The average population age/life expectancy are increasing worldwide, and lower urinary tract (LUT) function is particularly susceptible to aging.  The prevalence of bladder overactivity and detrusor underactivity increases with age and both can co-exist in women and men.  Furthermore, there is a variety of risk factors including neurological diseases, diabetes and other pathologies which also increase with aging.  Bladder outlet obstruction due to benign prostatic hyperplasia (BPH) is prevalent in aging males, while female population experiences changes following childbirth and/or menopause.  While existing data from animal studies may be as variable as data from humans depending on underlying risk factors, they are nonetheless important for understanding the progression of LUT changes with age.  Male rats lack a prostatic capsule present in humans and do not develop outlet obstruction due to BPH, and female rats used in experiments do not experience childbirth thus eliminating some of the risk factors leading to variability.  The aim of this study was to compare the age-related changes in bladder function in adult and aged male and female F-344 rats.

Male and female 10 and 24 months old F-344 rats were anesthetized with urethane (1.2 g/kg) and their bladder function was evaluated in vivo using voiding cystometrograms (CMGs, performed with saline infused at 0.05 ml/min) and, after bladder dissection, in vitro using length-tension recordings from bladder strips.  Histological staining was used for bladder wall structure observation, and collagen and mast cell quantification.  Experiments were carried out on n ≥ 4 rats in each group.  Unpaired student t-test determined differences between age groups.

CMGs from aged male rats demonstrated a significant decrease in intercontractile intervals and decreased compliance with some non-voiding contractions (Figure 1).  Length-tension measurements from isolated bladder strips showed a significant increase in passive tension/tissue stiffness in aged males compared to adults (Figure 2).  Modified Verhoeff Van Gieson staining showed significant collagen deposition and increased collagen:tissue ratio in aged male rats in comparison to adults.  In contrast, aged female rat bladders demonstrated significantly longer intercontractile intervals and higher bladder capacities.  Bladder compliance was also increased as was the pressure threshold, while maximal voiding pressure was lower than in adult female rats (Figure 1).  Tension recordings from female rats showed a slight decrease in passive tension in comparison to adults (Figure 2).  While there was limited collagen deposition in aged female bladders, most exhibited urothelial damage with an increase in activated mast cell numbers (18 ± 5 versus 7 ± 3 cells/mm2 aged females versus adult, respectively) suggestive of re-occurring inflammation.

Our studies demonstrate that aged male rats developed detrusor overactivity exhibited as a significant decrease in intercontractile intervals and decreased compliance as well as fibrosis which correlated with a significant increase in passive tension/tissue stiffness compared to adults.  Aged female rat bladders did not exhibit morphological changes associated with fibrosis.  On the contrary, aged female rats had increased bladder compliance, capacity and pressure thresholds suggesting diminished bladder afferent responses.  The damaged urothelial layer and increased mast cell numbers in the absence bladder overactivity in aged females support the hypothesis of decreased afferent nerve sensitivity

Our data suggest there are considerable gender differences in bladder pathophysiology associated with aging; male rats develop bladder fibrosis with detrusor overactivity while female rats exhibit inflammation, increased bladder compliance and capacity with decreased afferent sensitivity.  These differences in pathology require therapeutic approaches that target the varying underlying mechanisms.  A potential contributor to age-related gender differences is the renin-angiotensin system (RAS).  While it has well-known effects regulating systemic blood pressure, it also has a significant role in modulating tissue inflammation and fibrosis.  The RAS also has marked sex-linked differences consistent with our data; estrogen inhibits angiotensin type 1 receptors which have profibrotic actions, while testosterone inhibits angiotensin type 2 receptors which are antifibrotic.  Future studies will focus on the role of angiotensin receptors in age-related bladder changes.