsandreserve(Fig.1).Thecoreelementsofthiscyclearethosecommonlyidentifiedasclinicalsignsandsymptomsoffrailty(9)(10)(14)(15)(16).Frailtylikelyalsoinvolvesdeclinesinphysiologiccomplexityorreserveinothersystems,leadingtolossofhomeostaticcapabilitytowithstandstressorsandresultingvulnerabilities(2)(9)(11)(12).WehypothesizedthattheelementsidentifiedinFig.1arecoreclinicalpresentationsoffrailty,andthatacriticalmassofphenotypiccomponentsinthecyclewould,whenpresent,identifythesyndrome.Weevaluatedwhetherthisphenotypeidentifiesasubsetathighriskoftheadversehealthoutcomesclinicallyassociatedwithfrailty.Todothis,weoperationalizedadefinitionoffrailty,assuggestedbypriorresearchandclinicalconsensus(Fig.1),and,inapopulation-basedstudyofolderadults,evaluateditsprevalenceandincidence,cross-sectionalcorrelates,anditsvalidityintermsofpredictingtheadverseoutcomesgeriatriciansassociatewithfrailolderadults.Methods Population ThisstudyemployeddatafromtheCardiovascularHealthStudy,aprospective,observationalstudyofmenandwomen65yearsandolder.Theoriginalcohort(N=5201)wasrecruitedfromfourU.S.communitiesin1989–90.Anadditionalcohortof687AfricanAmericanmenandwomenwasrecruitedin1992–93fromthreeofthesesites.Participantswererecruitedfromage-andgender-stratifiedsamplesoftheHCFAMedicareeligibilitylistsin:SacramentoCounty,California;WashingtonCounty,Maryland;ForsythCounty,NorthCarolina,andAlleghenyCounty(Pittsburgh),Pennsylvania(32)(33).Bothcohortsreceivedidenticalbaselineevaluations(exceptthatthelatterdidnotreceivespirometryorechocardiogramsatbaseline)andfollow-upwithannualexaminationsandsemiannualtelephonecallsandsurveillanceforoutcomesincludingincidentdisease,hospitalizations,falls,disability,andmortality.BaselineEvaluation Standardizedinterviewsascertainedself-assessedhealth,demographics,healthhabits,weightloss,medicationsused,andself-reportedphysiciandiagnosisofcardiovascularevents,emphysema,asthma,diabetes,arthritis,renaldisease,cancer,andhearingandvisualimpairment.AversionoftheMinnesotaLeisureTimeActivitiesQuestionnaire(34)ascertainedphysicalactivitiesintheprior2weeks,plusfrequencyandduration.Physicalfunctionwasascertainedbyaskingaboutdifficultywith15tasksofdailylife,includingmobility,upperextremity,instrumentalactivitiesofdailyliving(IADL)andactivitiesofdailyliving(ADL)tasks(35).Frequencyoffallsintheprior6monthswasassessedbyself-report.Themodified10-itemCenterforEpidemiologicalStudies–Depressionscale[CES–D;(36)]ascertaineddepressivesymptoms.Cardiovasculardiseases[myocardialinfarction(MI),congestiveheartfailure(CHF),angina,peripheralvasculardisease,andstroke]werevalidatedbyascertainingmedicationsusedandthroughstandardizedexaminations:electrocardiogram,echocardiogram,andposteriortibial–brachialarterysystolic(ankle–arm)bloodpressureratio(32)(37)(38).Thesedataandmedicalrecordswerethenreviewedbycliniciansforconsensus-basedadjudicationofthepresenceofthesediseases,basedonstandardizedalgorithms(37).Additionalexaminationsascertainedweight;bloodpressure;carotidultrasoundmeasuringmaximalstenosisoftheinternalandcommoncarotidarteries(39);phlebotomy,underfastingconditions,withbloodanalyzedbytheLaboratoryforClinicalBiochemistryResearch(UniversityofVermont)forfastingglucose,serumalbumin,creatinine,andfibrinogen(32).Fastingplasmalipidanalyseswereperformed,andlow-densitylipoproteincholesterolwascalculated(32).CognitivefunctionwasassessedwiththeMini-MentalStateExamination(40)andtheDigitSymbolSubstitutiontest(41).Standardizedperformance-basedmeasuresofphysicalfunctionincludedtime(seconds)towalk15feetatusualpaceandmaximalgripstrength(kilograms)inthedominanthand(3measuresaveraged),usingaJamarhand-helddynamometer(32).Mortality