Read the Frailty and Sarcopenia article. summarize

Read the Frailty and Sarcopenia article. summarize ithe concept of frailty. Describe what you believe the concept of frailty could be used for by a gerontologist and researcher in gerontology? Consider the use of the frailty as a concept, now describe how it could be used by a geriatrician working in the clinical arena. Summarized the ideal of frailty in gerontology and the many uses that you can think of. <..n@bham.ac.uk(D.Wilson).1.Introduction1.1.FrailtyTheconceptoffrailtyisprobablyrecognisedbymostbiogeron-tologistsbutitsemergingimportanceasahallmarkofageinghasledtoamorerigorousmedicaldefinitionofphysicalfrailty.http://dx.doi.org/10.1016/j.arr.2017.01.0061568-1637/©2017TheAuthors.PublishedbyElsevierB.V.ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/). 2D.Wilsonetal./AgeingResearchReviews36(2017)1-10'Amedicalsyndromewithmultiplecausesandcontributorsthatischaracterizedbydiminishedstrength,endurance,andreducedphysiologicfunctionthatincreasesanindividual'svulnerabilityfordevelopingincreaseddependencyand/ordeath'(Morleyetal.,2013).Thisdefinitiondescribesthesyndromebutdoesnotattempttointerprettheconditionoritsunderlyingbiologicalmechanisms.Twointrinsicallydifferentmodelsoffrailtyhavebeenproposedinanattempttooperationalisethesyndrome.Thefirstmodel,thefrailtyphenotypemodel,wasproposedbyFriedandcol-leagues(Friedetal.,2001).Thissuggeststhatastep-wiseincreaseinself-reporteddisabilityisanalogouswithanincreasingfrailtystateandcorrelateswithadversehealthoutcomessuchasdeath,hospitalisationandfalls.Frieddemonstratesthatthepresenceof3components,outofatotalof5(unintentionalweightloss,self-reportedexhaustion,weakness,slowwalkingspeedandlowphysicalactivity),haspredictivepowerinidentifyingmortalityrisk.Friedextrapolatesthistosuggestthatthepresenceof3com-ponentsinapersonidentifiesthemasfrailandthepresenceof1or2componentsaspre-frail(Friedetal.,2001).ThemodelhasbeenvalidatedbyFriedandindependentgroupswithconcurrentorpredictivevalidityassessedin17differentsamplesorcohorts(Bouillonetal.,2013),butnoattempthasbeenmadetoassessthereliabilityofthephenotype.ConverselyRockwoodetal.suggestedthatfrailtywasnotacat-egoricalphenomenonbutbestdescribedasadynamic,continuousprocessofdeficitaccumulationandasaresulttheyproposedtheFrailtyIndex(Mitnitskietal.,2001).ThemoststrikingdifferencewiththeFrieddefinitionoffrailtywasthatanyvariablecouldbeconsideredadeficitaslongasitwasassociatedwithadversehealthoutcomes,increasedinprevalencewithageintothetenthdecadeandhadaprevalenceofatleast1%whichdidnotsaturateinolderage.UsingthismodelRockwoodshowedtherewasagreatercorre-lationoftimetodeathwithfrailtyindexratherthanage(Mitnitskietal.,2001).TheFrailtyIndexhasalsobeenwidelytestedforvalid-itywithconcurrentorpredictivevalidityassessedin13differentsamplesorcohorts(Bouillonetal.,2013),butnotreliability.Oneofthedifficultiesindecidinguponthemostelegantandclinicallyapplicablemodelisthateachmodeldescribesaslightlydifferentpopulation.TheFrailtyIndexhasbetterdiscriminatoryabilityforadultswithmoderateandseverefrailty(Rockwoodetal.,2007).Thisisprobablyduetoitsbroaderapproachtothediagnosisoffrailtyandtheinclusionofcognitiveandpsychosocialmarkersratherthansolelyrelyingonphysicalmarkers.TherearealsohigherratesoffrailtyreportedwiththeFrailtyIndex,likelyduetothecontinuousnatureofthemodel(Songetal.,2010).Thismaymakeitabetterobjectivemarkeroftheassessmentoftheefficacyofanintervention.Thefrailtyphenotypemayhaveutilityinidentifyingolderadultsatriskofdisability.Ithasbeensuggestedthattheseassessmentinstrumentsshouldnotbeconsideredasalternatives,butratherascomplementary.BoththeFrailtyIndexandtheFrailtyPhenotypeareutilisedinresearchbutthemoreglobalconceptoffrailtyasdescribedbytheFrailtyIndexisprobablybetteracceptedinthegerontologycom-munity.Thisisreflectedinrecentdiagnosticandscreeningtools,EdmontonFrailScaleandPRISMA7,includingtheassessmentofseveraldomainsofhealth(Rolfsonetal.,2006;Raicheetal.,2008).However,therelativeeaseofutilisingtheFrailtyPhenotypemeansitisstillusedinresearchasamethodofidentificationoffrailty.1.2.SarcopeniaSarcopeniacanbeconsideredasoneofthemainphysicaldriversoffrailtyorperhapsevenaprecursorstateifitispresentwithoutamedicalclassificationoffrailtyasdescribedabove.Aswithfrailty,definitionsofsarcopeniahaveevolvedovertimereflectinggreaterunderstandingofthecondition.Thecurrentbroadlyaccepteddef-initionincludestheeffectsonfunctionaswellasincludingmusclemassandstrength:'Asyndromecharacterisedbyprogressiveandgeneralisedlossofskeletalmusclemassandstrengthwithariskofadverseout-comessuchasphysicaldisability,poorqualityoflifeanddeath.'(Cruz-Jentoftetal.,2010a).SimilartothefrailtyphenotypetheEuropeanWorkingGrouponSarcopeniainOlderPeople(EWGSOP)recommendcategorisingsarcopeniaintopre-sarcopenia,sarcopenia,andseveresarcopeniadependingonthepresenceofcertaincriteria.Theysuggestthatthepre-sarcopeniastageischaracterisedbylowmusclemasswithnoimpactonmusclestrengthorphysicalperformance,whereasthesarcopeniastageislowmusclemasswitheitherlowmusclestrengthorlowphysicalperformanceandseveresarcopeniaisthepresenceofallthreecriteria(Cruz-Jentoftetal.,2010a).Thecutoffpointforeachcriterionisnotcurrentlystandardisedandisdependentonboththemethodofmeasurementandtheresearcher.Itisgenerallyacceptedthatlowphysicalperformanceisdefinedasagaitspeedoflessthan0.8m/sec.Lowmusclestrengthisusuallydefinedbyhandgripstrengthoflessthan30kgformenandlessthan20kgforwomen(Cruz-Jentoftetal.,2010a;Cruz-Jentoftetal.,2010b).Lowmusclemassisusuallymeasuredbyaskeletalmusclemassindexwithavarietyofcutoffsquotedintheliteraturerangingfrom7.23kg/m2to8.87kg/m2inmenand5.45kg/m2to6.42kg/m2inwomen(Baumgartneretal.,1998;Newmanetal.,2003;Chienetal.,2008;Cruz-Jentoftetal.,2010a).Thediversityinthecutoffs,particularlyindefininglowmusclemass,utilisedinresearchhasledtohugedisparityintheprevalenceofreportedlowmusclemasswithprevalencereportedasbetween3.3to41.5%incommunitypopulationsover65(vonHaehlingetal.,2010).ThishasbeenrecognisedbytheEWGSOPwhohaverecommendedthatmoreresearchisurgentlyneededinordertoobtaingoodreferencevaluesforpopulationsaroundtheworld.Theinclusionofbothmusclemassandstrengthwithinthedefi-nitionofsarcopeniahaspartiallyoccurredinresponsetoextensiveresearchwhichhasshownthatwhilstlossofmusclemassisasso-ciatedwithlossofmusclestrength,therelationshipisnotlinear;thedeclineinstrengthismorerapidthantheconcomitantlossofmusclemass.Goodpasteretal.demonstratedinacommunitydwellingpopulationagedbetween70and79thatmusclemassdeclinesat0.5-2%perannumcomparedto2-4%lossofmusclestrength(Goodpasteretal.,2006).Thusage-relatedchangesinthequalityofthemusclemaybeasimportantasthereducedmassandreducedmusclequality,notablylossoftypeIIfibres,reducedmitochondrialmassandincreasedfatinfiltration,maycontributetolossofmusclestrengthandpower(NariciandMaffulli,2010).Potentiallyamoreinclusivedefinitionofsarcopeniamayincorpo-ratethelossofmusclemass,reducedmusclequalityandalossoffunctionalstrength,asshowninFig.1,whichdepictsage-relatedchangesoccurringwithinthemusclefromthewholemusclelevelthroughtoacellularlevelandhowthesecontributetothelossofmusclemass,quality,strengthandpower.1.3.RelationshipsbetweenfrailtyandsarcopeniaTherelationshipbetweenfrailtyandsarcopeniaisnotyetfullycharacterisedbuttheseconditionssharemanyofthesameclini-caloutcomes,associationsandsuggestedpathophysiology.Despitethis,sarcopeniaisconsideredacomponentoffrailtybutfrailtyisnotconsideredacomponentofsarcopenia.However,thereisconsiderableoverlapbetweenthedefiningcriteriaoftheFrailtyPhenotypeandsarcopenia.SeveresarcopeniaasdefinedbyEWG-SOPispre-frailtybytheFriedphenotype.Sarcopeniaisoftenconsideredapre-cursorsyndromeorthephysicalcomponenttofrailty. D.Wilsonetal./AgeingResearchReviews36(2017)1-103Fig.1.Agerelatedchangedoccurringwithinthemuscle.Figuredepictingtheagerelatedchangedoccurringwithinthemusclefromawholemusclelevelthroughtoacellularlevelandtheirimpactonmusclemass,quality,strengthandpower.CSA-crosssectionalarea.Sarcopeniaisreportedtobetwiceascommonasfrailtyinthegeneralpopulation(vonHaehlingetal.,2010).Theprevalenceofbothconditionsisdependentonpopulationanddefinition.UsingtheEWGSOPdefinitionandcriteriaofsarcopeniatheprevalencerangesfrom4.6%,communitydwellingmenintheUKaged68-76(Pateletal.,2014),to68%,maleItaliannursinghomeresidentsover70(Landietal.,2012).Arecentsystematicreviewoffrailtypreva-lenceinacommunitypopulation(Collardetal.,2012)reportedtherangetobe4.0%,independentlymobilemenover65(Cawthonetal.,2007),to59.1%,communitydwellingDutcholderthan70(Metzelthinetal.,2010).ThecalculatedweightedaverageoffrailtyasdefinedusingtheFrailtyPhenotypeis9.9%(Collardetal.,2012).ResearchhasshownthatinfrailcommunitydwellingadultsthemostcommonpositiveFriedcriteriawasslowgaitspeed(43%)andweakness(54%),thefunctionaldefiningcriteriaofsarcopenia(Rothmanetal.,2008).Ithasalsobeenreportedthattherelativeriskofdevelopingweaknessandlowactivitywashigherthandevel-opinganyotherfrailtydefiningcriteriaover7.5yearsoffollowupininitiallynon-frailwomen(Xueetal.,2008).Thissuggeststhattheoreticallywhileitispossibletohavefrailtywithoutsarcopeniaclinicallyitisunlikely.However,arecentisolatedreportinvestigat-ingtheconcordanceoffrailtyandsarcopeniademonstratedthatfrailtywasmorecommonthansarcopeniaandtheconcordancebetweenfrailtyandsarcopeniawaspoor(Reijnierseetal.,2016).Thisistheonlyliteratureinvestigatingtheconcordanceoffrailtyandsarcopeniabutiscontrarytopreviousunderstandingandanisolatedreport.Importantlybothfrailtyandsarcopeniaareconsideredpartlyreversibleconditions.Severalepidemiologicalstudieshaveshownthatwhilsttransitionbetweenlesserandgreaterfrailtyisalwaysthemostfrequentoutcome,anumberofparticipantswilltransi-tionfromgreatertolesserfrailty(Gilletal.,2006;Fallahetal.,2011;Espinozaetal.,2012;Leeetal.,2014).Healthstatusandbaselinefunctionisimportant,asthosewithpoormobilityatbaselineinalongitudinalstudyexperiencedfasteraccelerationoftheirfrailtythanthosewithgoodmobility(Fallahetal.,2011).Thereversaloffrailtyhasalsobeendemonstratedininterventionstudies.Amul-tifactorialinterventionincommunitydwellingfrailadultsresultedinasignificantdifferenceinfrailtyprevalencebetweenthetwogroupswhowereidenticalatbaseline.Ofnote,theinterventionwasspecifictotheindividualdependingontheirpositivefrailtycriteriaatbaselineassessment,forexamplethosescoringforweightlosswouldbeassessedandmanagedbyadietician,consistentwithapersonalisedmedicineapproach.Importantly,thisstudyreportedanactualreductionindiagnosisoffrailtyintheinterventiongroupnotjustaslowingofprogression(Cameronetal.,2013).Itisalsopossibletoimprovecomponentsoffrailtyandsarcopenia.Severalresistanceexerciseprogrammeshavedocumentedimprovementsingaitspeedandstrengthingroupsoffrailolderadults,withpro-grammesof8-12weeksabletoreverselossofmusclestrengthequivalenttothatlostover20years(Fiataroneetal.,1994;Liu-Ambroseetal.,2004).Improvedunderstandingoftheprocessesunderlyingsarcopeniamayallowthedevelopmentofevenmoreefficaciousandtargetedinterventions.2.PathophysiologyofsarcopeniaandfrailtyThepathophysiologyofbothsarcopeniaandfrailtyiscom-plex.Proposedmodelsforbothsyndromesincorporatemultiplecauses,inter-relationshipsandelaboratepathways(Friedetal.,2009;Cruz-Jentoftetal.,2010a).However,bothsyndromesareincompletelycharacterisedandthereisinsufficientunderstandingoftheunderlyingcellularmechanismsdrivingthedevelopmentandmaintenanceofstatesoffrailtyandsarcopenia.Sarcopeniaisbetterunderstoodthanfrailtylargelyduetoitseffectsbeingcon-centratedonasinglesystem,theneuromuscularsystem,andforthisreasonithasbeensuggestedasaphysicalmodeloffrailty.2.1.RegulationofmusclemassOurcurrentunderstandingoftheregulationofmusclemassispredominatelybasedondatafromanimalstudies,withmuchlessknownofthekeyregulatoryprocessesinhumanmuscle.Stud-iesinrodentssuggestthatmusclesynthesisisintrinsicallylinkedwithmuscleatrophyviathePI3k-Aktpathwaywhichiscentraltobothprocesses(SchiaffinoandMammucari,2011).Musclesynthe-sisisactivatedbyinsulin-likegrowthfactor1(IGF-1)bindingto 