P-selectin delineates conserved functional heterogeneity in early hematopoietic stem cell aging in humans and mice.

Progressive aging of bone marrow hematopoietic stem cells (HSCs) underlies clonal hematopoiesis and age-associated hematologic disorders. Defining early molecular events driving HSC functional decline is essential for rejuvenation strategies. Here, we identify P-selectin (Selp) as a surface marker that stratifies HSCs into conserved functional and transcriptional states during organismal aging in humans and mice. P-selectin expression increases early during aging and remains elevated in old HSCs. Selphigh-HSCs exhibit increased DNA damage and bias towards megakaryocytic/myeloid lineage fate, whereas Selplow-HSCs maintain metabolic integrity, enhanced antioxidant capacity, and reduced myeloid skewing. Transcriptomic analysis revealed that Selphigh-HSCs adopt megakaryocytic-primed, pro-inflammatory, and oxidative stress programs, while Selplow-HSCs retain lymphoid-associated and redox-balanced signatures consistent with a more preserved stem-cell state. Further ATAC-seq analysis demonstrates distinct chromatin landscapes with Selphigh-HSCs being enriched for inflammatory and platelet-related regulatory elements and CTCF motifs, but Selplow-HSCs displaying accessible ETS-driven networks linked to metabolic fitness and stem cell resilience. Together, these findings uncover conserved heterogeneity during blood stem cell aging and establish P-selectin as an early biomarker and potential therapeutic target to mitigate age-associated hematopoietic decline.