Theprocessofagingcausesfunctionaldeclineofthehematopoieticsystem,includingreducedcapacityfor regeneration,increasedriskofinfections,andincreasedriskofcertainformsofbloodcancer.Thisisa significanthealthconcernduetotheincreasingageofourpopulationandincidenceoftheseage-related conditions.Nointerventiontherapiescurrentlyexisttoextendhematopoietichealthspanwithaging,largelydue toalackofunderstandingofthecellularandmolecularalterationsthatcausefunctionalhematopoieticdecline. Ournovelapproachistoidentifycellularandmolecularsignaturesoffunctionalhematopoieticdeclineatits ageofonset,withtherationalethatthesesignatureswillpointtoearlycausesofdeclineandhenceidentify primetargetsforextendinghematopoietichealthspan.Ourpreliminarydatademonstratethatfunctional hematopoieticdeclineoccursbymiddleage,thatalterationsinthebonemarrowmicroenvironmentatmiddle agearenecessaryandsufficienttocausefunctionalhematopoieticdecline,andidentifyalterationsinthe Insulin-likeGrowthFactor1(IGF1)signalingpathwayatmiddleageasastrongcandidatedriveroffunctional hematopoieticdecline.Thisprojectwillusecellularandmolecularbiologicalapproachesinagingmiceto characterizethehematopoieticcell-extrinsicandcell-intrinsicalterationsinIGFsignalingatmiddleagethat causefunctionalhematopoieticdecline.Resultsofthisprojectwillidentifytargeted,molecular-andcelltype- specifictherapeuticstrategiestopreserveregenerativecapacityandimmunecellfunctionduringaging.
TOPUBLICHEALTH Aging is a complex process that contributes to reduced function in tissues throughout the body, including the blood system. The impact of aging on human health is of increasing societal concern due to the worldwide increaseinageofourpopulation.Asnotherapiescurrentlyexisttopreventagingofthebloodsystem,thereis avitalneedtounderstandwhenandhowproperfunctionofthebloodsystembeginstofailduringaging.This research will provide important information that can be used to develop precision therapies to prevent this declineinfunctionandsustainahealthyandrobustbloodsystemduringaging.
