# Bladder Mucosal Dysfunction During Aging

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $599,041

## Abstract

Lower urinary tract symptoms (LUTS), in particular storage symptoms (urinary incontinence) are a
major health related problem in the elderly. Yet, there remains insufficient understanding of how aging alters
normal bladder physiology, and how these changes contribute to the etiology of LUT disorders in the elderly.
Much of research past and present, has focused on detrusor muscle function and changes in the central
neurological control of aging-related LUT function; however, much less is known about the role of the
urothelium (UT) in these events. While previously thought of as a simple barrier, the urothelium communicates
with the CNS via a local urothelial-afferent signaling pathway. Our preliminary data show that aged UT has
altered mitochondrial function, including increased production of reactive oxygen species (ROS), which we
hypothesize leads to lysosomal dysfunction, altered release of mediators, and defects in UT-afferent signaling,
culminating in abnormal urodynamic behavior. Thus, our overall hypothesis is that age-related changes in the
UT and adjacent bladder wall result in a pro-aging cellular phenotype that disrupts UT-cell signaling resulting in
abnormal urodynamic behavior in the elderly.
 Our multidisciplinary research team will elucidate the effect of aging and oxidative/lysosomal stress on
urothelial physiology and the impact this has on cross talk between the UT and other cells within the bladder
wall. Using an aging (3-30 mo) rat model, we will in Aim #1 define how changes in bioenergetics and oxidative
stress impact urothelial aging by using functional assays to measure changes in both mitochondrial function
and architecture. In Aim #2, we will determine how lysosomal dysfunction contributes to urothelial aging. Here
we will use stereology as well as biochemical and morphological tools to examine why degradation and
mitophagy are impaired in aging urothelium. In Aim #3, we will determine if increasing mitochondrial/lysosomal
function will enhance UT-signaling and resultant bladder function. We will use a multi-disciplinary approach
including measurement of transmitter release and sophisticated imaging techniques coupled with recording
bladder afferent nerve activity to examine how aging and increased mitochondrial oxidative stress alters UT-
cell communication. In each aim, we will also examine whether treatments (mitotempo; metformin) that reduce
oxidative stress/lysosome dysfunction can improve urothelial (and in vivo bladder function) in aged rats. In
sum, our intriguing preliminary data combined with our extensive expertise and resources places our research
team in a unique position to examine how direct and indirect factors promote UT dysfunction in bladder aging.

## Key facts

- **NIH application ID:** 9897459
- **Project number:** 5R01AG056944-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Gerard L Apodaca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $599,041
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897459

## Citation

> US National Institutes of Health, RePORTER application 9897459, Bladder Mucosal Dysfunction During Aging (5R01AG056944-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897459. Licensed CC0.

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