Single-Cell Mapping Identifies Aging-Associated Neutrophil Remodeling Across Multiple Organs.

Abstract

Aging is accompanied by progressive immune remodeling and functional decline across multiple organs. However, the role of neutrophils and their heterogeneous states in these processes remains incompletely understood. Here we integrated single-cell RNA sequencing datasets from multiple organs of young and aged mice to characterize aging-associated neutrophil remodeling. We identified organ-dependent changes in neutrophil abundance and state composition, together with neutrophil subsets enriched for inflammatory, oxidative stress, complement, and IL-6-related transcriptional programs. In vitro, exposure to conditioned media from neutrophils isolated from aged mice or IL-6-stimulated neutrophil-like cells increased inflammatory and senescence-associated responses in vascular smooth muscle and hepatocyte-derived cells. Bone marrow single-cell analysis further revealed aging-associated shifts in progenitor composition and transcriptional states, including an old-enriched HPC11 population characterized by enhanced myeloid priming. Silico perturbation analysis nominated FGF didate regulators of HPC subtype-specific transcriptional programs. Together, our study provides a multi-organ single-cell resource for defining neutrophil remodeling during aging and highlights candidate neutrophil states and potential signaling axes associated with age-related inflammatory tissue environments.