PROJECT SUMMARY/ABSTRACT The process of aging causes functional decline of the hematopoietic system, including reduced capacity for regeneration, increased risk of infections, and increased risk of certain forms of blood cancer. This is a significant health concern due to the increasing age of our population and incidence of these age-related conditions. No intervention therapies currently exist to extend hematopoietic healthspan with aging, largely due to a lack of understanding of the cellular and molecular alterations that cause functional hematopoietic decline. Our novel approach is to identify cellular and molecular signatures of functional hematopoietic decline at its age of onset, with the rationale that these signatures will point to early causes of decline and hence identify prime targets for extending hematopoietic healthspan. Our preliminary data demonstrate that functional hematopoietic decline occurs by middle age, that alterations in the bone marrow microenvironment at middle age are necessary and sufficient to cause functional hematopoietic decline, and identify alterations in the Insulin-like Growth Factor 1 (IGF1) signaling pathway at middle age as a strong candidate driver of functional hematopoietic decline. This project will use cellular and molecular biological approaches in aging mice to characterize the hematopoietic cell-extrinsic and cell-intrinsic alterations in IGF signaling at middle age that cause functional hematopoietic decline. Results of this project will identify targeted, molecular- and cell type- specific therapeutic strategies to preserve regenerative capacity and immune cell function during aging.