ABSTRACT Aging impairs the regenerative potential of hematopoietic stem and progenitor cells (HSPC) and skews HSPC differentiation towards the myeloid lineage. These defects in HSPC likely contribute to aging-related blood disorders, including increased susceptibility to infection, increased risk of anemia, and predisposition to myeloid neoplasms. The bone marrow (BM) microenvironment has recently been suggested to influence HSPC aging. However, the mechanisms whereby BM stromal cells mediate HSPC aging are not well understood. We recently reported that neuropeptide Y (NPY), one of the most abundant neurotransmitters releases in the BM microenvironment, critically regulates HSPC trafficking by controlling the BM vascular gateway function. In healthy young mice, our and other studies have shown that NPY genetic deficiency impairs BM niche cell survival and attenuates hematopoietic recovery after genotoxic stress. It has recently been reported that blood NPY levels decrease in the elderly human population. In preliminary studies, we have found that NPY levels reduced in the BM of aged mice and were accompanied by the alternation in BM niche cell and HSPC numbers. Aged mice BM niche mesenchymal stromal cell and endothelial cell showed increased reactive oxygen species (ROS) production, and NPY deficient young mice showed a similar increase in BM ROS levels. We also found that ex vivo treatment of aged HSPC with NPY substantially reverted aged HSPC autophagy defect. Based on these observations, we hypothesize that the aging mediated deficit of NPY signals in the BM impairs the crucial endogenous mechanisms that support BM niche activities and HSPC function leading to HSPC aging. This hypothesis will be tested in two Aims. Specific Aim 1 will investigate whether the aging-mediated deficit of NPY signals in the BM contributes to niche alternation and HSPC defects. We will use genetic and pharmacologic approaches to modulate the NPY levels in the mouse models and evaluate BM niche and HSPC aging phenotypes. In Specific Aim 2, we will identify the mechanism (s) by which NPY deficit/alternation contributes to age-related defects in the BM microenvironment and HSPC function. We will evaluate how aging-related deficiency in BM NPY contributes to niche and HSPC aging hallmarks, such as oxidative stress, autophagy impairment, and senescence, and identify the transcriptome pathways involved in these processes. The proposed studies will shed new light on how aging-related reduction in BM NPY signals contributes to BM niche alternation and blood stem cell defects and identify a potential therapeutic target to improve hematopoietic rejuvenation in elderly individuals.