🎗Senolytic therapy drives immune remodeling in the aged kidney microenvironment

Introduction: Due to organ shortages, kidneys from older donors are increasingly used for transplantation despite their reduced regenerative capacity and poorer post-transplant outcomes. Kidney aging is characterized by the accumulation of senescent cells, which adopt a pro-inflammatory secretory phenotype, alongside increased immune-cell infiltration. However, how cellular senescence shapes immune remodeling in the aged kidney microenvironment remains incompletely understood.
Methods: Young and aged mouse kidneys were analyzed using immunohistochemistry, senescence-associated beta-galactosidase staining, and RNAscope for p16Ink4a expression. Cortical gene expression was assessed using the Nanostring nCounter platform. Senescent cells were depleted using pharmacologic and genetic senolytic interventions. Spatial transcriptomics (Visium) was integrated with publicly available datasets from young and aged, non-injured kidneys.
Results: Aged kidneys showed increased senescence marker expression, inflammatory transcriptional changes, and marked immune-cell infiltration, with macrophages as the predominant population. Immune cells were preferentially localized to regions surrounding p16Ink4a-positive tubular structures, indicating a spatial association between senescence and immune cell accumulation. Senolytic interventions reduced overall renal immune-cell accumulation (Figure 1) and disrupted local immune clustering, although macrophages remained enriched near residual senescent cells. Spatial transcriptomic analysis identified a cortical cluster enriched for genes associated with failed-repair and dedifferentiated senescent cells, displaying strong senescent and immunomodulatory signatures. These regions showed co-localization of epithelial stress and macrophage-related gene expression programs.
Conclusion: Cellular senescence is a key driver of immune remodeling in the aged kidney, promoting a pro-inflammatory microenvironment through spatially organized interactions with immune cells. These findings suggest that aged donor kidneys harbor a pre-existing inflammatory and stress-associated state, which may contribute to inferior transplant outcomes. Targeting senescent cells represents a promising strategy to improve the quality and resilience of aged donor organs.