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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK118072-03
Application #
9984383
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2018-08-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609