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 worldwide increase in the age of the population and incidence of these
age-related conditions. No intervention therapies currently exist to prevent functional decline of the
hematopoietic system with aging, largely due to a lack of understanding of the cellular and molecular
alterations that occur at the age of onset to cause functional hematopoietic decline. As hematopoietic stem
cells assure long-term tissue maintenance, it is widely accepted based on experimental evidence that loss of
proper hematopoietic stem cell function in the bone marrow during aging is a major cause of hematopoietic
decline. Our preliminary data demonstrate that at the age of onset of functional hematopoietic decline,
alterations in the bone marrow microenvironment are necessary and sufficient to cause hematopoietic stem
cell aging, and identify reduced levels of the signaling molecule Insulin-like Growth Factor 1 (IGF-1) in the bone
marrow as a candidate driver of hematopoietic stem cell aging. This project will use cellular and molecular
biological approaches in aging mice to characterize the specific cellular and molecular alterations in the aging
bone marrow microenvironment and how these cause functional decline of hematopoietic stem cells, including
the specific cell type(s) responsible for reduced production of IGF-1 and how reduced IGF-1-mediated
signaling drives functional decline of hematopoietic stem cells. Results of this project will reveal the
mechanisms causing functional decline of the hematopoietic system with aging, and identify targeted,
molecular- and cell type-specific therapeutic strategies to preserve regenerative capacity and immune cell
function during aging.
