# A Scalable Organoid Model of Urothelial Aging for Metabolic Interrogation, Infection Modeling, and Reversal of Age‐Associated Changes

## TL;DR

Researchers developed a scalable organoid model of aged bladder tissue to study aging effects and potential treatments for bladder dysfunction.

## Contribution

The study introduces mouse bladder epithelium-derived organoids (mBEDOs) as a novel platform for modeling urothelial aging and testing metabolic interventions.

## Key findings

- Aged mBEDOs show oxidative stress, senescence, and DNA damage similar to aged bladder tissue.
- Supplementing with nicotinamide and d-mannose reduces DNA damage and restores mitochondrial function in aged mBEDOs.
- mBEDOs reveal age-related changes in purine, amino acid, and glycerophospholipid metabolism.

## Abstract

Aging leads to a progressive decline in overall bladder function resulting in lower urinary tract symptoms and increased susceptibility to infections. However, tissue‐specific mechanisms of aging, specifically the contributions of the urothelium, remain elusive. Here, we introduce mouse bladder epithelium‐derived organoids (mBEDOs) as a scalable platform to model urothelial aging. mBEDOs from aged mice recapitulate key features of age‐associated cellular reprogramming, including oxidative stress, senescence, and DNA damage. We demonstrate the utility of mBEDOs for modeling Uropathogenic
Escherichia coli
(UPEC) infection, generating assembloids between mBEDOs and macrophages to model epithelial‐immune interactions, and genetic perturbation. Using the mBEDO platform, we also identify urothelium‐specific changes in purine, amino acid, and glycerophospholipid metabolism, which may contribute to age‐associated cellular perturbations. Lastly, supplementation with depleted metabolites, nicotinamide and d‐mannose, reduces DNA damage and oxidative stress and restores mitochondrial integrity in aged mBEDOs. These findings establish mBEDOs as an effective platform for investigating molecular and cellular underpinnings of urothelial aging and exploring metabolism‐based interventions for age‐associated bladder dysfunction.

mBEDOs: a scalable platform for modeling urothelial aging. mBEDOs derived from aged mouse bladders capture essential molecular and cellular features of urothelial aging and provide a versatile system for high‐throughput metabolic profiling, therapeutic screening via metabolite supplementation, age‐ and sex‐based analyses, infection modeling, and immune–epithelial interaction studies.