4D.Wilsonetal./AgeingResearchReviews36(2017)1-10Fig.2.Relationshipsbetweeninflammaging,sarcopeniaandfrailty.Figuredepictingaproposedmodelofinflammaging,frailtyandsarcopenia.Themodeldescribesacentralroleforinflammagingwithinthecreationandmaintenanceoffrailtyandsarcopeniastates.IGF-1receptorwhichtriggerstheactivationofasignallingpath-wayincludingPI3k,Akt,andthemammaliantargetofrapamycin(mTOR),whichinturnphosphorylatesS6kinaseandotherfac-torswhichpromoteproteinsynthesis(SchiaffinoandMammucari,2011).Therearemultiplemodulatorsofthepathway,bothintrin-sicandextrinsic.IntrinsicregulatorsincludeS6kinase1inhibitionofinsulinreceptorsubstrate(IRS)(Harringtonetal.,2004)andmTORC2upregulationofAkt(Sarbassovetal.,2005).Extrinsicreg-ulatorsinclude:aminoacidswhichcandirectlyactivatemTORC1(Kimetal.,2008;Sancaketal.,2008)andbetaadrenergicagents(Klineetal.,2007)andWnt7awhichbothupregulatethePI3k-Aktpathway(vonMaltzahnetal.,2012).Muscleatrophyviaboththeubiquitinproteasomepathwayandautophagylysosomesiscentrallyregulatedbyforkheadboxproteins(FoxO).FoxOwhenpresentinthenucleusinducestheubiquitinE3ligasesatrogen-1andmuscleRINGfingerprotein-1(MuRF-1)(Williamsonetal.,2010)whichcausemyofibrildegrada-tion.FoxOalsoregulatesATGgeneswhichpromotemitochondrialdegradationviaautophagy(Polageretal.,2008).AsexpectedtherearemultiplemodulatorsofthesepathwaysandarguablythemostimportantistheeffectofAktonFoxO:AktphosphorylatesFoxOandtransportsitfromthenucleustothecytoplasmpreventingitfrominducingeitherE3ligasesorATGgenes(Stittetal.,2004;HuangandTindall,2007;Jangetal.,2007).Myostatin,viatheactionofSmad2and3,upregulatesFoxO(McFarlaneetal.,2006)andmus-cledisuseproducesneuronalnitricoxidesynthase(nNOS)whichenhancesFoxO3mediatedtranscriptionofE3ligases(Suzukietal.,2007).Themajorityofstudiesinvestigatingsarcopeniainhumanshavesuggestedthatlossofmusclemassisprimarilydrivenbyabluntedsyntheticresponsetobothfeedingandexercise,termedanabolicresistance(MurtonandGreenhaff,2009;Markofskietal.,2015;Walletal.,2015).Moreover,thereislittledatatosuggestthatatrogenesorubiquitinproteasomaldegradativepathwaysareenhancedinolderadults,indeedinthefastedstate(whenpro-teinbreakdownisatitshighest)thereisnodifferenceinproteinturnoverorsignallingthroughsyntheticpathwayssuchasAktbetweenyoungandoldadults(Francauxetal.,2016).Anabolicandcatabolicpathwaysmayberelevantinperiodsofextremeinactivity,suchasbedrest,andinchronicinflammatorystates,suchaschronicobstructivepulmonarydisease(COPD).Inarecent5daybedreststudyinwellcharacterisedhealthyyoungandoldsubjects,legleanmassandstrengthwerereducedonlyintheoldsubjects.BothsubjectgroupshadbluntedmTORC1sig-nallingandincreasedMURF1expressioninskeletalmuscleafterbedrest,butonlytheoldergrouphadreducedaminoacidinducedproteinsyntheticratesandincreasedatrogeneexpression(Tanneretal.,2015).Astudyinvestigatingtheeffectofresistancetrain-inginparticipantswithCOPD,achronicinflammatorycondition,demonstratedhigherlevelsofMAFbxandMURF1proteinexpres-sion(atrogenes)andincreasedphosphorylationofp70skinases(Constantinetal.,2013).Thesestudiessuggestadecreaseinmus-clesynthesisandanincreaseinmuscledegradation(dysregulatedmusclehomeostasis)isseenwithinactivityandchronicinflamma-toryconditions.Patientswithsepsisaresubjecttobothperiodsofextremeinactivityandapro-inflammatorystateandcouldthereforebeconsideredamodelofacceleratedageing(Singeretal.,2016).Fol-lowingsepsisandadmissiontocriticalcare70-100%ofpatientsreportedprolongedweakness(CallahanandSupinski,2009)whichisduebothtomusclelossandchangesinmusclecellfunctionality.Thisgroupdeservesfurtherstudyforalinkbetweeninflammationandsarcopenia. D.Wilsonetal./AgeingResearchReviews36(2017)1-1053.AgeingoftheimmunesystemThedeclineinimmunefunctionwithage,termedimmunese-nescence,iswelldocumentedandincludesincreasedsusceptibilitytoinfections,reducedvaccinationresponsesinolderadultsandincreasedriskofchronicinflammatorydiseasessuchasRheuma-toidArthritis(Weng,2006;Shawetal.,2010;GoronzyandWeyand,2013).Themanychangesthatoccurinthecomponentsoftheimmunesystemwithagehavebeenreviewedpreviously(Gruveretal.,2007;OngradiandKovesdi,2010;Shawetal.,2010)andwewillthusconsideronlythoseelementsofinnateimmunitythatcouldcontributetofrailtyandsarcopenia,primarilythroughtheirroleininflammation.Immunesenescenceincludesinflammaging,theincreasedpres-enceofalow-gradechronicsystemicpro-inflammatorystatewithage(Franceschietal.,2000;Baylisetal.,2013b).Inflammagingischaracterisedbyincreasedlevels(typically2-4foldthoseseeninhealthyyoungsubjects),ofpro-inflammatorycytokinessuchasinterleukin1(IL-1),interleukin6(IL-6)andtissuenecrosisfac-toralpha(TNF)aswellasc-reactiveprotein(CRP),andareducedserumlevelofanti-inflammatorycytokinesincludinginterleukin10(IL-10)(Baylisetal.,2013b)andIL-1ra.Thefactorsdrivinginflammagingaremultiple(Fig.2)andcanincludeincreasedoutputofpro-inflammatorycytokinesbyrestingmonocytes(Doyleetal.,2010;Jackamanetal.,2013;Pinkeetal.,2013),reducedIL-10pro-ductionbyregulatorylymphocytes(Duggaletal.,2013),increasedadiposityleadingtoproductionofpro-inflammatoryadipokinessuchasleptinandreducedanti-inflammatoryadipokinessuchasadiponectin(LutzandQuinn,2012),reducedphysicalactivitywithage(Woodsetal.,2012),andsenescentcellswhichbuildupwithageandsecretepro-inflammatorycytokines(Coppeetal.,2010).Neutrophilshaveafundamentalroleinthedefenceagainstbac-terialinfectionsandinolderadultsmanyaspectsoftheirfunctionsuchasphagocytosis,superoxideproduction,andNETgenerationareimpairedwithage(reviewedinHazeldineandLord,2015).Inthisreviewwefocusonreducedchemotacticability(Sapeyetal.,2014).Neutrophilsmigratefromthebloodtoasiteofinfectionortissuedamageinresponsetochemoattractants,movingthroughtissuebyreleasingproteasessuchasneutrophilelastaseattheirleadingedgeanddamaginghealthytissueintheprocessresultingininflammation(Cepinskasetal.,1999).Ourpreviousworkhasshownthatchemotaxisisreducedinolderadultsmakingmigra-tioninefficient,leadingtogreatertissuedamageandsecondarysystemicinflammation(Niwaetal.,1989;Wenischetal.,2000;Butcheretal.,2001;Hazeldineetal.,2014;Sapeyetal.,2014).Whilstinvestigationoftheroleoftheimmunesysteminfrailtyandsarcopenialagsbehindsimilarresearchintoageingandage-relatedconditions,thereisevidencethattheimmunesystem,anditsdysregulation,mayplayaroleinbothprocesses.3.1.RoleofincreasedsystemicinflammationMultipleassociationshavebeendemonstratedbetweenfrailtyandsarcopeniaandtheindividualcytokinecomponentsofinflam-maging,thoughevidenceofacausalrelationshipremainstobeproven.3.1.1.Inflammatorycytokines,IL-6andTNF ̨ThepotentialroleofIL-6insarcopeniaiscomplex.Thiscytokine,initiallythoughttobeonlyproducedbyimmunecells,waseventu-allyidentifiedasbeingproducedbymuscleandinthiscontextwastermeda'myokine'(PedersenandFebbraio,2008).InuninfectedindividualsmuscleisinfactamajorsourceofcirculatingIL-6.IL-6expressionincreasesacutelyincontractingskeletalmuscleandisreleasedfollowingexercise(Steensbergetal.,2000),enhanc-ingmusclemetabolism,fattyacidoxidation,andglucoseuptake(Kellyetal.,2009).However,thereisincreasingevidencethatIL-6canactviatheubiquitinproteasomemuscledegradationpathway,withraisedsystemicIL-6associatedwithincreasedubiquitinpro-teinandmRNA(DeJongetal.,2005),E3ligaseproteinandmRNA(Whiteetal.,2012)andproteasomeactivity(Ebisuietal.,1995).InadditionIL-6caninduceinsulinresistancewhichsuppressesAkt-mTORactivityandinhibitsmusclesynthesis(Febbraioetal.,2004;Franckhauseretal.,2008).Anotherpro-sarcopeniceffectofinflammationisonthegenerationofcortisolwithintissues.Corti-solisprofoundlycatabolicandcanbesynthesisedfrominactivecortisoneintissuesincludingmuscleandbone,bytheactionsoftheenzyme11HSD1(Morganetal.,2009).11HSD1activityincreaseswithageandisinducedbycytokinesincludingTNFandIL-6(Tomlinsonetal.,2004).Thesystemicincreaseininflammationwithagemayindirectlyimpactonmuscleturnoverviainductionof11HSD1.ApositiveassociationbetweenchronicallyraisedserumIL-6andTNFandfrailtyhasbeendemonstratedinseveralepidemi-ologicalstudies(Lengetal.,2002;Walstonetal.,2002;Lengetal.,2004).HigherserumlevelsofIL-6predictdevelopmentofsarcope-nia(Payetteetal.,2003;Schaapetal.,2006)andincreasedIL-6alsopredictsdisabilityandmortality,recognisedoutcomesoffrailtyandsarcopenia(Cesarietal.,2012).Inaddition,highserumIL-6andCRPatbaselineassessmenthavebeenassociatedwithatwotothreefoldgreaterriskoflosingmorethan40%ofgripstrengthoverthreeyears(Schaapetal.,2006).Usingcentenariansasamodelfor'healthyageing'hasalsogivensomesupportforalinkbetweenIL-6,withfrailtyandsarcopeniainhumans.Specifically,theIL-6174GGgenotype,whichisassociatedwithhigherplasmalevelsofIL-6,isunder-representedincentenarians(FranceschiandBonafe,2003).However,amajorlimitationinunderstandingtheroleofinflam-mationinsarcopeniaisthelimitednumberofstudiesthathavemeasuredinflammatorycytokines,whetheratthemRNAorproteinlevel,inhumanskeletalmusclewithage.Twostudiescomparinghealthyyoungandoldmalesreported3.3and2.8foldincreasesinmRNAforIL-1(Przybylaetal.,2006)andTNF(Legeretal.,2008)foroldermen.Astudycomparingfrailolderadults,definedbyphysicalfunctiontesting,withyoungsubjectsreportedraisedTNFmRNAandproteininmyocytesfromthefrailsubjects.More-over,anexerciseinterventioninthesefrailadultsreducedTNFmRNAandproteinlevelsandimprovedmusclestrength(Greiweetal.,2001).Incontrast,threestudieshavefoundnodifferencesinskeletalmuscleIL-6mRNAwithage(Hamadaetal.,2005;Przybylaetal.,2006;Trenerryetal.,2008)andtwofoundnoage-relatedincreaseinTNFmRNAinmales(Hamadaetal.,2005)orfemales(Raueetal.,2007).Theapparentdiscrepanciesbetweenstudiesofsystemicinflam-mationandsarcopeniamayindicatethatitisthedegreeandchronicityofinflammationthatdictatestheeffectonmusclemass,strengthandquality.Thusrelativelymildlevelsofinflammationsuchasthoseseenwithnormalageingorwithobesitymaynotbesufficienttoeffectlossofmusclemassorstrength,butcouldcontributetosarcopeniabyaffectingmetabolicquality(Murtonetal.,2017).Whensystemicinflammationismoresevereandaccompaniedbyinflammationinskeletalmuscleitself,asmaybeseeninfrailty(Greiweetal.,2001),theninflammationmayalsocontributetolossofmusclemassandstrength.InsupportofthisproposalexogenousadministrationofTNFtomicecauses:(1)anorexiaandmuscleloss,achievedviaseveralmechanismsincludingreducedaminoacidavailabilityviaupregulationoflep-tin(Grunfeldetal.,1996;Sarrafetal.,1997);(2)activationofthetranscriptionfactorNF-Binmuscleresultinginmyofibre;atro-phyandactivationoftheubiquitin-proteasomepathway(LiandReid,2000;Ladneretal.,2003;Caietal.,2004)and(3)suppressionoftheAkt-mTORpathwayofproteinsynthesis(Pijetetal.,2013).Inrats,infusionoflipopolysaccharidetomimicsepsisinducesa 6D.Wilsonetal./AgeingResearchReviews36(2017)1-10Fig.3.RelationshipsbetweendysregulationofPI3k-Aktpathwayinneutrophilsandsarcopeniaandfrailty.FiguredepictingproposedrelationshipsbetweendysregulationofPI3k-Aktpathwaywithinneutrophilsandmuscleandfrailtyandsarcopeniastates.significantsystemicinflammatoryresponseandincreasedexpres-sionofIL-6andTNFmRNAinskeletalmuscleassociatedwithlossofmusclemassandstrength(Crosslandetal.,2008).Moreover,dampeningoftheinflammatoryresponseinmuscle,bythecon-comitantadministrationofglucocorticoid,preservedmusclemass(Crosslandetal.,2010).TNFdirectlyupregulatestheNFpath-wayviaIkinase(IKK)andinducesMuRF-1expressionwhichcausesmyofibrildegradationviatheubiquitinproteasomepath-way(LiandReid,2000;Ladneretal.,2003).Multiplechronicinflammatoryconditionsareassociatedwithmusclelosseitherdescribedassarcopeniaorcachexia:can-cer,heartfailure,COPD,chronickidneydisease,Crohn'sdisease,rheumatoidarthritis,HIV(Evans,2010;Bioloetal.,2014).MusclelosshasbeeninvestigatedatacellularlevelinCOPD,andwhilstfurtherresearchisrequiredtoconfirmthedata,onbalancethereisanincreaseinubiquitinproteasomeactivityandadecreaseinproteinsynthesis(Constantinetal.,2013).Thissuggeststhattheanabolicandcatabolicpathwaysutilisingtheintra-cellularPI3K-Aktpathwayareimportantinthedevelopmentandmaintenanceofsarcopeniainchronicinflammatorystates.Similarresultshavebeenreplicatedinotherchronicinflammatoryconditions.3.1.2.Anti-inflammatorycytokinesIL-10,ananti-inflammatorycytokine,declinesinthecircula-tionwithageinhumans(Franceschietal.,2007;Bartlettetal.,2012).ThedevelopmentofanIL-10homozygousknockoutmousehasprovidedaninterestingandinformativemodelofsarcopeniaandfrailtyasitdevelopsincreasedmuscleweaknessanddecreasedstrengthwithageincomparisontowildtypemice(Walstonetal.,2008).ThismousealsohassignificantlyraisedlevelsofIL-6at50weeksofage(Walstonetal.,2008).At92weeksofagethesemicealsoshowcompromisedskeletalmusclequality,withreducedskeletalmuscleenergymetabolismintheformofreducedATPfluxviacreatinekinase,andlowerfreeenergyreleasedduringATPhydrolysiscomparedtowildtypemice(Akkietal.,2014).Thesemicealsoshowreducedmusclegrowthandregenerationafterinjury(Dengetal.,2012).Thesedataofferonepotentialexplanationforwhymusclestrengthdeclinesmorequicklythanmusclemassinsarcopenia,howevertherearecurrentlyfewreportsofassocia-tionsbetweenIL-10andfrailtyorsarcopeniainhumans.OnlyonestudyhascomparedIL-10expressioninmusclefromyoungandoldsubjectsandshownamodestincrease,1.4fold,inIL-10mRNAinhealthyoldermales(Przybylaetal.,2006)However,anIL-10polymorphism1082CC,associatedwithhighserumlevelsofIL-10,isover-representedincentenarians,suggestinganassociationwithlongevityatleast(FranceschiandBonafe,2003).ItisthereforeimportantnowtoconfirmifIL-10expressionisreducedinskeletalmusclefromsarcopenicolderadultstoprovidesupportforitsroleinmusclelossandfrailtyinhumans.Therearefewstudiesofotheranti-inflammatorycytokinesandtheirexpressioninskeletalmuscle.Onestudyfoundthatinterleukin-1receptorantagonist(IL1-ra)mRNAwasincreased7.2foldinhealthyoldermalesincomparisontoyoungermales(Przybylaetal.,2006)butthishasnotyetbeenconfirmedbyoth-ers.TheauthorssuggestedthismaybeafunctionalresponsetotheelevatedIL-1mRNAalsodemonstratedinthehealthyoldermales.Fig.2proposesarelationshipbetweeninflammaging,sarcope-niaandfrailty,representingacoalescenceofideasthatmayunderpinthepotentialrelationshipbetweeninflammagingandsarcopenia.Atpresentmechanisticinsightcannotbegivenasfur-therresearchisrequired,especiallyinhumansandevidenceofadirectcausalrelationshipisthusalsomissing.3.1.3.Leukocytes,sarcopeniaandfrailtyAge-relatedchangestothecellsoftheinnateimmunesystemmaycontributeindirectlytofrailtyandsarcopeniaviatheirroleintheage-relatedincreaseinsystemicinflammation.Whitecellcountsandneutrophilnumbersafteradjustmentforthemostcom-monconfoundersareraisedinpopulationsoffrailolderpeople(Lengetal.,2007;Lengetal.,2009;Collertonetal.,2012).Higher D.Wilsonetal./AgeingResearchReviews36(2017)1-107neutrophilcountsareassociatedwithlowlevelsofphysicalactiv-ityandfrailty(Fernandez-Garridoetal.,2014)andahigherwhitecellcountinhealthy60yearoldscanpredictfrailtytenyearslater(Baylisetal.,2013a).Howsuchchangesmightaffectfrailtyandsarcopeniaisstillpoorlyunderstoodbutweattempttooffersomeinsighthere.Neutrophilsarethemostabundantleukocyteinthebloodandwehaveshownthattheirchemotacticabilityisgreatlyreducedwithage.Consequentlymigrationisinefficient,theneutrophilsproducemoretissuedamageandsecondarysystemicinflamma-tionastheymigratethroughtissue(Niwaetal.,1989;Wenischetal.,2000;Butcheretal.,2001;Hazeldineetal.,2014;Sapeyetal.,2014).Thereforeitisplausiblethatneutrophilsplayakeyroleintheinflammatorymechanismsseeninsarcopeniaandfrailty.Neutrophilsarecentraltotissuerepairandresearchhasdemon-stratedinanumberofmodelsofmuscleinjurythatneutrophilsarerecruitedtothesiteoftheinjurywithinacoupleofhours(Smithetal.,1998;MacIntyreetal.,2000;Quindryetal.,2003).However,migratingneutrophilsalsocausesecondarydamagetohealthymuscleandstudiesreportthatmuscledamageisreducedwhenfunctioningneutrophilsarepreventedfrommigratingtothedamagedtissue(Jollyetal.,1986;Korthuisetal.,1988).Theoriginalstudiesusedanischaemiaandreperfusionmodelbutsubsequentstudieshaveutilisedamusclestretchinjurymodelanddirectlyvisualisedthemuscledamagebymicroscopy(Bricksonetal.,2003).Inefficientneutrophilmigrationmaythusbeamajorcontributortoincreasedinflammationinolderadultsespeciallyattimesofmuscledamage(Fig.3).Recentdatafromourgrouphasidentifiedthemechanismunderlyingreducedchemotaxisinneutrophilsfromolddonors.InaccuratechemotaxiswasassociatedwithconstitutivePI3Ksig-nallingandselectivepharmacologicalinhibitionofPI3KorPI3Krestoredneutrophilmigratoryaccuracy(Sapeyetal.,2014).More-over,thereducedneutrophilchemotaxiswasassociatedwithincreasedsystemicinflammationintheolderdonors,mostlikelyduetothetissuedamagethatoccursduringneutrophilmigration.AsthereareinhibitorsofPI3Kcurrentlyinclinicaltrial,thisoffersanovelroutetotherapyforimmunesenescenceandintheorythismayalsoimprovefrailtyandsarcopeniastates.Asmuscleagesitbecomesmoresusceptibletoinjuryandcertainlyasapersonagesdysregulationofentiresystems,forexam-plebalanceandcognition,resultinagreaternumberofinjuries(Campbelletal.,1981;vanDoornetal.,2003;Shavlakadzeetal.,2010;Shubert,2011).Itcanbepostulatedthatmuscleinjuryinanolderpersoncombinedwithimmuneageingwouldcausesecondarydamagetohealthymusclefromaberrantlymigratingneutrophilsresultinginmyocytedamageandapoptosisandlossofmusclefibres.Thislossofmusclequalityandmasscouldresultinthefunctionallossesandphysicalweaknessoffrailty.Researchisnowrequiredtoacquireevidencetotestthishypothesis.4.ConclusionsThehistoricaldifficultiesofdefinition,measurementandmod-ellinginbothsarcopeniaandfrailtyinadditiontothefundamentaldifficultiesofinvestigatingcomplex,multi-factorialsyndromeshasledtoalackofinformationregardingthepathophysiologi-calcausesoffrailtyandsarcopenia.Whilstthereissomelimitedresearchintoassociationsthereisverylittleinvestigatingmorecomplexpathwaysattemptingtolinkthetwosyndromes.Thesuggestedlinkofincreasedsystemicinflammationcouldexplaintherelationshipbetweensarcopeniaandimmunesenescence,withaberrantneutrophilmigrationpotentiallycontributingtoinflam-magingandtissuedamageassociatedwithsarcopeniaandfrailty.Furtherresearchonthecellpathwaysconnectinginflammaging,sarcopeniaandfrailtywouldhelptobetterunderstandthesecon-ditionsandprogresstopotentialnoveltherapiesforfrailtyandsarcopeniawhichcouldincludemodulationofPI3ktocorrectneu-trophilchemotaxis.AcknowledgmentsDaisyWilsonissupportedbyaclinicalresearchfellowshipfundedbytheMRC-ArthritisResearchUKCentreforMusculoskele-talAgeingResearch.ElizabethSapeyisfundedbytheMedicalResearchCouncil.WewouldliketothankProfessorPaulGreenhaffforhiscarefulreadingofthemanuscript.WewouldalsoliketothankAlexandriaClarkforherworkinimprovingthevisualappearanceofthefigures.ReferencesAkki,A.,Yang,H.,Gupta,A.,Chacko,V.P.,Yano,T.,Leppo,M.K.,Steenbergen,C.,Walston,J.,Weiss,R.G.,2014.SkeletalmuscleATPkineticsareimpairedinfrailmice.Age(Dordr)36,21-30.Bartlett,D.B.,Firth,C.M.,Phillips,A.C.,Moss,P.,Baylis,D.,Syddall,H.,Sayer,A.A.,Cooper,C.,Lord,J.M.,2012.Theage-relatedincreaseinlow-gradesystemicinflammation(Inflammaging)isnotdrivenbycytomegalovirusinfection.AgingCell11,912-915.Baumgartner,R.N.,Koehler,K.M.,Gallagher,D.,Romero,L.,Heymsfield,S.B.,Ross,R.R.,Garry,P.J.,Lindeman,R.D.,1998.EpidemiologyofsarcopeniaamongtheelderlyinNewMexico.Am.J.Epidemiol.147,755-763.Baylis,D.,Bartlett,D.,Syddall,H.,Ntani,G.,Gale,C.,Cooper,C.,Lord,J.,Sayer,A.,2013a.Immune-endocrinebiomarkersaspredictorsoffrailtyandmortality:a10-yearlongitudinalstudyincommunity-dwellingolderpeople.Age35,963-971.Baylis,D.,Bartlett,D.B.,Patel,H.P.,Roberts,H.C.,2013b.Understandinghowweage:insightsintoinflammaging.Longev.Healthspan2,1-8.Biolo,G.,Cederholm,T.,Muscaritoli,M.,2014.Musclecontractileandmetabolicdysfunctionisacommonfeatureofsarcopeniaofagingandchronicdiseases:fromsa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