Insights Into the Interplay Between the Senescent Cells and Immune Cells

Vollständiger Abstract

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ABSTRACT Aging kidneys exhibit accumulation of senescent cells together with sterile low‐grade inflammation. However, the spatial organization of senescence‐associated immune cell accumulation in the aging kidney remains poorly defined. We systematically analyzed kidneys from young, middle‐aged, and aged mice, focusing on the spatial relationship between senescent tubular cells and distinct immune cell populations. Senescent tubular cells showed significant local enrichment of immune cells, with macrophages representing the most prominent associated immune cell population. This spatial association was more closely linked to p16 Ink4a burden as an indicator of biological aging than to chronological age alone, as kidneys with higher p16 Ink4a levels displayed enhanced inflammatory and SASP‐associated transcriptional signatures. Complementary spatial transcriptomic analyses identified a cortex‐restricted senescence‐associated neighborhood enriched for inflammatory, macrophage‐related, and failed‐repair tubular transcriptional programs, supporting the presence of localized senescence‐associated inflammatory niches at the transcriptomic level. Both, genetic and pharmacological senolytic interventions reduced senescent‐cell burden and decreased immune cell accumulation in aged kidneys. However, macrophages remained preferentially localized near residual senescent tubular structures after senolysis, consistent with persistent local immune senescent cell interactions. Our findings provide quantitative spatial evidence that senescence‐associated inflammatory niches emerge in the aging kidney cortex and can be modulated by senolytic intervention. Together, these results establish a spatial framework for renal inflammaging and highlight senescence‐associated inflammatory microenvironments as potential therapeutic targets in kidney aging.