ProjectAbstract Oldageisthesinglegreatestriskfactorformanydiseasesincludingperiodontaldisease,dementia, diabetes,andheartdisease.Agingisassociatedwithfailuretomaintainhomeostasis,andoneresultisthe senescenceoftheimmunesystem,whichresultsin?inflammaging.?Bydelayingorreversingthebiological agingprocesses,suchasinflammaging,itmaybepossibletoreducetheimpactofage-relateddiseases, whichcouldhaveprofoundbenefitsforqualityoflife. ThemechanisticTargetofRapamycin(mTOR)hasbeenestablishedasanevolutionarilyconserved regulatoroflongevitythroughstudiesshowingthatreducingmTORactivityextendlifespanandimprove healthspanininvertebratesandmice.Rapamycin,aspecificinhibitorofmTOR,isapromisingcandidatefor delayingage-relateddiseasesandmayact,atleastinpart,byreducinginflammaging.Anage-associated inflammatorydiseaseintheoralcavityisperiodontaldisease.RecentepidemiologicdataintheU.S.revealed 64%ofadultsaged65yearsandolderhadperiodontitis.Hereweproposetotestthehypothesisthat mTORhyperactivationduringagingleadstoimmunecellsenescence,inflammation,andultimately leadstodetrimentalchangestotheoralmicrobiomethatunderliesoralpathologyduringaging. ThiswillbeaccomplishedfirstbyassessingmTORsignalingintheperiodontiumduringagingthrough quantificationofphosphorylationofmTORpathwaycomponentsandinflammatorymarkers.Todetermineif theperiodontiumofnormallyagedmiceiscomparabletoaninducedinflammatorystate,comparisonofaged rodentstoaligature-inducedperiodontitismodelwillbecompleted.Inpreliminarystudies,wehaveshownthat age-associatedperiodontalbonelossinmicewasimprovedafterrapamycintreatment.Thus,theabilityof rapamycintoattenuateage-associatedoralpathologyandeffectsoninnateimmuneresponseinligature- inducedperiodontitiswillbeexplored.Furthermore,theconsequenceofagingandmTORinhibitionontheoral microbiomewillbeinvestigated. TheproposedF30projectwasdevelopedtohelpprovideafoundationforanaspiringdentist-scientist andcontributetounderstandingthemechanisticandmolecularbasisforage-associatedchangesinthe periodontium.InvestigatingmTORsignalingintheperiodontium,andunderstandingtheroleofrapamycinin delayinginflammagingintheoralcavitywillhaveasignificantimpactonthefieldsofgeroscienceanddentistry, andcouldpotentiallyyieldmajorimprovementsinpublichealth.Withstronginstitutionalsupportfromthe UniversityofWashingtonandexcellentmentorship,weareconfidentthatthisF30awardwillaidinthebasic sciencesandclinicaltrainingrequiredtobeasuccessfuldentist-scientist.
Agingisassociatedwithchronicinflammationcalledinflammaging,whichcontributestoperiodontaldisease thatafflictsmorethan6outof10peopleovertheageof65.1-6,15Thegoalofthisproposalistodefinethe molecularmechanismsbywhichagingandinflammagingcontributetoperiodontaldiseaseanddeclineinoral health.ThiswillbeaccomplishedbytestingthehypothesisthataberrantsignalingthroughthemTORgrowth promotingpathwaydrivesinflammationintheoralcavityandevaluatingtheimpactofrapamycin,anFDA approvedinhibitorofmTOR,onprogressionofage-associatedperiodontaldiseaseinmice.
| An, Jonathan Y; Darveau, Richard; Kaeberlein, Matt (2018) Oral health in geroscience: animal models and the aging oral cavity. Geroscience 40:1-10 |
| An, Jonathan Y; Quarles, Ellen K; Mekvanich, Surapat et al. (2017) Rapamycin treatment attenuates age-associated periodontitis in mice. Geroscience 39:457-463 |
