Document Type
Article
Publication Date
2-1-2025
Original Citation
Al-Naggar I,
Antony M,
Baker D,
Wang L,
Godoy L,
Kuo C,
Fraser M,
Smith P,
Xu M,
Kuchel G.
Polyploid superficial uroepithelial bladder barrier cells express features of cellular senescence across the lifespan and are insensitive to senolytics. Aging Cell. 2025;24(2):e14399.
Keywords
JGM, Cellular Senescence, Animals, Urinary Bladder, Mice, Senotherapeutics, Urothelium, Polyploidy, Mice, Inbred C57BL, Dasatinib, Female, Epithelial Cells, Humans
JAX Source
Aging Cell. 2025;24(2):e14399.
ISSN
1474-9726
PMID
39644167
DOI
https://doi.org/10.1111/acel.14399
Abstract
Lower urinary tract dysfunction (LUTD) increases with aging. Ensuing symptoms including incontinence greatly impact quality of life, isolation, depression, and nursing home admission. The aging bladder is hypothesized to be central to this decline, however, it remains difficult to pinpoint a singular strong driver of aging-related bladder dysfunction. Many molecular and cellular changes occur with aging, contributing to decreased resilience to internal and external stressors, affecting urinary control and exacerbating LUTD. In this study, we examined whether cellular senescence, a cell fate involved in the etiology of most aging diseases, contributes to LUTD. We found that umbrella cells (UCs), luminal barrier uroepithelial cells in the bladder, show senescence features over the mouse lifespan. These polyploid UCs exhibit high cyclin D1 staining, previously reported to mediate tetraploidy-induced senescence in vitro. These senescent UCs were not eliminated by the senolytic combination of Dasatinib and Quercetin. We also tested the effect of a high-fat diet (HFD) and senescent cell transplantation on bladder function and showed that both models induce cystometric changes similar to natural aging in mice, with no effect of senolytics on HFD-induced changes. These findings illustrate the heterogeneity of cellular senescence in varied tissues, while also providing potential insights into the origin of urothelial cancer. We conclude that senescence of bladder uroepithelial cells plays a role in normal physiology, namely in their role as barrier cells, helping promote uroepithelial integrity and impermeability and maintaining the urine-blood barrier.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.