The physical frailty syndrome as a transition from homeostatic ...

Frailty in aging marks a state of decreased reserves resulting in increased vulnerability to adverse outcomes when exposed to stressors. Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature natureaging perspectives article Thephysicalfrailtysyndromeasatransitionfromhomeostaticsymphonytocacophony DownloadPDF Subjects AgeingDiseasemodelDynamicalsystemsEndocrinesystemandmetabolicdiseasesNonlineardynamics AbstractFrailtyinagingmarksastateofdecreasedreservesresultinginincreasedvulnerabilitytoadverseoutcomeswhenexposedtostressors.ThisPerspectivesynthesizestheevidenceontheaging-relatedpathophysiologyunderpinningtheclinicalpresentationofphysicalfrailtyasaphenotypeofaclinicalsyndromethatisdistinctfromthecumulative-deficit-basedfrailtyindex.Wefocusonintegratingtheconvergingevidenceontheconceptualizationofphysicalfrailtyasastate,largelyindependentofchronicdiseases,thatemergeswhenthedysregulationofmultipleinterconnectedphysiologicalandbiologicalsystemscrossesathresholdtocriticaldysfunction,severelycompromisinghomeostasis.Ourexegesispositsthatthephysiologyunderlyingfrailtyisacriticallydysregulatedcomplexdynamicalsystem.Thisconceptualframeworkimpliesthatinterventionssuchasphysicalactivitythathavemultisystemeffectsaremorepromisingtoremedyfrailtythaninterventionstargetedatreplenishingsinglesystems.Wethenconsiderhowthisframeworkcandrivefutureresearchtofurtherunderstanding,preventionandtreatmentoffrailty,whichwilllikelypreservehealthandresilienceinagingpopulations. 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MainWhydosomeolderpeopledieinthefaceofheatwavesandothersdonot?WhathascreatedtheheightenedriskofmortalityfromCOVID-19inolderpeople?Thisvulnerabilitycomesinpartfromtheeffectsofchronicdiseasesandotherhealth-relatedconditionsthataccumulatewithincreasingage.Wehypothesizethatitalsoresultsfromwhatcliniciansterm‘frailty’,astateofdepletedreserveresultinginincreasedvulnerabilitytostressorsthatemergesduringagingindependentlyofanyspecificdisease.Definitionsoffrailtyareabound.Thetwodominantlyusedare‘phenotypicfrailty’,whereavalidatedclinicalpresentationmarksadistinctclinicalsyndromeandpathophysiology1,2,anda‘deficitaccumulationmodel’frailtyindex,whichsummarizesthepresenceofmultipleclinicallyidentifieddiseases,theirclinicalandlaboratorymanifestationsandconsequences,andriskfactorsintoacompositeindexforriskprediction3,4.Thesetwodistinctconceptualizationsbothcarrythesamenomenclatureandbothpredicthighmortalityandinstitutionalizationrisk,buttheydenotedifferenttheory,etiologies,measuresandpossiblyprocesses,andidentifyconsiderablydifferentpopulationsanddifferenttargetsofintervention5.Otherdefinitionsoffrailtyhaveintegratedadditionalconstructs,particularlycognitivefrailty,asproposedbytheInternationalAssociationofGerontologyandGeriatrics/InternationalAcademyonNutritionandAging(IAGG/IANA)6,7.However,suchintegrationhasthepotentialtoobscuremeaningfuldifferences,asexemplifiedbytheobservationthat22%ofpeoplewithAlzheimer’sdiseasehadnophysicalindicatorsoffrailty8.Thisisreinforcedbyclinicalencounterswitholderadultswhoarephysicallyrobustbutcognitivelyfrailandviceversa.Accordingly,weviewothertypesoffrailty,whethertheyarecognitive,emotionalorpsychosocialfrailty,asimportantbutdistinctconstructsthatcanbemostfruitfullymeasuredseparatelyfromeachotherandfromphenotypicfrailty.Bothphenotypicallyidentifiedfrailtyandthefrailtyindex,finally,alsolinktootherconstructsingerontology,notably,‘allostasis’,‘homeostasis’,‘robustness’,‘reserve’and‘resilience’.Athoroughdisambiguationoftheserelatedconceptsisbeyondourscope,butprovisionaldefinitionsaregiveninBox1andconsideredbelow.Thesyndromeofphenotypicfrailty—henceforthtermed‘physicalfrailty’—isthefocusofthisPerspective.Clinicalpresentationofthephenotypedenotesadistinctivehigh-riskclinicalstatethatindicatesdecreasedreservesandhighvulnerabilitytostressors.Thestateisclinicallyrecognizablethroughthepresenceofthreeormoreoffivekeyclinicalsignsandsymptoms:weakness,slowwalkingspeed,lowphysicalactivity,fatigueorexhaustion,andunintentionalweightloss(Fig.1andBox1)1,2.Prevalenceinpeople65yearsandoldervariesacrosspopulations,withapredominantrateof7–10%incommunity-dwellingolderadults,whichincreasestoover25%inthoseover85yearsold1,2,9,10,11.Theconstellationofthreeormorecriteriaconstitutesadiagnosisoffrailty,whichhasbeenvalidatedtopredictadverseoutcomesincludingdeath,disability,lossofindependence,falls,hospitalization,diminishedresponsetodisease-targetedtherapies,higherriskofadverseoutcomeswithsurgeryanddelayedrecoveryfromillness1,2,12,13.Consistentwithaclinicalsyndrome2,thephenotypeislinkedtospecificpathophysiology.Physicalfrailtyoftenpresentswithoutclinicaldiseasesordisability,butitcanalsoco-occurwithdiseaseanddisability1,2,14,15(Box1).Thisisconsistentwithsubstantialresearchtodisentanglemultimorbidity,disabilityandfrailty,whichshowsthatthesearedistinctentitiesthatcanariseindependentlyaswellasbecausallyrelated16.Risksoffrailtyonsetorprogressionareespeciallyhighinthefaceofstressors1,soitisconsideredtobeastateofheightenedvulnerability.Fig.1:Ahierarchical,multiscalerepresentationofthephysiologicaldysregulationandlikelybiologicaldriversofphysicalfrailty.Theschemadepictstheclinicalsyndromeofphysicalfrailtyasanemergentproperty,atthehighestlevelofthehierarchy,underlainbyphysiologicalmodules(systems)atasmallerscaleandcellular/molecularmodules(systems)atanevensmallerscale.Goldcirclesrepresentthethreemajorphysiologicalmodules(systems)withthemostevidenceofinteractionsandthemostevidenceofarelationshipwithfrailty.Orangeovalsrepresentsubmodules(subsystems)withinthesethreelargermodules.Stressorsfromage-relatedbiologicalchangesatthecellular/molecularscale,representedinpurpleovals,likelyunderliedysregulationofthephysiologicalmodulesrepresentedabove,whichalsointeractwitheachother.Theaggregatephysiotypeofdysregulation(darkorangeoval)isassociatedwithboththephenotypeofphysicalfrailty,inthetopoval,andthevulnerabilityassociatedwithitsstate.Adaptedfromref.106.FullsizeimageIncontrast,thedeficitaccumulationmodelisconceptuallybasedontheclinicalobservationthatamultiplicityofclinicalproblemsinapatientcreatesaggregateriskofpooroutcomes,suchasmortalityandinstitutionalization.Thishasbeenoperationalizedasa‘frailtyindex’,whichcalculatesthepercentageofconditionsor‘deficits’identifiedclinically,relativetothenumberassessed,includingdiseases,symptoms,signs,impairments,disabilitiesandmeasuredfunctionallimitations,socialsettings,physicalactivity,mentalhealth,cognitivestatus,self-ratedhealthandsometimeslaboratoryvalues3,4.Thisarticlefocusesonthepathophysiologyofthesyndromeofphysicalfrailty,examininghowthephenotypemayemergeasadistinctstatelinkedtoseveredysregulationofkeyphysiologicalandbiologicalsystems:thestress-response,metabolismandmusculoskeletalsystems.Inhealthyadults,multiplephysiologicalsystemsfunctionwellandinteractharmoniouslyinacomplexdynamicalsystem,asinasymphony,tomaintainallostasisandhomeostasis.However,aspeopleage,individualphysiologicalsystemsdeclineintheirefficiency17andcommunicationbetweencellsandbetweensystemsdeteriorates18.Wehypothesizethatthisresultsinacacophonyofmultisystemdysregulation,whicheventuallycrossesaseveritythresholdandprecipitatesastateofhighlydiminishedfunctionandresilience,physicalfrailty.Thishypothesisrestsonaconceptualizationofthephysiologicalandbiologicalpathwaysunderlyinghealthandresilienceaslinkedelementsofacomplexdynamicalsystem(seeBox1foraglossaryoftermsandBox2forabriefintroduction),withseveredysregulationofthissystemunderlyingphysicalfrailty.Whilecomplexdynamicalsystemsmaysoundformidabletosome,thekeyinsightissimplythatone’sphysiologicalstateresultsfromnumerousinteractingcomponentsatdifferenttemporalandspatialscales(forexample,genes,cells,organs)thatcreateawholeunpredictablymorethantheparts19.Foranalogy,consideraclenchedfistasastateofthehand:thereisnodoubtthatthisstateiscontributedbycellsandmolecules.Nonetheless,themostimportantinsightsintothatfistarelikelytocomefromthehand’sstructure(fivedigits,opposablethumb,muscle–bone–motorneuronstructure)andfrominsightintotheteleologicalcontrolatahigherlevel(anger,aggression,evolutionaryusesofhands,andsoon).Applyingasimilarlogictophysicalfrailty,knowingthestateofalltheunderlyingbiologicalcomponentsmaynotadditivelysumtotheoverallstateofhealthoraccuratelyinfertheintegratedcapabilitiesofthehigher-levelorganism.Thisexampleillustratestheimportanceofhierarchyincomplexdynamicalsystems,whereinteractionsamongnestedandparallellevelsofcomposition(forexample,cells,tissues,physiology)contributeessentiallytotheoverallfunction.Thinkingoncomplexdynamicalsystemsoffersadditionalcompellingconceptualframeworkelementsforcharacterizingphysicalfrailty.Specifically,wesummarizebelow,inastepwiseprogression,evidencethatthepathophysiologyoffrailtymeetscriteriaforcriticaldysregulationofthecomplexdynamicalsystemnecessaryforhomeostasis:(1)physiologyismodularlyorganizedinhealthyorganisms,andnumerousmodulesaredysfunctionalinphysicalfrailty;(2)thedysfunctionisparticularlyapparentintheabilityofthesystemsandmodulestorespondtostressors;(3)thedysfunctiondoesnotproceedindependentlyineachsystembutratherisfundamentallyaboutinteractionsamongsystemsviafeedbackloops;(4)theimpactsofthedysfunctionarenotlinearbutexhibitexponentialand/orthresholdeffects;and(5)thesedynamicscanleadtocriticaltransitionsandabruptshiftsinphysiologicalstate.Wethenconsiderthebiologicalhallmarksofaging18thatcoulddiffuselyaffectallfunctionsofthiscomplexdynamicalsystemandmaybeaffectedbythephysiologicaldysfunctionsassociatedwiththephenotypeitself.Weconcludebyconsideringimplicationsandnext-stageresearchagendas.Box1AglossaryofkeyterminologyAdaptation.Achangeinthestructureorfunctionofanorganismthatincreasesthefitnessoftheorganismforsurvivaland/orreproduction.Thisisafundamentalattributeofacomplexsystem:thatitcanchangeitsrulesofoperationinresponsetoachangingenvironment.Allostasis.Theconceptofallostasisisbasedonthepremisethatthegoalofregulationisnottoachieveaconstantinteriormilieu(asinhomeostasis)buttocontinuallyadjustthemilieutopromotesurvivalandreproduction.Allostaticloadisthecostofmaintainingstabilitywhentheorganismisrepeatedlyconfrontedwithstressfulsituations109.Complexsystem.SeeBox2foradetailedcharacterizationofcomplexsystems.Criticaltransition.Atypeofemergentpropertyofacomplexsystem.Itisasharporabruptchangeinthestateofasystemwhenthecontrolsettingsofthesystemchangeminimally.Anexampleisthephasetransitionofwaterfromaliquidstatetoasolidstateinvolvingasmallamountofchangeinambienttemperaturearound273.15 K.Dynamicalsystem.Asystemwhosestatechangesovertime.Emergence.Occurrenceofnew,unexpectedphenomenainacomplexsystem.Typically,theemergentphenomenaoccuratahigherspatialortemporalscalethanthescaleatwhichthesystemcomponentsareinteracting110.Frailtycumulativedeficitindex.Increasedvulnerabilitytoadverseoutcomesandmortalityisconceptuallymeasuredasarisingfromtheaccumulationofhealthdeficits.Healthdeficitaccumulationisoperationalizedinafrailtyindexwhereinthedeficitscanincludeanysetofsymptoms,signs,medicalillnesses,polypharmacy,cognitiveimpairment,functionalimpairment,andpoormobilityandbalance(orevenlaboratorybiomarkers).Frailtyindexiscalculatedastheproportionofhealthdeficitspresentinagivenindividual3.Frailtyphenotype(physicalfrailty).Aclinicalsyndromewithadistinctphenotypeassociatedwithdecreasedreserveandhighvulnerabilitytostressorsandwithriskofadverseoutcomesincludingmortality.Asastatedistinctfromthediseasesanddisabilitypresent,thephenotypeappearstobeassociatedwithadistinctpathophysiologyresultingfromcumulativedeclinesinmultiplephysiologicalsystems,especiallyalteredstress-response,metabolicandmusculoskeletalsystems,andwithunderlyingbiologicaldrivers.Thephysicalfrailtyphenotypeistheclinicalpresentationofthesyndromeandisdefinedbypresenceofthreeoffiveofthefollowingcriteria:weakness,slowness,lowphysicalactivity,exhaustion(orfatigue)andunintentionalweightloss(0,robust;1–2,prefrail;≥3,frail)1,2.Homeostenosis.Age-relateddecreaseintheamountofphysiologicalreservethatisavailableforrespondingtostressors,asaresultofwhicholderadultsbecomevulnerabletotheimpactofstressors111.Modularity.Asystemismodularifitismadeupofbuildingblocks,eachofwhichmayalsobeconsideredtobeanindependentsubsystem.Modularityisahallmarkofcomplexsystems,whichtendtobehierarchical(forexample,genes,cells,tissues,organs,humans,families,societies)112.Network.Asystemcomposedofhighlyinterconnected,interactingcomponents.Abstractly,networkscanberepresentedinagraphwhosenodes(vertices)denotetheelementsofthesystemandwhoseedges(links)denotetheinteractionamongtheelements.Nonlinearity.Inlinearsystems,theresponsechangesinamannerproportionaltothechangeininput,whereasinanonlinearsystemtheresponsecanincreaseordecreasedisproportionatelydependingonthemagnitudeoftheinput.Inputcanbeanexternalperturbationofthesystemoraninternalchangeinthecomponentsofthesystem.Correspondingly,themagnitudeofaninputisthemagnitudeoftheexternalperturbationorchangeininternalcomponents(forexample,theintensityofaphysicalactivity,concentrationofanenzymeinthecell).Linearsystemsaresuperimposableinthesensethattheresponseselicitedbytwodifferentinputsactingsimultaneouslyareadditive,whereasinnonlinearsystemsthemultipleinputsactnon-additively,forexample,exhibitingsynergyordysynergy.Reserve.Physiologicalreservecanbequantifiedbyaweightedaverageofthemaximumworkcapacityminusthebasalworkoutput(basalworkoutputistheworkrequiredtomaintainhomeostasisunderminimalstressconditions)ofeachphysiologicalsubsysteminvolvedinstressresponse113.Resilience.Theabilityofasystemtorecoverfromastressorofsufficientlylargemagnitudethatthesystemispushedintoastatefarfromitsoriginalequilibriumstateandultimatelyretainsitsessentialidentityandfunction114.Robustness.Theabilityofacomplexsystemtomaintainitsstructureandfunctionintact(phenotypicstability)inthefaceofinternalandexternalperturbations114.System.Acollectionofinteractingelementsthatformsanintegratedwhole.Aphysiologicalsystemisdelineatedanddistinguishedfromitssurroundingsbymotifssuchasfunction(forexample,immunesystem)andstructure(forexample,mitochondria).Usedheresynonymouslywith‘module’.Box2AbriefintroductiontocomplexbiologicalsystemsHerbertSimon19definesacomplexsystemas“onethatismadeupofalargenumberofpartsthatinteractinanon-simpleway.Insuchsystems,thewholeismorethanthesumoftheparts,notinanultimatemetaphysicalsense,butinanimportantpragmaticsensethat,giventhepropertiesofthepartsandthelawsofinteractions,itisnotatrivialmattertoinferthepropertiesofthewhole.”Complexsystemsareoftenadaptive,reorganizingtheirinternalstructurewithouttheinterventionofanexternalagent.Theevolutionofbiologicalcomplexsystemsisfundamentallydrivenbythedemandforrobustnesstouncertainenvironments115,116,117,whichresultsinhierarchicalstructures(forexample,geneticmutations,cellularoxidation,glucosemetabolism,musclefunctionandclinicalmanifestation)andmodularorganizationateverylevelofthehierarchy(forexample,atthephysiologicallevelthereareenergy,skeletalmuscleandstress-responsesystems).Themodulararchitecturesarecomposedofelaboratehierarchiesofprotocolsandlayersoffeedbackregulation112.Thereareinteractionsbetweenthemoduleswithinandacrossthelevelsofthehierarchy,althoughwithin-levelinteractionsaregenerallymuchstronger.Diminutionofsystemfunctionandweakenedinteractionsbetweensystemsarelikelytoberevealedwhentheorganismischallenged.Becausetheinteractionsarenonlinear,thebehaviorofthesystemasawholecannotbepredictedfromitsstructuralcomposition.Thisisknownas‘emergence’—amanifestationofradicallynovelbehavioratahigherlevelofthehierarchythatisunpredictableandnon-deduciblefromlower-levelorganization.Animportanttypeofemergenceiscriticaltransitions(forexample,water–iceorwater–steamphasetransitions),wherethesystemchangesabruptlyandanewstateoffunctionemerges67,118.Methodologically,thecomplexsystemstoolboxisbynowpackedwithmethodstoanalyzenetworks,dynamics,emergenceandmanyotherfeatures118,119,120.Oneofthemoststrikingfeaturesofcomplexsystemsistheirtranslatability:principlesthatapplyinonesystemtendtoapplyinmanyothers,suchthateconomists,climatescientists,physicists,ecologistsandevenliterarytheoristsfindtheyhavemuchtolearnfromeachother.Complexsystemstheoryisstandardfareinmanyfieldsbutrareamongbiologists.Thisissurprising,asmanyofthecanonicalexamplesofcomplexsystemscomefrombiology;forexample,cellulardynamics,theimmunesystem,neuralnetworksandecosystems119,121.Thisislikelybecausethemathematicalformalismischallengingandrequiresintegrationacrossdistinctareasofbiologicaldiscovery.Complexsystemframeworkswouldresultinverydifferentpredictionsthantraditionalmodelsofsignalingpathwaysanddirectphysiologicaleffectsofsinglesystems.PhysicalfrailtyisanemergentstateofacompromisedcomplexdynamicalsystemWepresenthereevidencethatphysicalfrailtyinagingemergesasacompromisedstateofadysregulatedcomplexdynamicalsystem.Thisevidenceispresentedprogressivelyintermsofthecriteriaforcomplexdynamicalsystems:themodularsystemsandsubsystemswhichfunctionbothindependentlyandinjointfeedforwardandfeedbackregulationthatcharacterizessuchsystemsandiscriticalformanagingallostasisandhomeostasis;theevidencethatsuchcoreregulatorysystemsassociatedwithphysicalfrailtyco-regulateeachotherandtheiraggregatedysfunctionisassociatedwiththephenotypeoffrailty;thatdysregulationofthesemultiplesystemsismadevisiblewhenchallenged;thatpastathresholdofaggregatephysiologicdysfunction,frailtyemergesasastateoflowerfunctionofthewholeorganism,andtheassociationisnonlinear;andthatthereisapointofnoreturnbeyondwhichfunctionatalowerstateisnolongercompatiblewithlife.AhealthyorganismiscomposedofmodularsystemswhosefunctionisabnormalwhenpeoplearephysicallyfrailAhealthyorganismiscomposedofsystems,ormodules,withlargelyindependentfunctions.Thefunctionofmostsystemsdeteriorateswithage17,18.Amongthefullpanoply,thereisacoresetofsystemsandsubsystemsthatarecriticalformanaginghomeostasisandwhichhavealsobeenshowntofunctionatabnormallevelswhenpeoplearephysicallyfrail20.Thesesystemsincludethemetabolic,musculoskeletalandstress-responsesystems(Fig.1).Wesummarizebrieflyhereevidenceoftheseassociations.Physicalfrailtyprevalenceandincidencehavebeenlinkedtoalteredenergymetabolismthroughbothmetabolicsystems,includingglucose–insulindynamics21,glucoseintolerance22,insulinresistance23andalterationsinenergy-regulatoryhormonessuchasleptin,ghrelinandadiponectin24,25,26,27,andalterationsinmusculoskeletalsystemfunction,includingtheefficiencyofenergyutilization28andmitochondrialenergyproductionandmitochondrialcopynumber29,30.Notably,acrossthesesystems,bothenergyproductionandutilizationareabnormalinthosewhoarephysicallyfrail.Theaggregatestress-responsesystemanditssubsystemsarealsoabnormalinphysicalfrailty.Specifically,inflammationisconsistentlyassociatedwithbeingfrail,includingsignificantassociationswithelevatedlevelsofinflammatorymediatorssuchasC-reactiveprotein,interleukin(IL)-6andwhitebloodcellsincludingmacrophagesandneutrophils,amongothers31,32,33,34,35,inabroadpatternofchronic,low-gradeinflammation36,37,38,39.Indicatorsofautonomicnervoussystemdysregulationinfrailtyincludediminishedsecond-to-secondheartratevariability40,41,42andcompromisedorthostatic43andcardiac44control.Physicalfrailtyisalsoassociatedwithdysregulationoffunctionsofthehypothalamic–pituitary–adrenal(HPA)axis,includinghigherlevelsandblunteddiurnalvariationofsalivarycortisol45,46andlowerlevelsoftheadrenalandrogenDHEAS47,48.Together,thesestudiescharacterizefrailindividualsaslessabletofinelytuneresponsestoenvironmentalvariation.Whilethesystemsidentifiedhereareneitherdefinitivenorexclusive,theylikelyformahubofdominantpathophysiologicalcharacteristicsinthephysicallyfrail.ExperimentalevidenceofimpairedphysiologicalresponsivenessofkeysystemsinthefrailTheabnormallevelsofbiomarkersinthethreesystemsaboveisnotablebutdoesnotofferformalevidenceoftheclinicalvulnerabilitytostressorsinfrailolderadults.Complexsystemstheorypredictsthatcompromiseddynamicalfunctioningofsystemsmaynotbeapparentinarestingornon-stressedstatebutemergesclearlyunderconditionsofstressortheneedtoadapt.Stimulus–responseexperimentsprovideaparticularlycompellingmethodtoelucidateandcharacterizeresponseunderconditionsofstress49.Wesummarizeherefiveexperimentsexposingcommunity-dwellingolderadultstominorphysiologicalstressorsinthesystemsdescribedabove(Fig.1)andtheresultingphysiologicalresponsesinphenotypicallynonfrail,prefrailandfrailindividuals.Althoughthefirstfourexperimentsrepresentpilotresearch,takentogether,theparallelismofthestress–responsefindingsisnotable(Fig.2)andsuggestiveofanensemblerole.Thefirstthreewereconductedinasinglecohortofwomen85–94yearsofageparticipatinginsubstudiesoftheWomen’sHealthandAgingStudy(WHAS)II.Fig.2:Stimulus–responseexperimentsinolderadultsmeasuringphysiologicalresponsetominorstressorsincommunity-dwellingolderadultswhowerecharacterizedasnonfrail,prefrailorfrail.Pilotstudiesina–cwereconductedincommunity-dwellingwomen85–94yearsofageinWHASII.Thestudyindwasofmaleandfemalevolunteersages70andolder,includingWHASIIparticipants.a,Glucose(left)andinsulin(right)dynamicsduringOGTTbyphysicalfrailtystatus;dataareshownasthemean ± standarderror(s.e.;errorbars)forglucoseandinsulinvaluesat0,30,60,120and180 minutesafteradministrationofaglucoseloadof75 gbyfrailtystatus.ThePvaluesforcomparisonsoftheareaunderthecurve(AUC)were0.82(prefrailversusnonfrail)and0.02(frailversusnonfrail)forglucoseand0.26(nonfrailversusprefrail)and0.27(nonfrailversusfrail)forinsulin33.Panelreproducedfromref.21.b,Timeto95%recoveryofPCrlevelsaftermildexercise,calculatedas3/k,wherekistherateconstantofthemonoexponentialfit.ThePvaluesforcomparisonsofthegroupmeansinthispilotwere0.57(prefrailversusnonfrail)and0.22(frailversusnonfrail),likelyowingtothesamplesizeof30(ref.50).Panelreproducedfromref.50.c,DHEAresponsetoACTHstimulationtestbyfrailtystatus.Dataareshownasthemean ± s.e.(errorbars)forDHEAvaluesat0,30,60and120 minutesafteradministrationof250 μgACTH.ThePvalueforaglobaltestofdifferenceinmeanbyfrailtystatuswas0.86(ref.63)inthispilotstudyof51women.Panelreproducedfromref.52.d,Responsetoinfluenzavaccinationinpeople70yearsandolder;dataareshownasthegeometricmeanHIantibodytiter(GMT)ratiostoH1N1,H3N2andBstrainsinallstudyparticipantsandbyfrailtystatus(left)andtherateofILIandlaboratory-confirmedinfluenzainfection(right)duringthepost-vaccinationseason.ThePvaluesfortheGMTratios(0.04,0.01and0.05forH1N1,H3N2andBstrains,respectively)wereobtainedfromlinearregressionforastepwisetrendofdecreasefromnonfrailtoprefrailtophysicallyfrailindividuals,adjustedforage;thecorrespondingPvaluesforILI(0.005)andinfluenzainfection(0.03)rateswereobtainedfromlogisticregressionanalysisforastepwisetrendofincreasefromnonfrailtoprefrailtofrailindividuals,adjustedforage53.Panelreproducedfromref.53.Physicalfrailtycriteria:0,nonfrail;1–2,prefrail;3–5,frail1.FullsizeimageMetabolicsystemandglucosemetabolismWomenwithoutdiabeteswereadministeredastandardoralglucosetolerancetest(OGTT;n = 73)(Fig.2a).Therewaslittledistinctioninmeanbaselineglucoseorinsulinlevelsbyfrailtystatus.Followingstresschallenge,physicallyfrailwomenshowedanexaggeratedriseinbothmeasures,togetherwithprolongedresponses,incomparisontoprefrailandnonfrailwomen,whenadjustingforage21.Overall,themeanpeakglucoselevelwasincreasedbymorethan30%inthefrailgroupversustheothertwogroups,andthemeanpeakinsulinlevelwasincreasedby75%.Further,therewasadysregulatedresponseoftheappetite-stimulatinghormoneghrelinintheOGTT,withphysicallyfrailwomenmaintaininglowerlevelsthroughoutthe2-hourexperimentincomparisontononfrailwomen24.Notably,only27%ofallstudyparticipantshadanormalfastingglucoselevel(<100 mg dl–1),whereas48%hadprediabetes(2-hourglucose<140 mg dl–1)and25%hadundiagnoseddiabetes.Dysregulationofglucoseappearedtobethenormamongthesewomen,buttheresponsetochallengewasmarkedlymoredysregulatedamongthefrailsubset.SkeletalmusclesystemWomen(n = 30)engagedinisometricexerciseofthedominantlowerextremityfor30 secondswithinamagneticresonancespectroscopyimagingunit(Fig.2b).OxidativephosphorylationinbufferingATPlevelsinskeletalmusclewasassessed:thephosphocreatine(PCr)recoverykineticsweresloweramongfrailwomen(189 ± 20 seconds)thanamongprefrail(152 ± 23 seconds)andnonfrail(132 ± 32 seconds)women50.Thus,thefrailandprefrailgroupshadPCrrecoverythatwas57and20 secondsslower,respectively,thanforthenonfrailgroup.Arecentlypublishedstudyshowsrapidenergeticdeclineintheexercisedskeletalmuscleoffrailcomparedtononfrailolderadults,furtherdemonstratingstress-inducedenergydysfunctioninfrailty51.Stress-responsesystem,HPAaxisAstandardadrenocorticotropichormone(ACTH)stimulationtestwith250 µgACTHwasperformedin51womenwhowerenottakingcorticosteroids(Fig.2c).Dehydroepiandrosterone(DHEA)responseswereexaminedat0,30,60and120 minutesafteradministrationofACTH.Pre-andpost-ACTHstimulatedDHEAlevelsdidnotdifferstatisticallybyfrailtystatus;however,thedose–responsecurvessuggesteddivergenceafterstimulation,withamoreexaggeratedDHEAresponsewithincreasingphysicalfrailtyandstepwiseincreaseddysregulationacrossnonfrail,prefrailandfrailindividuals,inlinewithprogressivelyinadequatenegativefeedback52.Stress-responsesystem,innateimmunesystemandactiveimmunityInmaleandfemalevolunteersaged70yearsandolder(n = 71,includingsomeindividualsfromWHASII),frailtywasassociatedwithsignificantlyimpairedresponsetotrivalentinactivatedinfluenzavaccine,asmeasuredbyvaccine-inducedstrain-specifichemagglutinin-inactivating(HI)antibodytiters,whenadjustingforage(Fig.2d).Ratesofinfluenza-likeillness(ILI)andlaboratory-confirmedinfluenzainfectionshowedstepwiseincreasesfromnonfrailtoprefrailtophysicallyfrailindividuals53.Thus,frailtystatusmayidentifythoselesslikelytorespondtoinfluenzavaccinationandathigherriskofseasonalinfluenzaanditscomplicationsdespitevaccination.Stress-responsesystem,autonomicnervoussystemfunctionIrishparticipantsaged60yearsandolder(n = 442)underwentalying-to-standingorthostaticbloodpressure(BP)testwithconcurrentBPmonitoringbyfingercuff.Physicalfrailtyprevalencewasenrichedamongthoseexperiencingorthostatichypotension(initialcriterion)inresponsetothetest(14.1%versus5.4%fornonfrailindividuals)54.Accordingly,boththestatic(seeabove)anddynamicresponsecapacityofparallelphysiologicalsystemshavebeenlinkedtophysicalfrailty,withsystemsthatmayappearnormalinsteadystatedemonstratingdysregulationwhenchallenged.Thesefindingssupporttheconceptofphysicalfrailtyasastatecharacterizedbycompromisedresponsivenesstostressorstimulusinaffectedsystems(Fig.3).Thisisconsistentwithcomplexsystemstheoryandalsomaycontributetounderstandingofthehighaging-relatedvulnerabilityofsomeolderadultstostressorssuchasCOVID-19infection.Fig.3:Hypothesizednaturalhistoryoffrailty:deteriorationofphysiologicalintegrityinresponsetorepeatedstressorsandnaturalaging.Thephysiologicalintegrityofthesystemisdefinedbythecapacitytomaintainahealthyequilibriuminthefaceofstressors.Therollingballrepresentsstress-responsedynamics.Thelevelofphysiologicalintegrityistheorizedtobeafunctionofthereservesrepresentedbyboththedepthofeachbowlandtheradiusofthecurvature,withgreaterdepthandcurvaturerepresentinggreaterreserveandresiliencetostressors.Timetorecoveryafterastressorisameasureofthisresilience(forexample,seeFig.2aforglucoserecoverycurvesintheOGTTshowingthatfrailolderadultshaveamuchslowertimetorecovery).Bothepisodic(forexample,stroke,fall)andchronic(forexample,chronicinflammation)insultsarehypothesizedtodecreasetheintegrityofthesystem,thusdegradingtheabilitytoreturntoequilibriumandtorespondtosubsequentstressors.Progressionoffrailtyconsistsofaseriesofcriticaltransitions(denotedbyasterisks)betweenstatesofequilibriumofdecreasingintegrity;ataparticularcriticaltransitionpoint,thesystembecomesoverwhelmedandcannolongerharnesstheresourcesneededtomaintainintegrity,resultingintheclinicalphenotypeofphysicalfrailty.Reproducedfromref.7.FullsizeimageWeakenedinteractionsandfeedbackbetweensystemsunderpinningphysiologicalvulnerabilityoffrailtyAnotableaspectofthethreephysiologicalsystemsdominantlydysregulatedinphysicalfrailtyisthattheirfunctionsinteractwiththoseoftheothersystemsinfeedforwardorfeedbackeffects55,56,57.AhealthystateinvolvesthesystemsinFig.1interactingwitheachotheroptimally58,59,60,61,62.Forexample,immunesystem-generatedcytokinesdrivearobustresponsetoaninfectionthroughinflammatorycytokinesandshutthatsameresponsedownthroughanti-inflammatorycytokines63.However,iftheinflammatorysignalingcontinueschronically,inafeedforwardway,asisobservedinphysicalfrailty,itimpactsothersystemsandtissueswithresultsincludingalteredHPAaxisactivityandenergymetabolismbypromotionofinsulinresistanceandglucoseintoleranceaswellasdecreasedmitochondrialenergyproduction,alteredredbloodcellformationandskeletalmuscledecline58,64,65.Bothinflammatorysignalingandskeletalmuscleinactivityamplifycortisol,theproductoftheHPAaxis,tomorerapidlycatabolizeskeletalmuscle.Cortisolnormallytampsdowninflammatorysignaling66.However,inthefaceofchronicityandloweredabilitytoblockinflammatorysignaling,cortisolcanimpactenergymetabolismviainsulinresistance64,66,67.Theseexamplesoffersupportfordysregulationofthefeedbackloopsbetweencoresystemsassociatedwiththephysicallyfrailstateandforthenetworkednatureofphysiologicaldysregulation,inlinewithacomplexdynamicalsystem(Boxes1and2).Theseobservationsalsosupportdysregulatedcommunicationandinformationprocessingasacorefeatureofphysicalfrailty.Thereisfurtherevidencethatfeedbackrelationshipsamongthesesystemsarealteredasaconsequenceofcumulativestressoverthelifecourse,calledallostaticload,compromisingtheabilityoftheintegratedphysiologicalsystemstoadapt,termedallostasis57.Physicalfrailtymaybeamoreseverestateofallostaticcompromise68,69,propelledbyagingprocessesaswellasstressors.However,weshouldbecautiousininterpretingthedysregulatedlinksbetweensystemsasautomaticallyimplyingacascadeofdysregulation.Contrarytothewidespreadassumptionthatagingisapurelydetrimentalprocess,therearemanyaspectsofaging—notably,muchofimmunosenescence—thatrepresentadaptationseithertootherdetrimentalprocessesortochangingneedsatdifferentages70,71.Thisraisesthespeculationthatthefrailstatemightitselfbeadaptive,awayofstavingoffdeathorovertdiseasestates.EvidencefornonlinearityintherelationshipbetweenthenumberofdysregulatedsystemsandfrailtyThedynamicsofcomplexsystemsgenerallyrenderthemnonlinear(Box1),wherethemultipleinputsactnon-additively,exhibitingsynergisticorantagonisticeffects.Ifphysicalfrailtyisastatethatresultsfromathresholdlevelofdysregulationofthecomplexdynamicalsystemofhumanhomeostasis,thetransitionfromastateofstandardfunctioningtoacriticallydysregulatedstatewouldtheoreticallybeexpectedtobenonlinear.Thatis,asthenumberofsystemsmalfunctioningincreases,theriskoffrailtyescalatesnonlinearly.Thepreliminaryevidenceisconsistentwiththeory.Apopulation-basedstudyofwomen70–80yearsofageevaluatedthehypothesesthatdysregulationofmultiplephysiologicalsystemsisassociatedwiththeriskoffrailty,thatnosinglesystemexplainsthisandthatthestrengthofassociationacceleratesinanonlinearfashionwithincreasingnumbersofdysregulatedsystems72.Assessingeightmarkersfromdifferentphysiologicalsystemsindependentlyrelatedtophysicalfrailty((inflammation(IL-6 > 4.6pg ml–1),anemia(hemoglobin 6.5%),micronutrientdeficiencies(≥2),adiposity(tricepsskinfoldthickness 31.9 