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PreprintCited by 4Urinary Bladder and Prostate ResearchGenetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and Senescence

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A scalable organoid model of urothelial aging for metabolic interrogation, infection modeling, and reversal of age-associated changes

Open access
Parab, Adwaita R., Salazar, Arnold M., Bark, Steven J., Divenko, Margarita, Putluri, Vasanta, Lieu, D’Feau, Singh, Aadya S., Putluri, Nagireddy, Mysorekar, Indira U.·2025·Aging Cell
DOI 10.1101/2025.06.27.662009PMC PMC12830083

Preprint — published as 10.1111/acel.70391

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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 aged 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 (NAM) and D-mannose, reduce DNA damage and oxidative stress and restore 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.

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Metadata

Authors
Parab, A. R., Salazar, A. M., Bark, S. J., Divenko, M., Putluri, V., Lieu, D., Singh, A. S., Putluri, N., & Mysorekar, I. U.
Affiliations
Baylor College of Medicine (US)
Corresponding author
Mysorekar, Indira U.
ORCID
Venue
Aging Cell
Publisher
openRxiv
Published
2025-07-03
Volume
25
Issue
2
Pages
e70391-e70391
ISSN
1474-9718 (ISSN-L)
DOI
10.1101/2025.06.27.662009
PMC
PMC12830083
OpenAlex
W7125581217
Cited by
4
References
1
Citations by year
2026: 4
FWCI
27.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
National Institutes of Health (R56 AG084691-01A1)
Topics
  • Health Sciences › Medicine › Urology › Urinary Bladder and Prostate Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Keywords
cellular senescence, oxidative stress, DNA damage, epithelial-immune interactions, macrophages, purine metabolism, amino acid metabolism, glycerophospholipid metabolism, nicotinamide, D-mannose, mitochondrial integrity, lower urinary tract symptoms

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