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.
(Relevance) Lower urinary tract symptoms (LUTS) are major health related problems of the elderly and represent significant, and very costly health and quality of life problems of our society. In view of the complex control of the lower urinary tract, including anatomical, neurological and other mechanisms affected by aging- our team of collaborators is in a unique position (by virtue of extensive expertise and resources) to provide new insights into how aging alters mitochondrial dysfunction and oxidative stress that result in abnormal urodynamic behavior. These studies will provide a translational foundation for the development of new modalities targeting pathophysiological processes for the treatment of age-related bladder control problems.
|Truschel, Steven T; Clayton, Dennis R; Beckel, Jonathan M et al. (2018) Age-related endolysosome dysfunction in the rat urothelium. PLoS One 13:e0198817|
|Cheng, Fangzhou; Birder, Lori A; Kullmann, F Aura et al. (2018) Layer-dependent role of collagen recruitment during loading of the rat bladder wall. Biomech Model Mechanobiol 17:403-417|