Aging-associated transcriptional programs are spatially organized within psoriatic skin through distinct immune- and stromal-associated tissue contexts, with immune-aging programs enriched in IFN-linked inflammatory domains and stromal-aging programs localized to extracellular matrix-remodeling domains.
Key Findings
Results
Aging-associated signals were not uniformly distributed across psoriatic lesions but instead localized to distinct spatial compartments.
Three compartment-informed aging signatures were defined: global old-up, stromal-aging, and immune-aging.
Global old-up and immune-aging programs were higher in APC/immune-enriched and immune-inflammatory domains.
Stromal-aging localized to fibro-inflammatory and extracellular matrix-remodeling domains.
These patterns were identified by integrating a normal aging human skin single-cell RNA-seq dataset with discovery and external psoriasis spatial transcriptomic datasets.
Results
Immune-aging-high regions in psoriatic tissue showed enrichment for IFN-linked chemokine, inflammatory, and immune-activation features.
Score-defined immune-aging-high regions were dominated by IFN-linked chemokine, inflammatory, and immune-activation gene programs.
Stromal-aging-high regions were dominated by collagen organization and extracellular matrix remodeling programs.
Sensitivity analyses used an overlap-removed immune-aging score and immune/APC-adjusted analyses to confirm findings.
External spatial transcriptomic analysis reproduced selected antigen-presentation- and interferon-linked features.
Results
Immune-aging activity was increased in lesional psoriasis at the tissue-section level and was associated with IFN gamma response and antigen-presentation activity.
Immune-aging scores were elevated in lesional compared to non-lesional psoriatic tissue sections.
The association with IFN gamma response and antigen-presentation activity was observed using both the primary immune-aging score and the overlap-removed immune-aging score.
Similar patterns were observed across discovery and external spatial transcriptomic datasets.
These findings suggest spatial co-localization of aging-immune transcriptional programs with interferon-driven inflammation in psoriatic lesions.
Results
Doxorubicin-induced senescence-like stress in human foreskin fibroblasts (HFF-1) was compatible with retained IFN-gamma-responsive antigen-presentation and chemokine programs.
Doxorubicin induced a senescence-like DNA damage-associated state in HFF-1 fibroblasts.
IFN-gamma induced expression of HLA-ABC, B2M, CD74, CXCL9, and surface HLA-DR in these cells.
IFN-gamma-responsive programs remained detectable after doxorubicin-induced stress.
Human foreskin fibroblasts were used as a reductionist system to test the compatibility of senescence-like stress with inflammatory responsiveness.
The authors note these findings support coexistence of senescence-like stromal stress and IFN-gamma-responsive immune activation but do not establish a causal relationship.
Results
Stromal-aging transcriptional programs were spatially associated with extracellular matrix remodeling and collagen organization rather than immune-inflammatory activity.
Stromal-aging scores localized to fibro-inflammatory and ECM-remodeling domains in psoriatic tissue.
Stromal-aging-high regions were characterized by collagen organization and extracellular matrix remodeling gene programs.
This pattern was distinct from immune-aging-high regions, which were enriched for IFN-linked and immune-activation features.
The spatial separation of stromal-aging and immune-aging programs indicates compartment-specific roles for aging-associated transcriptional activity.
Methods
Integration of normal aging skin single-cell RNA-seq data with psoriasis spatial transcriptomics enabled the definition and projection of compartment-informed aging signatures onto psoriatic tissue architecture.
A normal aging human skin single-cell RNA-seq dataset was integrated with discovery and external psoriasis spatial transcriptomic datasets.
Three aging signatures (global old-up, stromal-aging, immune-aging) were defined and projected onto psoriatic tissue.
Sensitivity analyses included an overlap-removed immune-aging score and immune/APC-adjusted analyses.
This cross-dataset integration approach allowed spatial mapping of aging-associated transcriptional programs within psoriatic lesional architecture.
What This Means
This research suggests that the biological processes associated with aging do not spread evenly throughout inflamed skin in psoriasis, but instead concentrate in specific tissue neighborhoods. By combining data from aging skin studies with detailed spatial maps of psoriatic skin tissue, the researchers found that aging-related gene activity linked to immune cells clustered in areas with active immune responses and interferon signaling, while aging-related gene activity in structural (stromal) cells was found in areas undergoing tissue remodeling and collagen reorganization. This spatial organization implies that 'old-looking' gene programs have distinct roles depending on which type of cells and tissue zones they occur in.
The study also tested whether skin fibroblasts (structural cells of the skin) that were experimentally pushed into a senescence-like (cellular aging) state could still respond to immune signals. The researchers found that even after inducing a stress-related, senescence-like state with a DNA-damaging drug, fibroblasts retained the ability to respond to interferon-gamma—an important immune signaling molecule—by activating genes involved in antigen presentation and immune recruitment. This suggests that structurally aged or stressed cells in psoriatic skin may still participate in immune communication rather than being purely 'burned out.'
These findings matter because they add spatial detail to how aging and inflammation intersect in a common inflammatory skin disease. Rather than aging simply amplifying inflammation everywhere, the results point to distinct tissue compartments where age-related immune programs and age-related structural programs operate separately. The authors are careful to note that while these processes appear to coexist in psoriatic skin, the study does not prove that cellular aging causes the inflammatory changes observed, leaving open important questions for future research.
Wu X, He M, Chen H, Gan L. (2026). Aging-associated immune and stromal programs mark interferon- and remodeling-linked spatial contexts in psoriatic skin.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1903929