In the aging population, millions of individuals in the US are affected by age-related Lower Urinary Tract Symptoms (LUTS) including impaired detrusor contractility and decreased bladder sensation often resulting in incomplete bladder emptying. The term underactive bladder (UAB), the symptom-based correlate of detrusor underactivity, has been used to cover the general condition of incomplete bladder emptying, regardless of the underlying cause. However, though there is a clear correlation between UAB and advanced age, the underlying causative factors that may contribute to this condition- for which there are no effective treatments- is not known. Our preliminary findings show that age-related UAB is associated with changes in bladder levels of the purinergic nucleoside inosine- a uro-protective purine- and its downstream metabolite hypoxanthine, a uro- damaging purine that produces harmful reactive oxygen species (ROS). Further, treatment of aged animals with a purine analog that inhibits the formation of this uro-damaging hypoxanthine and increases uro-protective inosine actually reverses bladder dysfunction. Thus, our overall hypothesis is that age-related LUTS/UAB is mediated in part by uro-damaging hypoxanthine which increases bladder oxidative stress. A corollary of our central hypothesis is that: inhibition of purine nucleoside phosphorylase (PNPase) with 8-aminoguanine (8-AG) will prevent and reverse UAB by simultaneously increasing uro-protective inosine and decreasing uro- damaging hypoxanthine. Our multidisciplinary research team will elucidate the effect of aging on altered purine metabolism/signaling as it relates to bladder pathophysiology. Using an aging (3-30 mo) rat model, we will in Aim #1 define how the aging process changes purine metabolism in the bladder. Here we will use cutting edge analytical methods to study effects of aging on bladder levels of oxidative stress//inflammation and the purine metabolome. Where possible, we will compare the changes we identify in rats to those observed in patient samples and will also examine whether chronic treatment of aged rats with 8-AG (inhibits conversion of inosine to hypoxanthine) will improve biomarkers of oxidative stress and decrease bladder levels of uro-damaging hypoxanthine and their precursors/metabolites.
In Aim #2, we will test the concept that aging-associated changes in purine metabolism/oxidative stress alters peripheral nerve/bladder functions. We will also examine whether these and other age-related changes (i.e., vascular perfusion, smooth muscle morphology) can be mitigated with chronic treatment of aged rats using oral 8-AG. We will use a multi-disciplinary approach including sophisticated imaging techniques and biochemical, morphological and electrophysiological tools and, when possible, we will also compare changes in sensory nerve and bladder function in rats to those observed in patients using standard clinical assessment. In sum, our intriguing preliminary data combined with our extensive expertise and resources places our research team in a unique position to examine mechanisms that may be responsible for underlying symptoms (inability to empty) involved in the aging bladder.
(Relevance) Lower urinary tract symptoms are major health related problems of the elderly. 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 to provide new insights into how aging alters purine metabolism which, via increases in oxidative stress results in abnormal urodynamic behavior (underactive bladder). 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.