Figure 1. Role of purine nucleoside phosphorylase (PNPase) in purine metabolism. ROS indicates reactive oxygen species.

Figure 2. Clinical relevance of 8-aminoguanine.

Age-associated lower urinary tract (LUT) disorders (LUTDs) erode quality of life for millions and increase enormously the costs for both health care and eldercare.¹ The specific factors that are associated with aging and lead to LUTDs are not well understood and vary among patients, though changes in the structure and function of both cellular and extracellular components of the LUT are most likely to be important contributing factors. These pathological changes and their consequent physiological disorders converge to produce LUT symptoms and signs including urgency, urinary incontinence, impaired bladder contractility, increased residual urine, nocturia, decreased bladder sensation, and other attendant conditions including urinary tract infection. Health providers often underestimate the detrimental effects of LUTDs on patients’ lives, especially in the older population. Since demographic studies indicate a steep increase in LUTDs beginning in the fifth decade of life in both sexes that worsens with advanced age,² the burden of LUTDs is particularly high in the elderly.

Oxidative damage is a known contributor to and driving factor of multiple age-associated diseases.³ While the underlying causes of LUTDs in older adults remain to be established, one of the most widely accepted hypotheses is that LUTDs arise because of increased oxidative stress, for example generation of reactive oxygen species (ROS) due to mitochondrial dysfunction.⁴ In this regard, chronic ischemia and associated oxidative stress increase with age, and accumulation of oxidative damage—associated with increased ROS—over time negatively affects all components of the LUT system yielding the LUT system prone to LUTDs regardless of the proximal initiating cause. Despite evidence supporting a role for oxidative damage in the pathophysiology of age-associated disorders, numerous clinical trials have failed to show a benefit of antioxidants for the prevention and/or treatment of such disorders. This suggests that antioxidants per se are insufficient to treat LUTDs and that a treatment that engages multiple mechanisms, including ROS reduction, is required.

There is emerging evidence that changes in levels/activity of an enzyme called purine nucleoside phosphorylase (PNPase) contribute to the extent and magnitude of both oxidative injury and inflammation leading to cellular damage.⁵ PNPase metabolizes “tissue-protective” anti-inflammatory purine metabolites to “tissue-damaging” ROS-generating metabolites (Figure 1); thereby, PNPase may contribute to age-related inflammation and ROS production leading to LUT injury. A recent report that decreases in “tissue-protective” purines in COVID-19 patients are associated with acute kidney injury⁶ provides evidence that abnormally low levels of protective purines (ie, adenosine, inosine, and guanosine) may contribute to a broad range of disorders including those impacting the LUT.

To test our hypothesis that PNPase contributes to the pathophysiology of LUTDs, we tested the concept that “redirecting the purine metabolism” in the urinary bladder using 8-aminoguanine (8-AG), an inhibitor of PNPase, would reverse LUTDs by increasing uroprotective and decreasing urodamaging purine metabolites. Indeed, we observed that 8-AG provides beneficial effects on the LUT and reverses age-related changes in both bladder structure and function.^7,8 Our preclinical studies were performed in rats near the end of their life span that had already developed severe bladder pathologies which were unlikely to be reversed by any treatment. However, PNPase inhibition with 8-AG completely reversed all of the molecular, cellular, and functional bladder abnormalities associated with aging. It is conceivable that these remarkable results with 8-AG were due not only to inhibition of PNPase, but also to other pleiotropic effects of 8-AG.

Though additional studies are required to validate the potential of 8-AG treatment for LUTDs, these and other findings support the conclusion that 8-substituted amino purines (such as 8-AG) should be included in the drug development pipeline for LUTDs. In addition to LUTDs, 8-AG exhibits wide-ranging beneficial effects on the form and function of other organ systems negatively impacted by aging, for example, retinal degeneration (Figure 2). These and other findings suggest that an inhibitor of PNPase may be “geroprotective,” targeting fundamental mechanisms of aging (eg, oxidative damage, inflammation, senescence) that make aging a risk factor for LUTDs in the older adult. We have observed that 8-AG increases life span in hypertensive Dahl SS rats on a high-salt diet by completely preventing strokes,⁹ providing additional support that 8-AG may be a geroprotector which could improve frailty in patients. Though further evidence of safety and efficacy is needed, PNPase inhibitors could offer an effective pharmacological treatment approach—either alone or as an adjunct with current treatments, which could lead to a reduction in the dose of a monotherapy, thus reducing the risk of side effects. This could result in better outcomes (improving efficacy and tolerability) for age-associated LUTDs as well as other age-related diseases.