Deathswereidentifiedatsemi-annualcontactsandconfirmedthroughintensivesurveillance(37)(42).Mortalityascertainmentwas100%completethroughtheeighthyear.OperationalizationofthefrailtyphenotypeinCHS. Basedonthescientificrationaleabove,aphenotypeoffrailtywasproposedtoincludetheelementssummarizedinTable1,columnA.ItwasoperationalizedutilizingdatacollectedinCHSatbaselineforCohort1andyears3(baselineforCohort2)and7forbothcohorts(Fig.2andTable1,columnB).Wespecifiedthataphenotypeoffrailtywasidentifiedbythepresenceofthreeormoreofthefollowingcomponentsofthehypothesizedcycleoffrailty(Fig.1):Shrinking:weightloss,unintentional,of≥10poundsinprioryearor,atfollow-up,of≥5%ofbodyweightinprioryear(bydirectmeasurementofweight).Weakness:gripstrengthinthelowest20%atbaseline,adjustedforgenderandbodymassindex.Poorenduranceandenergy:asindicatedbyself-reportofexhaustion.Self-reportedexhaustion,identifiedbytwoquestionsfromtheCES–Dscale(36),isassociatedwithstageofexercisereachedingradedexercisetesting,asanindicatorofV̇O2max(43),andispredictiveofcardiovasculardisease(44).Slowness:Theslowest20%ofthepopulationwasdefinedatbaseline,basedontimetowalk15feet,adjustingforgenderandstandingheight.Lowphysicalactivitylevel:Aweightedscoreofkilocaloriesexpendedperweekwascalculatedatbaseline(34)(45),basedoneachparticipant'sreport.Thelowestquintileofphysicalactivitywasidentifiedforeachgender.Formeasuresthatidentifiedthelowestquintile,thelevelestablishedatbaselinewasappliedtofollow-upevaluations.Acriticalmassofcharacteristics,definedasthreeormore,hadtobepresentforanindividualtobeconsideredfrail.Thosewithnocharacteristicswereconsideredrobust,whereasthosewithoneortwocharacteristicswerehypothesizedtobeinanintermediate,possiblyprefrail,stageclinically.DataAnalysis UsingCHSdata,weidentifiedthenumberoffrailtycharacteristicspresent,asperdefinitionsabove.Thoseconsideredevaluableforfrailtyhadthreeormorenonmissingfrailtycomponentsamongthefivecriteria(Table1).WeexcludedthosewithahistoryofParkinson'sdisease(n=47),stroke(n=245),orMini-Mentalscores<18(n=84),andthosewhoweretakingSinemet,Aricept,orantidepressants(n=235),astheseconditionscouldpotentiallypresentwithfrailtycharacteristicsasaconsequenceofasingledisease.Therewere4,735intheoriginaland582intheAfricanAmericancohortwhowereeligible;thetotalbaselinesamplesizeafterapplyingtheexclusioncriteriawas5,317.Forthefirstcohort,frailtycomponentswereascertainedatbaseline,andthen3yearsand7yearsintothestudy.Thesecondcohort,recruited3yearsaftertheinitialcohort,hadfrailtycomponentsascertained4yearslater(correspondingtoyear7forthefirstcohort;Fig.2).Forassociationsoffrailtywithotherfactors,thetrendpvaluebasedontheCochran-Mantel-Haenszel(CMH)testwasused.Comorbiditywasdefinedasthepresenceoftwoormoreofnineconditions:self-reportedclaudication,arthritis,cancer,hypertension,chronicobstructivepulmonarydisease(COPD),andvalidateddiabetes(ADAdefinition),CHF,angina,orMI.AVenndiagramillustratestheoverlapofdisabilityandcomorbiditywithfrailtyatbaseline;percentagesarebasedonallfrailsubjects.Kaplan-Meierestimateswereusedtodeterminethepercentageofsubjectsfreeofanevent(e.g.,hospitalization,fall,death)at3yearsafterstudyentryand7yearsafterstudyentry.Cohort1hadalongerfollow-upperiod(median79months,range73–84)thanCohort2(median38months,range37–43),soestimatesat7yearswerebasedonlyonCohort1.Thepvaluesreportedforthedifferenceinsurvivalcurvesbetweenfrailtyphenotypegroupswerebasedonthelogranktest.PredictiveValidity