Frontiers in Immunology · Oct 30, 2026
Cross-species single-cell atlas of the olfactory mucosa reveals cell-type specific senescence linked to neuroepithelial dysfunction and chronic inflammation
By Sandeep Goswami, Jeffanie Wu, Krishna C. Josyula et al.
Introduction: Aging of the olfactory mucosa is associated with progressive olfactory dysfunction, impaired neuroepithelial regeneration, and persistent inflammation. However, the cellular and molecular mechanism linking age-related changes, cellular senescence, and chronic inflammation in the olfactory epithelium remain unclear. We hypothesized that aging promotes cell-type-specific senescence programs, which contribute to inflammatory remodeling and impaired neuroepithelial homeostasis in the olfactory mucosa. Methods: We integrated publicly available single-cell RNA sequencing (scRNA-seq) datasets from young and aged human and mouse olfactory mucosa to characterize age-associated changes in cellular composition and transcriptional states. Cellular senescence was assessed using canonical senescence-associated genes, including CDKN2A/p16, SenMayo gene-signature scoring, and SenePy based cell-type-specific senescence scoring. Differential gene expression, cell-type-specific transcriptional profiles and senescence-associated inflammatory programs were evaluated across age groups and compared between species. Our in-house human chronic rhinosinusitis (CRS) scRNA-seq cohort was additionally analyzed to determine whether chronic sinonasal inflammation was associated with amplification of age-related senescence programs. Results: Analysis revealed conserved cellular complexity and identified approximately twenty transcriptionally distinct clusters in both species. In older samples, aging was associated with substantial remodeling of cellular composition and increased cell-type-specific senescence signatures across the olfactory mucosa. Senescence-enriched epithelial and stromal populations showed increased expression of senescence-associated secretory phenotype (SASP) programs, including inflammatory cytokines, neutrophil-recruiting chemokines, and inflammasome-related genes. Cross species analysis identified both conserved and species-specific patterns of senescence, with epithelial involvement in humans and greater stromal and immune involvement in mice. Senescence in fibroblasts emerged as a conserved feature across species. Our in-house CRS cohort showed that chronic inflammatory disease was associated with increased enrichment of age-related senescence programs, particularly within epithelial and stromal cells. Discussion: We found that cellular senescence in the aging olfactory mucosa follows a consistent pattern across cell types. The data also link inflammatory signaling to chronic inflammation and impaired neuroepithelial homeostasis. The expansion of these programs in CRS suggests that cellular senescence may represent an important mechanistic link between aging, persistent sinonasal inflammation, and olfactory dysfunction, and supports future functional studies to evaluating senescence-targeted approaches aimed to restoring olfactory tissue regeneration.