s)),physicalfrailtywasfoundtobeassociatedwithanincreasednumberofimpairedsystemmarkers,independentlyofassociationswithindividualbiomarkers.Theoddsratioforthosewith1–2abnormalsystemswas4.8(comparedtothosewithnoabnormalsystems),increasingto11-and26-fold-increasedrisk,respectively,forthosewith3–4and5ormoresystemsatabnormallevels(95%confidenceintervalsexclude1).Comorbiddiseaseswereassociatedwithphysicalfrailty,independentlyofthenumberofabnormalsystems.Commensurately,therewasanonlinearincreaseinfrailtyprevalencewithincreasingnumbersofabnormalphysiologicalsystems(Fig.4).ThesefindingsfromtheWHASIandIIstudy72haverecentlybeenreplicatedinanadditionalpopulationfromQuebec69.Fig.4:Nonlinearincreaseintheprevalenceofphysicalfrailtybynumberofdysregulatedphysiologicalsystemsatbaselineamongwomenaged70–79yearsparticipatingintheWHASIandIIstudies(n = 704).Thefilleddotsconnectedbythesolidlinesegmentsareprevalenceestimatescorrespondingtothenumberofdysregulatedsystems,basedonageneralizedlinearmodelwithabinomialfamilydistributionforbeingfrail(versusnonfrail)andidentitylinkwhiletreatingthenumberofdysregulatedsystemsasdummyvariables.Theverticalbarsrepresent95%confidenceintervalsfortheprevalenceestimates.Whenfittingaquadraticequationtothecurve,thequadratictermwasstatisticallysignificant,atP = 0.027.Thedashedlineshowsthatalinearmodeldoesnotfittheincreaseinprevalenceofphysicalfrailty.Adaptedfromref.72.FullsizeimageThefactthatmultisystemdecrements,notanysubgroups,weresignificantlyassociatedwithfrailtyindicatesthatamultiplicityofphysiologicalabnormalitiesiswhatisofimport,morethananyonespecificsystem,inphysicalfrailty.Thisspeakstothediffusenessordistributednatureoftheunderlyingprocess,akeypredictionforanemergentpropertyinacomplexsystem,andoffersatheoreticalbasisforthenullfindingsfromnumeroussingle-hormonereplacementtrials73,74,75:replacingadefectivepartdoesnotsolvetheproblemofthedysregulatedwhole.Insummary,thecombinationofmultisystemdysregulationandnonlinearityintherelationshipwithphysicalfrailtysupportscomplexdynamicalsystemdysregulationasadistinctpathophysiologyassociatedwiththeclinicalpresentation.EvidenceforcriticaltransitionsinphysiologyandinclinicalseverityCriticaltransitionsareabruptchangesinthestateofcomplexdynamicalsystemsresultingfromtheinternaldynamicsofthesystem(Boxes1and2).Theabovefindingsonnonlinearitysupportthehypothesisthatfrailtyresultsfromacriticallevelofdysregulationofacomplexdynamicalsystem,resultinginacriticaltransitiontoanewemergentstate76,77,78,inthiscaseoneoflowerfunction.Thisisconsistentwithpriorreportsthatindividualsenescentprocessesdisplayquasilinearpropertiesofdeclineacrossthelifecoursebuttheiraggregateeffectisnonlinear79.Thereareatleastthreepotentialtypesofcriticaltransitionsassociatedwithphysicalfrailty:transitiontoaphysiologicallyvulnerablestate,transitiontoaclinicallyapparentphenotypeandtransitiontodisabilityanddeath.Figure3conceptuallyexemplifiesthesequenceofcriticaltransitionsduetoage-relatedprogressivedeteriorationinphysiologicalintegritythatresultsinanimpairedabilitytorespondtostressorsandindistinctclinicalstates(forexample,prefrailandfrailstates,death).Theabovedataonstimulus–responseexperiments(Fig.2)andonnonlinearity(Fig.4)agreewiththiscriticaltransitiontheory.AsinFig.3,therearecriticalage-relatedtransitionsinphysiologicalintegritythatunderlietransitionsinclinicalstates.Withinclinicalstates,thereisalsoevidenceoftransitiondynamics.Forexample,thereisahierarchyintheemergenceofcriteriainthephenotypeofphysicalfrailty(Fig.1),startingwithmuscleweakness,slownessandlowphysicalactivity;exhaustion(orfatigue)andweightlossaregenerallythetippingpointsfortheonsetofphysicalfrailty80.Thecriticaltransitiontophysicalfrailtyportendsacompromisedstressresponse(Fig.2)andriskforadverseoutcomes.Finally,theevidencetodateraisesthequestionofwhetherthemostseveremanifestationsofphysicalfrailtyareacriticaltransitionpointtofurtherdeclineanddeath.Theevidenceisthatthereisasharpescalationinriskofadverseoutcomesofdisabilityanddeathwhenindividualsmanifestthephenotypeofphysicalfrailty1(Fig.1),andmeetingallfivephysicalfrailtycriteriasignalsthebeginningofatransitiontowardapointofnoreturn,beyondwhichtheprocessbecomesirreversibleanddeathbecomesimminent81.PotentialdriversofthecomplexsystemdysregulationunderlyingphysicalfrailtyTheevidencethatmultiplesystemsaredysregulatedinparallelinphysicalfrailtyraisesthequestionofwhetherthereisasharedbiologicaldriverofthisparalleldysregulationandtheaggregateeffects.Figure1describesaconceptualframeworkinwhichmolecularchangesdrivephysiologicalchangesinenergy,musculoskeletalandstress-responsesystems.Itisplausiblethatcellularandmolecularhallmarksofagingmaycontributetophysicalfrailty,includinggenomicinstability,telomereattrition,epigeneticalterations,proteostasisloss,dysregulatednutrientsensing,mitochondrialdysfunction,cellularsenescence,stemcellexhaustionandalteredintercellularcommunication18.Thealtereddynamicalphysiologicalsystemspointtoatleastthreeofthesehallmarks,intercellularcommunication,cellularsenescenceandmitochondrialdysfunction,aspotentialdriversofphysicalfrailty.Forcellularsenescence,thisplausibilityreferencesacommonfeatureofphysicalfrailty:highlevelsofinflammatorymediators(chronicinflammation),whichareknowntobeheavilysecretedfromsenescentcelltypes82.Thereisalsodirectevidencethatcellularsenescenceandmitochondrialfunctionhavearoleinphysicalfrailty.Senescentcellsinjectedintoyoungermiceaccelerateatrajectorytowardphysicalfrailty,whilesenolytictreatmentreversesthis83.Evidenceofmitochondrialenergyproductiondeficitsexistsinbothhumansandamousemodeloffrailty28,84.Inhumans,PCrrecoverytime,ameasureofmitochondrialoxidativephosphorylation,isreduced50,51.Inamousemodeloffrailtyderivedthroughchronicinflammation,skeletalmuscleATPkineticsareimpairedanddecreasedmitochondrialdegradationinskeletalmusclehasbeenidentified28,85.Finally,indirectevidencecomesfromstudiesdemonstratingthatmitochondrialdysfunctionishighlyrelatedtoglucoseintoleranceatatissuelevel86,whichisassociatedinhumanswithphysicalfrailty21,51.Lookingthroughadifferentlensatthedataalreadypresented,thereisnowearlyevidencesuggestingthataging-relatedenergydysregulationisanunderlyingdriverofgeneralizedphysiologicaldysregulationandtheemergenceofafrailstate.Considerthatthephenotypeofphysicalfrailtyisassociatedwithcompromiseincellularrepletionofenergy(Fig.2b)50,withdysregulatedglucosemetabolismaffectingenergyavailability,insulinresistanceandglucoseregulation(Fig.2a),andwithenergyintakeviatheimpactofghrelinonappetiteregulation21,24.Skeletalmuscleenergeticdepletionandcataboliteaccumulationhavebeenshowntobeadeterminantoffatigue,orexhaustion,ahallmarkmanifestationofphysicalfrailty1,20,87,andsarcopeniaisassociatedwithdecreasedefficiencyofmuscularenergyutilization28,88.Additionally,frailolderadultsexhibitdysregulationoftherestingmetabolicrate,withgreatervariancethanthosewhoarenotfrailorprefrail89.Further,inarecentstudyinfrailmice,cellularenergeticsinvolvingmitochondrialenergyproductionandoxidativestresswerefoundtobecentraltothestressresponse28,90.MitochondrialdysfunctionswereshowntoaltertheHPAaxis,sympatheticadrenal–medullaryactivationandcatecholaminelevels,theinflammatorycytokineIL-6,circulatingmetabolitesandhippocampalgeneexpressionresponsestostress91.Inolderadults,therearealsostrongassociationsofalteredmitochondrialfunctionandgeneexpressionwithphysicalfrailty29,30.Finally,theapriorihypothesisaboutthephenotypeoffrailtyitselfwasthatthefivecriteriaforfrailtyconstitutedasetofmarkersconnectedinaviciouscycleofapparentdysregulatedenergetics1,92.Onthebasisofthisevidence,wehypothesizethatnotonlydoenergeticsunderliethehealthyfunctioningofthehumanorganismbutenergeticimbalanceisakeydriverofphysicalfrailty—andoftheclinicalviciouscycleofthephenotypeoffrailtyanditsadverseoutcomes(Fig.1).Livingorganismscanbeviewedasthermodynamicmachinesefficientlyexchangingenergywiththeirenvironment.Eventually,theenergyexchangeandutilizationbecomecriticallysuboptimal,owingtoaging,stressanddisuse.Thelesstheenergyflowsthroughthesystem(duetodecreasedactivity),thegreaterthediscordbetweenstructureandfunction,aswellasbetweentheorganismanditsenvironment.Withenergeticimbalance,thesystemshrinksandisdriventoafrailstate,withaseverelycompromisedabilitytowithstandstressors.Notably,ifenergycanexplainthesimultaneousandparalleldysregulationsanddiminishedinteractionswithinandbetweensystems,physicalactivitycouldbeconsideredasamodelinterventiontopreventthefrayedcomplexdynamicalsystemunderlyingfrailty93,asitupregulatesallrelatedsystemsandincreasestheenergyflowthroughthe‘entire’organism,makingthethermodynamicsoflifefavorableforthriving.WalterBortzputsthisbeautifully:“everycell,everyorgan,everysystemofthebodyisbeholdentotheenergeticimperative.Webecomewhatwedo.Frailtyiswhathappenswhenwedon’t”94.DiscussionWehavesummarizedtheaboveevidencesupportingthethesisthatphysicalfrailtyarisesfromcriticaldysregulationofacomplexdynamicalsystem,whoseprimarycomponentsarehighlightedinFig.1,andthatitistheoutcomeofacriticaltransitiontoadistinctstateofsuboptimalfunctioningandhighriskwhenstressed.Thisframeworkchangesthesearchforsuccessfulpreventionortreatment.First,criticaltransitionsnecessitateearlyaction,beforethetransitionisimminent.Second,thisapproachcanexplainwhyreplenishmentofasingle-systemdeficithasnotbeenfruitfulinfrailtypreventionandtreatmentoffrailty(whichmayrequire,instead,tobemosteffective)interventionstotuneandoptimizephysiologyasawhole.Aggregatemultisystemfitnesstomaintainhomeostasisandresilienceandtopreventphysicalfrailtylikelyrequiresmacro-levelinterventionsthatarenon-reductionist—forexample,interventionstoimprovephysicalactivityorsocialengagement;thelatter,apartfromcontributingtopsychologicalwell-being,alsocanincreasephysicalandcognitiveactivity95,96,97.PhysicalactivityimprovesfunctionateverylevelofFig.1,includingtheelementsofthephenotypeandeachofthecoresystemsinthehubofphysiologicalfrailty,andupregulatesmitochondrialfunction,simultaneouslymodulatingmultipleinterconnectedregulatorysystems93.Thereisstrongevidencethatfrailtyisbothpreventedandamelioratedbyphysicalactivity,withorwithoutaMediterraneandietorincreasedproteinintake98,99,100,101.Thesemodelinterventionstodatearenonpharmacological,behavioralones,emphasizingthepotentialforpreventionthroughacomplexsystemsapproach.Twoothermajortypesofinterventionareusedtoamelioratefrailty:individuallytailoredgeriatriccaremodelsandpharmacologicalinterventions.Individuallytailoredmulticomponentgeriatriccaremodelsprescribeinterventionsbasedonapatient’sspecificimpairments.Theresultssofarhavebeenmixed87,102.Pharmacologicalinterventions,ontheotherhand,havebeenfocusedonsinglesystemswithtwoprimarytargets:inflammationandanabolichormones.Thereisnodirectevidenceofefficacyofpharmacologicalinterventionsonphysicalfrailtybeyondphenotypiccomponentssuchasmusclestrength,bodyweightandfatigue103.Interventionsdesignedtotargetthephenotypiccomponentsoffrailtyorasingle-system-focusedonedeficit/onetherapymodelinthecaseofhormonaltherapywilllikelybeineffectiveinalleviatingtherootcause(s)offrailty104,105.Rather,pharmacologytoimprovemultiplesystemssimultaneouslyand/orindividuallytailoredpharmacologyviaprecisionmedicinetopersonalizehowequilibriumisrestoredmayberequired.Untilthattime,directclinicalinterventionneedstobettermanagefrailolderadultsthroughminimizingaggravatingfactorssuchaspolypharmacy,environmentalhazards(forexample,fallprevention)anddiscontinuitiesofcarewhileoptimizinghealth-andresilience-producingbehaviorssuchasphysicalactivity.Forallpotentialfrailtyandfunctionalperformanceassessments,itiscriticallyimportanttoassesstheseoutcomemeasuresinbothobservationalandinterventionalclinicaltrials.Morebroadly,understandingfrailtyastheoutcomeofbothlifecoursestressorsresultinginallostaticload57andage-relateddysregulationofourcomplexdynamicalsymphonycouldofferaparadigmshiftinthinking.TheconceptsinFig.3mayofferawaytoworkinreversetounderstandthefabricofhealthandrobustnessand,then,forwardtounderstandhowthefrayingofthisfabricisinitiallycompensatedbyresiliencebutprogressionresultsintransitiontoastateoffrailty.Conceptualizingfrailty—andhealth—asarisingfromourintertwineddynamicalphysiologyisaprototypicallygerontologicalapproach,takingaholisticviewofthewell-beingofolderadultsandusingawidearsenaltopromotephysical,mentalandemotionalhealth,meaningandqualityoflife.Theexistingworkisstillearly,however.Webrieflyindicateheretheresearchneedsderivingfromthisframework.FurtheringthecurrentevidenceTheevidenceonstress-responseexperimentscitedabovelargelyresultedfrompilotstudies.Confirmatorystudiesareneededthatelicitresponsesinmultiplesystemswithinindividualsandimplementfinerrepeatedmeasurementofresponsecurvesoverlongerrecoverytimes,withasufficientnumberofparticipantstoallowtheparametersgoverningfitnessandinteractionsofthephysiologicalensembletoberelatedtofrailty.Studiesofmultisystemdynamicscouldthenprobetheincrementaleffectsofcombineddysregulations,characterizingthephysiotypeandphenotypeofphysicalfrailtythatjointlymakeuptheclinicalsyndrome.Further,longitudinalresearchisneededtoelucidatetheimplicationsofchangesinphysiologicalfitnessforfrailtyincidenceandprogression—particularlyaddressingmultisystemfunction.Theevidencefornonlinearityreportedaboveisintriguingbutnotdefinitive.Studiesareneededthatdeliberatelyelicitmeasuresinthecollectionofphysiologicalsystemsandsubsystemsthathavebeenmoststronglyimplicatedinfrailty(asopposedtousingavailablemeasuresinanexistingstudy)andthatdosoinsufficientbreadthanddepththatcriticalinflectionsintherelationshipofdysregulationburdenwithfrailtyriskcanbedetected.High-priorityresearchfrontiersAssumingaccomplishmentofthenext-stagegoalsdescribedabove,canwedeterminewhetherthereisaspecificbiologicaldriverofthemultisystemphysiologicaldysregulationofphysicalfrailtythatcouldbetargetedwithpreventionortreatmentstrategies?Givenevidencealreadydeveloped,energymetabolismand/ordysregulatedactivationoftheinnateimmunesystemrequirefurtherstudy.Second,developmentoffrailty-relatedphysiologicalmeasuresthatbetterpredictimpendingcriticaltransitions,includingtoprefrailty,mayacceleratethecreationofeffectiveprimaryandsecondaryprevention,aswellastreatment,strategies.Third,researchisneededtobetterdistinguishphysicalfrailtyandchronicdisease.Thelikelihoodthatthesecoexistishigh,as,evenifnotetiologicallyrelated,bothincreaseinprevalencewithage.Further,somechronicdiseasessuchascongestiveheartfailuremayhavefeaturesoffatigue,weaknessandlowactivity,thusresemblingphysicalfrailtyphenotypiccriteria.Theterm‘secondaryfrailty’hasbeenusedtodescribesuchanoverlappingphenotype,incontrastto‘primaryfrailty’,whichdenotesauniqueage-relatedclinicalentitywithadistinctpathophysiology106.Suchsecondaryfrailtyappearstobeaconsequenceofcatabolicchronicdiseases107.Futurestudiesoffrailtyinpersonswithdiseaseneedtodemonstratethatdifferencesinfunctionandriskbetweenfrailandnonfrailindividualsdonotmerelyreflecttheseverityofdisease-specificpathology.Itmaybe,then,thatcontinuedrefinementoftheclinicalphenotypetodistinguishitclearlyfromsignsandsymptomsofotherspecificdiseaseswillbeneeded.Further,inthecaseofsecondaryfrailty,itremainstobedeterminedwhetherinterventionstargetingphysicalfrailty-relatedmultisystemdysregulationaremoreorlesseffectivethantreatmentofdisease-specificetiology.Finally,interventionstrategiestocreatehealthinagingandpreventfrailtycouldwellbuildonconceptsofcompromisedhomeostasis,robustnessandresiliency,aswellasphysicalfrailty,tocontributetothedevelopmentofamoreunifiedtheoryofagingandhealth.Wehypothesizethatrobustness,resilienceandfrailtyreflectdifferentpointsonacontinuumofphysiologicalfitnessandreserve—robustnesstotheeffectsofmoderatestressors,typicallyseeninhealthyyoungeradults;resilience,oratemporaryimpairmentfollowedbyrecovery,seeninlesshealthyyoungeradultsandhealthierolderadults;andfrailty,seeninolderadultswhosephysiologicalfitnessandreservehavebeendepletedpastacriticalthreshold,leavingthemvulnerabletosustainedadverseoutcomes.Thissuggestsanordering:frailtyimplieslackofresilienceandrobustness;conversely,robustnessimpliesresilienceandnonfrailty.Thistheoryastoacontinuumremainstobedemonstrated.Thefindingspresentedheremayhaveimplicationsbeyondfrailty,suggestingthatanarchitectureofagingcanbedevelopedusingtheblueprintofcomplexsystems.ThisenterprisewouldbeanalogoustothatoftheSantaFeInstituteanditsnetworkofresearcherswhohavebeenpursuingarevolutioninsciencebasedoncomplexsystemsthinking108.Webelievethatsuchanapproachmayultimatelyunifyamultitudeofagingconceptsincludingfrailty,homeostenosisandallostasistogetherwithrobustness,resilienceandhealth,aswellasrevealnovelinsights,suggestnewavenuesforresearchandlaunchaparadigmshiftfortheoptimizationofhealth. 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GoogleScholar  DownloadreferencesAcknowledgementsWededicatethisarticletoDr.RichardSuzman,whoconsistentlyenvisionedandenabledtransformativeagingresearch.WearegratefulforsupportbytheNationalInstituteonAging,includingforWHASI(N01AG012112),WHASII(M01R000052),PathogenesisofPhysicalDisabilityinAgingWomen(MERITAward,R37AG019905)andthefrailty-focusedJohnsHopkinsUniversityClaudeD.PepperOlderAmericansIndependenceCenter(P30AG021334).WethankM.A.O’Brienforheroutstandingassistanceinpreparationofthemanuscript.AuthorinformationAuthornotesTheseauthorsjointlysupervisedthiswork:KarenBandeen-Roche,RaviVaradhan.AffiliationsColumbiaUniversityMailmanSchoolofPublicHealth,NewYork,NY,USALindaP.FriedGroupederecherchePRIMUS,DepartmentofFamilyMedicine,UniversitédeSherbrooke,QuebecCity,Quebec,CanadaAlanA.CohenJohnsHopkinsCenteronAgingandHealth,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,USAQian-LiXue & KarenBandeen-RocheSchoolofMedicine,JohnsHopkinsUniversity,Baltimore,MD,USAJeremyWalstonJohnsHopkinsBloombergSchoolofPublicHealth,JohnsHopkinsUniversity,Baltimore,MD,USAKarenBandeen-RocheDivisionofBiostatisticsandBioinformatics,SidneyKimmelComprehensiveCancerCenter,JohnsHopkinsUniversity,Baltimore,MD,USARaviVaradhanAuthorsLindaP.FriedViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAlanA.CohenViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarQian-LiXueViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJeremyWalstonViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKarenBandeen-RocheViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarRaviVaradhanViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto LindaP.Fried.Ethicsdeclarations Competinginterests Theauthorsdeclarenocompetinginterests. AdditionalinformationPeerreviewinformationNatureAgingthankstheanonymousreviewer(s)fortheircontributiontothepeerreviewofthiswork.Publisher’snoteSpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.RightsandpermissionsReprintsandPermissionsAboutthisarticleCitethisarticleFried,L.P.,Cohen,A.A.,Xue,QL.etal.Thephysicalfrailtysyndromeasatransitionfromhomeostaticsymphonytocacophony. 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