Coxproportionalhazardmodelswereusedtoassesstheindependentcontributionofbaselinefrailtystatustoincidenceofmajorgeriatricoutcomesover3and7years,including:(a)incidentfalls(evaluatedevery6months);(b)worseningmobilityorADLfunction(evaluatedannually);(c)incidenthospitalization:fromtimeofstudyentrytodischargedateforthefirstconfirmedovernighthospitalization;(d)death.Indicatorsforfrail(3ormorefrailtycomponents)andat-risk(1or2frailtycomponents)werecreated,withthenonfrailgroup(0frailtycomponents)servingasthereferencegroup.Unadjustedinstantaneoushazardratios(referredtoasrelativerisk[RR]estimates)wereestimatedforeachoutcome.Covariate-adjustedCoxmodelswerealsofit,utilizingbaselinecovariatesshowntobepredictiveofmortalityinthiscohort(42):age,gender,income,smokingstatus,diureticusewithoutahistoryofhypertensionorcongestiveheartfailure,fastingglucose,albumin,creatinine;objectivemeasuresofsubclinicaldisease,including:brachialandtibialsystolicbloodpressure,abnormalleftventricularejectionfraction(LVEF;byechocardiography),majorECGabnormality,forcedvitalcapacity(FVC),andmaximalstenosisoftheinternalcarotidartery(byultrasound),congestiveheartfailure(validatedhistory),digitsymbolsubstitutionscore,depressivesymptoms(CES–Dscoreexcludingthetwoquestionsutilizedinthefrailtydefinition),anddifficultyin≥1IADL.Weightandphysicalactivitywerealsofoundtobeindependentpredictorsofsurvival,buttheywerenotincludedinthecovariate-adjustedmodels,astheyarecomponentsoftheoverallfrailtyscore.Covariatesselectedwerebasedonanalysesperformedonthefirstcohort;externalvalidationusingthesecondcohortshowedgoodagreement.However,FVCandLVEFabnormalitywerenotavailableatstudyentryforthesecondcohort,sotheywerenotincludedinthecovariate-adjustedfrailtymodels.Addingthesetwocovariatestomodelsbasedonlyonthefirstcohortdidnotalterthefrailtyresults.Finally,alogisticmodelwasusedtoevaluatewhethertheintermediatefrailtygroup(1,2criteria)wasathigherriskofincidentfrailtythanthosewhowerenotfrail(0criteria)atstudyentry.Onlysubjectswhowerealive,eligible(satisfiedexclusioncriteria),andevaluable(atleast3nonmissingfrailtycomponents)atthesubsequentvisitwereincludedintheanalysis.Thecovariate-adjustedlogisticmodelincludesthesamecovariatesdescribedfortheproportionalhazardsmodels(above).Results The5,317peopleevaluatedwere65to101yearsofage;58%werefemaleand15%AfricanAmerican,withabroadrangeofsocioeconomic,functional,andhealthstatus(Table2,columnA).FrailtymarkerspresentatbaselineareshowninTable3.Overall,7%ofthecohorthad≥3frailtycriteria,and46%hadnone.Sixpercentoftheinitialcohortand12%oftheAfricanAmericancohortwerefrail.Prevalenceoffrailtyincreasedwitheach5-yearagegroup,andwasuptotwofoldhigherforwomenthanmenbyagegroup(Table4).Theexceptionwasthose90yearsandolder,whereprevalencewaslowerinbothsubgroupsofwomenandmenintheminoritycohort.Three-yearincidenceoffrailtywas7%foryears0–3andwas7%,aswell,for4-yearincidenceoffrailtyfromyears3–7,forthefirstcohort.Thesecondcohorthada4-yearincidencerateof11%.Theseincidenceratesarelikelyunderestimates,astheydonotincludelosstomortalityorthosewhowerenotevaluableforfrailtyatfollow-upduetomissingdata.Thosewhowerefrailwereolder,morelikelytobefemaleandAfricanAmerican,andhadlesseducation,lowerincome,poorerhealth,andhigherratesofcomorbidchronicdiseasesandofdisabilitythanthosewhowerenotfrailorwereintheintermediategroup(p<.05foreachcomparison thisworkproposesastandardizedphenotypeoffrailtyinolderadultsanddemonstratespredictivevalidityforthea dverseoutcomesthatgeriatriciansidentifyfrailolderadultsasbeingatriskfor:falls>4kg(48).Theyfoundasimilarprevalenceof6%(26/440),andsimilarunadjustedassociationswithmortalityanddisability,providingevidenceforconsistencyoffindingsacrosspopulation.Thephenotypeproposedhereoffersgreaterpredictivevalidity,comparedwithusingonlytwocriteria.Thecharacterizationoffrailtyofferedherealsoprovidesnewinsightsintopotentialetiologies.Frailtyinthisstudywasstronglyassociatedwithanumberofmajorchronicdiseases,includingcardiovascularandpulmonarydiseasesanddiabetes,suggestiveofetiologicassociationswiththesesinglediseases.However,therewasagreaterlikelihoodoffrailtywhentwoormorediseaseswerepresentthanwithanyone.Conversely,theobservationthatasubsetofthosewhowerefrailreportednoneofthediseasesassessedsupportsthehypothesisthattheremaybetwodifferentpathwaysbywhichindividualsbecomefrail:one,aresultofphysiologicchangesofagingthatarenotdisease-based(e.g.,aging-relatedsarcopenia[16]oranorexiaofaging[(30),(31),(49),(50)]),andtheotherafinalcommonpathwayofseverediseaseorcomorbidity,assuggestedbythehigherratesofpoorhealthstatusandgreaterextentofsubclinicalphysiologicchangesinthefrailgroup.Individualorcomorbiddiseasescouldpotentiallyinitiatefrailtyviaanypointonthehypothesizedcycle(Fig.1).Thesehypothesesremaintobeconfirmed.Thelikelihoodoffrailtywasalsohigheramongwomenand/orthosewithlowersocioeconomicstatus.Femalegendercouldconferintrinsicriskoffrailtyduetowomenstartingwithlowerleanmassandstrengththanage-matchedmen;thereafter,womenlosingleanbodymasswithagingmightbemorelikelytocrossathresholdnecessaryforfrailty.Womencouldalsohavegreatervulnerabilitytofrailtyviaextrinsiceffectsonsarcopenia(e.g.,becauseolderwomenhaveagreaterlikelihoodofinadequatenutritionalintake,comparedtomen,duetolivingalonemoreoften[19]).Thisstudyofferssupportforgeriatricians'contentionthatfrailtyisaphysiologicsyndrome(9)(10)(11)(12)(13)(14)(15)(16),anditdelineatesfrailtyfromcomorbidityanddisability—characteristicsthatareoftentreatedassynonymouswithfrailty.Ourfindingssupportthehypothesisthatfrailtycausesdisability,independentofclinicalandsubclinicaldiseases(Table7).Thesyndromeoffrailtymaybeaphysiologicprecursorandetiologicfactorindisability,duetoitscentralfeaturesofweakness,decreasedendurance,andslowedperformance.Theaspectsoffunctionlikelyaffectedbyfrailtyarethosedependentonenergeticsandspeedofperformance(e.g.,mobility).Itisnotablethatonly27%ofthosewhoweredisabledinADLtaskswerealsofrail(Table2),suggestingthatfrailtybeginsbyaffectingmobilitytasksbeforecausingdifficultyinendstagefunctionsuchasADLs,orthatthereareadditionalpathwaysbywhicholderadultscanbecomedisabled.Forexample,disabilityduetoarthritisofthehandsmightveryspecificallyaffectabilitytograsporeat,withouthavinganyrelationshiptofrailty.Thus,frailtydoesnotappeartobesynonymouswitheitherdisabilityorcomorbidity.Giventhefindingshere,thetermsappeartoapplytodistinct,butrelated,entitiesandshouldnotbeusedinterchangeably.Thedefinitionoffrailtyofferedandvalidatedhereprovidesastandardized,physiologicallybaseddefinitionapplicabletothespectrumoffrailtypresentationsseenincommunity-dwellingolderadults.Theclearcriteriaarerelativelyeasyandinexpensivetoapply,andofferabasisforstandardizedscreeningforfrailtyandriskoffrailtyinolderadults.Theycan,potentially,beusedtoestablishclinicalriskofadverseoutcomes.Theyalsoprovideaphenotypeapplicabletofutureresearchonetiologyandinterventionstopreventorretardtheprogressionoffrailty.Themajorlimitationofthisstudyisthatthemeasuresutilizedtooperationalizethephenotypeoffrailtywerelimitedtothosethatwerefortuitouslycollected10yearsagoforotherpurposesinthislongitudinalstudy.Inaddition,weightlosspriortobaselinewasnecessarilydrawnfrombaselineself-report.Ontheotherhand,fewstudiescanofferthelengthoffollow-uporthebreadthofhealthanddemographiccharacteristicsavailableinthiscohortforuseinunderstandingfrailty.Anumberofquestionsremaintobeevaluated,