Presentation Authors: Bronagh McDonnell, Amanda Wolf-Johnston, Aura Kullmann, Anthony Kanai, Gerard Apodaca, Sruti Shiva, Lori Birder*, Pittsburgh, PA
Introduction: Lower urinary tract symptoms (LUTS), in particular storage disorders and decreased sensation, are major health related problems that increase with age. Considering the large costs associated with LUTS dysfunction there is little understanding of how aging affects normal bladder physiology. Our preliminary studies have revealed that aged urothelium (UT) exhibit altered mitochondrial (MITO) function which we hypothesize leads to altered release of mediators (ATP) culminating in abnormal urodynamic behavior. The objective of this study was designed to elucidate the effects of aging on UT physiology and the impact this has on bladder function.
Methods: Bladder function in female F344 rats (3-25mo) was assessed with metabolic (24hr) cages; tactile/abdominal sensitivity was assessed using von Frey filaments. Following these procedures, animals were sacrificed, and bladders collected for cell culture, ATP release and western immunoblotting.
Results: We find that aged rat UT exhibit a significant increase in the senescent marker p16 (2-fold increase) versus UT from younger animals. Further, using Seahorse methodology to examine UT bioenergetics, we find aged UT shows a decrease in both maximal cellular respiration as well as spare respiratory capacity (SRC- extra capacity available to cells to produce energy in response to stress). Aged UT exhibit a decrease in MITO membrane potential (marker of MITO health) and also exhibit a decreased ability to release ATP in response to a mechanical (hypotonic) stimuli as well as decreased overall ATP content. In addition, we also observed a decrease in tactile (abdominal and somatic) stimuli in aged rats as well as decrease in voiding frequency as compared to younger rats.
Conclusions: Age-related perturbations of the UT could have a significant impact on bladder function via a local UT-afferent signaling pathway that can regulate sensory input to the CNS. MITO are considered major players in energy production and are associated with a number of age-related diseases. Our findings indicate that UT MITO are significantly affected by aging. We propose that dysregulation of MITO dynamics in the aging bladder may lead to defects in UT-afferent signaling that over time ultimately lead to altered sensation and incontinence in the elderly.
Source of Funding: R01 AG056944 and R37DK54824