Single‐Cell Analyses Reveal Dysregulation of Ribosomal Protein Genes During Hematopoietic Stem and Progenitor Cell Aging
Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong blood production, yet the molecular mechanisms underlying their functional decline with age remain incompletely understood. Understanding how aging alters the transcriptomic landscape of HSPCs is critical to uncovering the origins of immune system aging. We performed a comprehensive single‐cell RNA sequencing analysis integrating over 300,000 bone marrow‐derived HSPCs from 50 healthy individuals spanning 19 to 84 years of age. Aging was associated with immune lineage skewing, marked by increased myeloid and decreased lymphoid output in both bone marrow and peripheral blood. Subtle increases in HSCs, MEPs, and myeloid progenitors alongside reductions in lymphoid progenitors were already evident in aged bone marrow, suggesting that lineage bias is encoded at the progenitor level. Age‐associated transcriptional changes included extensive upregulation of ribosomal genes encoding small (RPS11, RPS12, RPS23) and large (RPL9, RPL19, RPL24) cytoplasmic ribosomal subunit proteins, as well as pro‐inflammatory mediators (IL1B, IL18, TGFB1, S100A8). Enrichment analysis identified mitochondrial function, ribosome biogenesis, chromatin remodeling, and inflammatory signaling as key ontologies disrupted during HSPC aging. Our study identifies molecular signatures of systemic aging rooted in bone marrow HSPCs and suggests that dysregulated ribosomal protein gene expression is an under‐appreciated hallmark of hematopoietic stem cell aging.