includingtheroleoffrailtyinhealthoutcomesfordifferentsubgroups(e.g,AfricanAmericansandCaucasians).Inthissameissue,weseparatelyexaminetheassociationoffrailtywithcardiovasculardiseases(51).Overall,thesefindingsprovidesupportforthehypothesesofaphysiologiccycleoffrailty(14)thatservesasthebasisforthephenotypeconsideredhere(Fig.1).Thisincorporatespriorresearchdemonstratingpairwiseassociationsbetweeneachtwocomponentsinthecycle(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).Thishypothesizedcycleoffrailty,representinganadverse,potentiallydownwardspiralofenergetics,isconsistentwiththeclinicalmarkersoffrailtyidentifiedbygeriatriciansandgerontologists(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)andourfindingsandothers'proposals(46)(52)(53)ofanintermediateandlaterstageoffrailtyincommunity-dwellingolderadults.Amoreadvancedstagemaybeobservedinmoredebilitatedpopulations,suchasinnursinghomes.Thisphenotypemaynot,however,fullyexplainthemoresubtlebiologicunderpinningsofdecreasedreservesandabilitytomaintainhomeostasis(11)(12)(13),whichmaybelatentpriortoaninsult,butbeabasisforvulnerabilitytostressors(10)(11)(14).Furtherunderstandingofthebasisforriskassociatedwithfrailtymayultimatelybefoundinthealterationsinmultisystemfunction,complexity,andreservewithaging(12).Itispossiblethatearlyfrailty,orprogressionfromtheintermediatestagetofrailty,mighthaveonesetofetiologicfactors,whereasprogressionofthefrailtyobservedheretoamoreend-stagepointmightbeassociatedwithothers,suchasdeclinesinweight,albumin,orcholesterolasconsequencesofmalnutritionorcatabolism.Thisendstagehasbeenreportedtobeirreversibleandpresagedeath(19)(24)(52)(53). Table1.OperationalizingaPhenotypeofFrailtyA.CharacteristicsofFrailty B.CardiovascularHealthStudyMeasure* Shrinking:Weightloss(unintentional)Sarcopenia(lossofmusclemass) Baseline:>10lbslostunintentionallyinprioryear Weakness Gripstrength:lowest20%(bygender,bodymassindex) Poorendurance;Exhaustion “Exhaustion”(self-report) Slowness Walkingtime/15feet:slowest20%(bygender,height) Lowactivity Kcals/week:lowest20%males:<383Kcals/weekfemales:<270Kcals/week  C.PresenceofFrailty  Positiveforfrailtyphenotype:≥3criteriapresent  Intermediateorprefrail:1or2criteriapresent A.CharacteristicsofFrailty B.CardiovascularHealthStudyMeasure* Shrinking:Weightloss(unintentional)Sarcopenia(lossofmusclemass) Baseline:>10lbslostunintentionallyinprioryear Weakness Gripstrength:lowest20%(bygender,bodymassindex) Poorendurance;Exhaustion “Exhaustion”(self-report) Slowness Walkingtime/15feet:slowest20%(bygender,height) Lowactivity Kcals/week:lowest20%males:<383Kcals/weekfemales:<270Kcals/week  C.PresenceofFrailty  Positiveforfrailtyphenotype:≥3criteriapresent  Intermediateorprefrail:1or2criteriapresent  Openinnewtab Table1.OperationalizingaPhenotypeofFrailtyA.CharacteristicsofFrailty B.CardiovascularHealthStudyMeasure* Shrinking:Weightloss(unintentional)Sarcopenia(lossofmusclemass) Baseline:>10lbslostunintentionallyinprioryear Weakness Gripstrength:lowest20%(bygender,bodymassindex) Poorendurance;Exhaustion “Exhaustion”(self-report) Slowness Walkingtime/15feet:slowest20%(bygender,height) Lowactivity Kcals/week:lowest20%males:<383Kcals/weekfemales:<270Kcals/week  C.PresenceofFrailty  Positiveforfrailtyphenotype:≥3criteriapresent  Intermediateorprefrail:1or2criteriapresent A.CharacteristicsofFrailty B.CardiovascularHealthStudyMeasure* Shrinking:Weightloss(unintentional)Sarcopenia(lossofmusclemass) Baseline:>10lbslostunintentionallyinprioryear Weakness Gripstrength:lowest20%(bygender,bodymassindex) Poorendurance;Exhaustion “Exhaustion”(self-report) Slowness