Sex-specific proteostasis and urothelial responses to senolytic therapy in the aged mouse bladder.
Document Type
Article
Publication Date
3-10-2026
Original Citation
Kasturi S,
Salazar A,
Hardy C,
Korstanje R,
Mysorekar I.
Sex-specific proteostasis and urothelial responses to senolytic therapy in the aged mouse bladder. J Gerontol A Biol Sci Med Sci. 2026;81(4):glag059.
Keywords
JMG, Animals, Female, Mice, Male, Proteostasis, Urinary Bladder, Aging, Unfolded Protein Response, Urothelium, Quercetin, Senotherapeutics, Endoplasmic Reticulum Stress, Dasatinib, Sex Factors, Cellular Senescence, Autophagy
JAX Source
J Gerontol A Biol Sci Med Sci. 2026;81(4):glag059.
ISSN
1758-535X
PMID
41741369
DOI
https://doi.org/10.1093/gerona/glag059
Grant
This work was supported in part by National Institutes of Health (NIH) grants, R56 AG084691-01A1 to I.U.M. and U54 AG079753 and P30 AG038070 to R.K
Abstract
Lower urinary tract dysfunction (LUTD) increases with age and disproportionately affects women, yet the molecular mechanisms underlying this sex bias remain poorly defined. The aging bladder plays a central role in this decline, and our previous work identified increased cellular senescence, oxidative stress, and activation of the PERK arm of the unfolded protein response (UPR) as key features of bladder aging. In this study, conducted as part of the NIH Common Fund SenNet program to investigate cellular senescence in mice, we explored the therapeutic potential of a senolytic drug combination of Dasatinib and Quercetin (D&Q) in male and female aged (25-month-old) bladders from genetically diverse Diversity Outbred mice. We first assessed sex differences in aged bladders (>20 months of age), then evaluated whether D&Q treatment could improve bladder health by modulating ER stress. We identified significant baseline sex differences in UPR and ER-associated degradation (ERAD) proteins, with higher expression of PERK pathway ER stress components in females and more efficient ERAD and autophagy flux in males. While D&Q did not broadly alter ER stress or autophagy markers, it selectively increased ERAD markers in females. D&Q also enhanced uroplakin expression and urothelial thickness in aged females, suggesting potential benefit to urothelial integrity. These findings suggest a potential sex-specific regulatory mechanism within the UPR pathway that may contribute to the increased vulnerability of aged females to bladder dysfunction.