Abstract
Aging-related blood disorders are linked to defects in the regenerative and multilineage differentiation ability of hematopoietic stem and progenitor cells (HSPCs). While remodeling of the bone marrow (BM) microenvironment where HSPCs reside is known to contribute to these age-associated defects, the underlying factors and mechanisms remain poorly defined. Here, we discovered that the age-related decline of the neurotransmitter neuropeptide Y (NPY) in the BM is a critical driver of HSPC dysfunction. Using mouse models, we demonstrated that NPY levels decrease in the BM with age, and that genetic NPY overexpression or exogenous NPY administration in old mice substantially reverses aging-associated phenotypic and functional defects in HSPCs. Transcriptome analysis revealed that NPY supplementation in old mice restores aging-disrupted molecular pathways in their HSCs, including oxidative stress responses, myeloid differentiation, stemness, mitochondrial activity, and RhoA signaling. However, NPY genetic loss in young mice led to a decline in HSCs regenerative capacity and increased oxidative stress. Importantly, NPY levels also decline in elderly humans, and ex vivo treatment of human BM-derived HSPCs with NPY enhances their in vivo repopulating capacity. These results suggest that NPY supplementation or preservation of NPY-producing nerve fibers could be a therapeutic strategy to rejuvenate aged HSC function.