Walkingtime/15feet:slowest20%(bygender,height) Lowactivity Kcals/week:lowest20%males:<383Kcals/weekfemales:<270Kcals/week  C.PresenceofFrailty  Positiveforfrailtyphenotype:≥3criteriapresent  Intermediateorprefrail:1or2criteriapresent  Openinnewtab Table2.BaselineAssociationofDemographicandHealthCharacteristicsWithFrailty,inPercentages:theCardiovascularHealthStudyFactor ATotal(5317) BNotFrail(n=2469) CIntermediate(n=2480) DFrail(n=368) ETrendpValue FAgeAdjustedTrendpValue Age       65–74 67.3% 76.1% 62.9% 38.0% <.001>12years 43.5 49.0 39.2 36.2   Income       <12K 25.6 18.7 29.9 44.3 <.001>50K 13.2 16.5 10.6 9.3   Self-AssessedHealth       Excellent 14.3 19.5 10.7 3.5 <.001>23 93.7 97.0 91.7 84.9   DepressiveSymptoms       CES–D≥10 9.9 2.6 14.0 31.0 <.001>12years 43.5 49.0 39.2 36.2   Income       <12K 25.6 18.7 29.9 44.3 <.001>50K 13.2 16.5 10.6 9.3   Self-AssessedHealth       Excellent 14.3 19.5 10.7 3.5 <.001>23 93.7 97.0 91.7 84.9   DepressiveSymptoms       CES–D≥10 9.9 2.6 14.0 31.0 <.001 openinnewtab table2.baselineassociationofdemographicandhealthcharacteristicswithfrailty>12years 43.5 49.0 39.2 36.2   Income       <12K 25.6 18.7 29.9 44.3 <.001>50K 13.2 16.5 10.6 9.3   Self-AssessedHealth       Excellent 14.3 19.5 10.7 3.5 <.001>23 93.7 97.0 91.7 84.9   DepressiveSymptoms       CES–D≥10 9.9 2.6 14.0 31.0 <.001>12years 43.5 49.0 39.2 36.2   Income       <12K 25.6 18.7 29.9 44.3 <.001>50K 13.2 16.5 10.6 9.3   Self-AssessedHealth       Excellent 14.3 19.5 10.7 3.5 <.001>23 93.7 97.0 91.7 84.9   DepressiveSymptoms       CES–D≥10 9.9 2.6 14.0 31.0 <.001 openinnewtab table3.prevalenceoffrailtyphenotypecomponentsinpercentages:cardiovascularhealthstudy table4.prevalenceoffrailtyatbaseline:cardiovascularhealthstudy table5.distributionoffrailtystatusamongthosewithadisabilityatbaseline table6.incidenceofadverseoutcomesassociatedwithfrailty:kaplan-meierestimatesat3yearsand7years table7.baselinefrailtystatuspredictingfalls table8.associationof tablea.criteriausedtodefinefrailty>173cm ≥6seconds Women  Height≤159cm ≥7seconds Height>159cm ≥6seconds •GripStrength,stratifiedbygenderandbodymassindex(BMI)quartiles:  Men Cutoffforgripstrength(Kg)criterionforfrailty BMI≤24 ≤29 BMI24.1–26 ≤30 BMI26.1–28 ≤30 BMI>28 ≤32 Women  BMI≤23 ≤17 BMI23.1–26 ≤17.3 BMI26.1–29 ≤18 BMI>29 ≤21 •Weightloss:“Inthelastyear,haveyoulostmorethan10poundsunintentionally(i.e.,notduetodietingorexercise)?”Ifyes,thenfrailforweightlosscriterion.Atfollow-up,weightlosswascalculatedas:(Weightinpreviousyear–currentmeasuredweight)/(weightinpreviousyear)=K.IfK≥0.05andthesubjectdoesnotreportthathe/shewastryingtoloseweight(i.e.,unintentionalweightlossofatleast5%ofpreviousyear'sbodyweight),thenfrailforweightloss=Yes.  •Exhaustion:UsingtheCES–DDepressionScale,thefollowingtwostatementsareread.(a)IfeltthateverythingIdidwasaneffort;(b)Icouldnotgetgoing.Thequestionisasked“Howofteninthelastweekdidyoufeelthisway?”0=rarelyornoneofthetime(<1day),1=someoralittleofthetime(1–2days),2=amoderateamountofthetime(3–4days),or3=mostofthetime.Subjectsanswering“2”or“3”toeitherofthesequestionsarecategorizedasfrailbytheexhaustioncriterion.  •PhysicalActivity:BasedontheshortversionoftheMinnesotaLeisureTimeActivityquestionnaire,askingaboutwalking,chores(moderatelystrenuous),mowingthelawn,raking,gardening,hiking,jogging,biking,exercisecycling,dancing,aerobics,bowling,golf,singlestennis,doublestennis,racquetball,calisthenics,swimming.Kcalsperweekexpendedarecalculatedusingstandardizedalgorithm.Thisvariableisstratifiedbygender.  Men:ThosewithKcalsofphysicalactivityperweek<383arefrail.  Women:ThosewithKcalsperweek<270arefrail.  •WalkTime,stratifiedbygenderandheight(gender-specificcutoffamediumheight).  Men CutoffforTimetoWalk15feetcriterionforfrailty Height≤173cm ≥7seconds Height>173cm ≥6seconds Women  Height≤159cm ≥7seconds Height>159cm ≥6seconds •GripStrength,stratifiedbygenderandbodymassindex(BMI)quartiles:  Men Cutoffforgripstrength(Kg)criterionforfrailty BMI≤24 ≤29 BMI24.1–26 ≤30 BMI26.1–28 ≤30 BMI>28 ≤32 Women  BMI≤23 ≤17 BMI23.1–26 ≤17.3 BMI26.1–29 ≤18 BMI>29 ≤21  Openinnewtab Tablea.CriteriaUsedtoDefineFrailty•Weightloss:“Inthelastyear,haveyoulostmorethan10poundsunintentionally(i.e.,notduetodietingorexercise)?”Ifyes,thenfrailforweightlosscriterion.Atfollow-up,weightlosswascalculatedas:(Weightinpreviousyear–currentmeasuredweight)/(weightinpreviousyear)=K.IfK≥0.05andthesubjectdoesnotreportthathe/shewastryingtoloseweight(i.e.,unintentionalweightlossofatleast5%ofpreviousyear'sbodyweight),thenfrailforweightloss=Yes.  •Exhaustion:UsingtheCES–DDepressionScale,thefollowingtwostatementsareread.(a)IfeltthateverythingIdidwasaneffort;(b)Icouldnotgetgoing.Thequestionisasked“Howofteninthelastweekdidyoufeelthisway?”0=rarelyornoneofthetime(<1day),1=someoralittleofthetime(1–2days),2=amoderateamountofthetime(3–4days),or3=mostofthetime.Subjectsanswering“2”or“3”toeitherofthesequestionsarecategorizedasfrailbytheexhaustioncriterion.  •PhysicalActivity:BasedontheshortversionoftheMinnesotaLeisureTimeActivityquestionnaire,askingaboutwalking,chores(moderatelystrenuous),mowingthelawn,raking,gardening,hiking,jogging,biking,exercisecycling,dancing,aerobics,bowling,golf,singlestennis,doublestennis,racquetball,calisthenics,swimming.Kcalsperweekexpendedarecalculatedusingstandardizedalgorithm.Thisvariableisstratifiedbygender.  Men:ThosewithKcalsofphysicalactivityperweek<383arefrail.  Women:ThosewithKcalsperweek<270arefrail.  •WalkTime,stratifiedbygenderandheight(gender-specificcutoffamediumheight).  Men CutoffforTimetoWalk15feetcriterionforfrailty Height≤173cm ≥7seconds Height>173cm ≥6seconds Women  Height≤159cm ≥7seconds Height>159cm ≥6seconds •GripStrength,stratifiedbygenderandbodymassindex(BMI)quartiles:  Men Cutoffforgripstrength(Kg)criterionforfrailty BMI≤24 ≤29 BMI24.1–26 ≤30 BMI26.1–28 ≤30 BMI>28 ≤32 Women  BMI≤23 ≤17 BMI23.1–26 ≤17.3 BMI26.1–29 ≤18 BMI>29 ≤21 •Weightloss:“Inthelastyear,haveyoulostmorethan10poundsunintentionally(i.e.,notduetodietingorexercise)?”Ifyes,thenfrailforweightlosscriterion.Atfollow-up,weightlosswascalculatedas:(Weightinpreviousyear–currentmeasuredweight)/(weightinpreviousyear)=K.IfK≥0.05andthesubjectdoesnotreportthathe/shewastryingtoloseweight(i.e.,unintentionalweightlossofatleast5%ofpreviousyear'sbodyweight),thenfrailforweightloss=Yes.  •Exhaustion:UsingtheCES–DDepressionScale,thefollowingtwostatementsareread.(a)IfeltthateverythingIdidwasaneffort;(b)Icouldnotgetgoing.Thequestionisasked“Howofteninthelastweekdidyoufeelthisway?”0=rarelyornoneofthetime(<1day),1=someoralittleofthetime(1–2days),2=amoderateamountofthetime(3–4days),or3=mostofthetime.Subjectsanswering“2”or“3”toeitherofthesequestionsarecategorizedasfrailbytheexhaustioncriterion.  •PhysicalActivity:BasedontheshortversionoftheMinnesotaLeisureTimeActivityquestionnaire,askingaboutwalking,chores(moderatelystrenuous),mowingthelawn,raking,gardening,hiking,jogging,biking,exercisecycling,dancing,aerobics,bowling,golf,singlestennis,doublestennis,racquetball,calisthenics,swimming.Kcalsperweekexpendedarecalculatedusingstandardizedalgorithm.Thisvariableisstratifiedbygender.  Men:ThosewithKcalsofphysicalactivityperweek<383arefrail.  Women:ThosewithKcalsperweek<270arefrail.  •WalkTime,stratifiedbygenderandheight(gender-specificcutoffamediumheight).  Men CutoffforTimetoWalk15feetcriterionforfrailty Height≤173cm ≥7seconds Height>173cm ≥6seconds Women  Height≤159cm ≥7seconds Height>159cm ≥6seconds •GripStrength,stratifiedbygenderandbodymassindex(BMI)quartiles:  Men Cutoffforgripstrength(Kg)criterionforfrailty BMI≤24 ≤29 BMI24.1–26 ≤30 BMI26.1–28 ≤30 BMI>28 ≤32 Women  BMI≤23 ≤17 BMI23.1–26 ≤17.3 BMI26.1–29 ≤18 BMI>29 ≤21  Openinnewtab Figure4.OpeninnewtabDownloadslideSurvivalcurveestimates(unadjusted)over72monthsoffollow-upbyfrailtystatusatbaseline:Frail(3ormorecriteriapresent);Intermediate(1or2criteriapresent);Notfrail(0criteriapresent).(Dataarefrombothcohorts.)Figure4.OpeninnewtabDownloadslideSurvivalcurveestimates(unadjusted)over72monthsoffollow-upbyfrailtystatusatbaseline:Frail(3ormorecriteriapresent);Intermediate(1or2criteriapresent);Notfrail(0criteriapresent).(Dataarefrombothcohorts.) Figure1.OpeninnewtabDownloadslideCycleoffrailtyhypothesizedasconsistentwithdemonstratedpairwiseassociationsandclinicalsignsandsymptomsoffrailty.Reproducedwithpermissionfrom(14).Figure1.OpeninnewtabDownloadslideCycleoffrailtyhypothesizedasconsistentwithdemonstratedpairwiseassociationsandclinicalsignsandsymptomsoffrailty.Reproducedwithpermissionfrom(14). Figure2.OpeninnewtabDownloadslideTimingofassessmentsoffrailtycomponentsforbothcohortsintheCardiovascularHealthStudy.*NotethatCohort2wasrecruitedandtheirbaselineexaminationoccurred3yearsafterthatofCohort1.Althoughclinicvisitsweredoneannually,frailtywasevaluatedlessfrequently.Figure2.OpeninnewtabDownloadslideTimingofassessmentsoffrailtycomponentsforbothcohortsintheCardiovascularHealthStudy.*NotethatCohort2wasrecruitedandtheirbaselineexaminationoccurred3yearsafterthatofCohort1.Althoughclinicvisitsweredoneannually,frailtywasevaluatedlessfrequently. Figure3.OpeninnewtabDownloadslideVenndiagramdisplayingextentofoverlapoffrailtywithADLdisabilityandcomorbidity(≥2diseases).Totalrepresented:2,762subjectswhohadcomorbidityand/ordisabilityand/orfrailty.nofeachsubgroupindicatedinparentheses.+Frail:overalln=368frailsubjects(bothcohorts).*Comorbidity:overalln=2,576with2ormoreoutofthefollowing9diseases:myocardialinfarction,angina,congestiveheartfailure,claudication,arthritis,cancer,diabetes,hypertension,COPD.Ofthese,249werealsofrail.**Disabled:overalln=363withanADLdisability;ofthese,100werefrail.Figure3.OpeninnewtabDownloadslideVenndiagramdisplayingextentofoverlapoffrailtywithADLdisabilityandcomorbidity(≥2diseases).Totalrepresented:2,762subjectswhohadcomorbidityand/ordisabilityand/orfrailty.nofeachsubgroupindicatedinparentheses.+Frail:overalln=368frailsubjects(bothcohorts).*Comorbidity:overalln=2,576with2ormoreoutofthefollowing9diseases:myocardialinfarction,angina,congestiveheartfailure,claudication,arthritis,cancer,diabetes,hypertension,COPD.Ofthese,249werealsofrail.**Disabled:overalln=363withanADLdisability;ofthese,100werefrail.AddresscorrespondencetoDr.RichardKronmal,CHSCoordinatingCenter,CenturySquareBuilding,15014thAvenue,Suite2105,Seattle,WA98101.ThisstudywassupportedbycontractsN01-HC-85079,N01-HC-85080,N01-HC-85081,N01-HC-85082,N01-HC-85083,N01-HC-85084,N01-HC-85085,N01-HC-85086,andN01-HC-15103fromtheNationalHeart,Lung,andBloodInstitute(NIH),Bethesda,MD.TheauthorsthankRayBurchfieldformanuscriptpreparationandCarolHanforherassistanceindevelopmentoffigures.TheopinionsandassertionsexpressedhereinarethoseoftheauthorsandshouldnotbeconstruedasreflectingthoseoftheUniformedServicesUniversityoftheHealthSciencesoroftheU.S.DepartmentofDefense.References 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