Over half of the adult population has experienced lower urinary tract (LUT) symptoms and the prevalence of LUT disorders is expected to increase by 18% over the next 10 years due to increasing life expectancy [1]. Oxidative stress, associated with mitochondrial dysfunction, may explain the increasing prevalence of LUT disorders in the aging population [2]. The goal of this systematic review was to evaluate the relationship between oxidative stress and age-related lower urinary tract (LUT) disorders with the aims of: (a) summarizing evidence on oxidative stress in studies characterizing age-related LUT disorders; (b) analyzing common manifestations and biomarkers; and (c) identifying future areas of research.

This systematic review utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) protocol. PubMed, Scopus, CINAHL, and Embase were searched for peer-reviewed studies published between 01/01/2000 and 03/01/2021. Both animal and human studies that reported on the impact of oxidative stress in age-related LUT disorders were included. Two authors independently screened and assessed all articles; all discrepancies were resolved by consensus with input from a third author. 

Articles were screened for studies that met the following inclusion criteria: (1) study evaluated oxidative stress in LUT disorders; (2) study was an original article published between January 2000 and March 2021; (3) study evaluated any age-related lower urinary tract disorder; (4) study was preclinical dealing with human/animal subjects or clinical dealing with human participants; and (5) study assessed results by appropriate statistical methods (e.g., ANOVA, t-tests). Studies were excluded in title and abstract sorting if the participants were less than 18 years old, the focus was on non-LUT disorders, treatments or interventions were analyzed, analysis did not focus on both LUT disorders and oxidative stress, or focus was on organs not in the LUT. Full text articles were excluded if the focus was on primary mitochondrial defects, data was insufficient (e.g., case studies), article presented a narrative review, or article fell under a previous exclusion criterion not apparent in title and abstract review.

Included studies were grouped based on nature of the study (animal or human). Data was extracted and summarized from all included studies and associated protocols. Quality of studies was assessed using the Gradings of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria, suitable for both animal and human studies, and level of evidence for human studies was rated according to the criteria provided by the Oxford Centre for Evidence-Based Medicine (OCEBM).

Of 882 articles identified, 124 duplicates were removed and title and abstracts of 758 articles were screened; 712 studies were excluded, leading to full text sorting of the remaining 46 studies. Of these, 25 articles were excluded, and 21 studies were included for qualitative synthesis. 13 studies were preclinical animal studies and 8 were human studies. Based on the GRADE criteria, a quality of evidence rating of low (5 studies), moderate (11 studies), or high (5 studies) was given. With the OCEBM criteria applied to human clinical studies, three studies were level 2b and four studies were level 3b.

The animal studies analyzed rats or rabbits with the sample size ranging from 12-54 (age range: 2-18 months). The human studies had population sizes of 25-79 patients with sex representation ranging from 0% male to 100% male (age range: 37-79 years). All animal studies were experimental and had durations of days to 1.5 years. Human studies were either experimental (2 studies), prospective cohort (3 studies), or case control studies (4 studies). For prospective cohort studies, the duration ranged from days to 2 years. LUT disorders evaluated included BPH (6 studies), BOO/PBOO (5 studies), ischemia-reperfusion injury (I/R) (10 studies), acute urinary retention (1 study), prostate neoplasia and cancer (1 study), and detrusor overactivity (1 study).
 
In the age-related LUT disorders analyzed, common structural changes were increasing bladder and prostate weights, ischemic damage, nerve damage and detrusor muscle hypertrophy, and common functional changes included decreased bladder contraction, increased bladder sensation, increased detrusor excitability, decreased perfusion, and increased inflammation. The following biomarkers were noted to increase: ROS, malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), ischemia modified albumin (IMA), hypoxia inducible factors (HIFs), N-(hexanoyl) lysine, advanced oxidation protein products (AOPP), PI3K/Akt, Hsp70, GRP75, purinoceptor isoform (P2X), muscarinic receptors (M1 and M2), nerve growth factor (NGF), 8-isoprostane, nitrotyrosine, Pb, Cd, NF-Kb, IL-8, IgE, and CRP. The following biomarkers decreased: M3, total antioxidant capacity (TAC), nitric oxide synthase (NOS), and superoxide dismutase (SOD). Nrf2 showed variability (Tables 1 & 2). The effect on biomarkers was greater in aged groups compared to younger groups.

The impact of increased reactive oxygen species (ROS), due to aging and mitochondrial damage, on the cellular level explains many noted structural and functional changes in the LUT. ROS damages cellular structures, macromolecules, mitochondrial DNA, and tissues through inflammation and fibrosis. ROS activates enzymes, damages DNA, and stimulates fibroblast proliferation, causing structural changes such as increased bladder and prostate weights, stromal thickening, and detrusor hypertrophy. These ROS-driven mechanisms also explain functional changes in the LUT, such as decreased bladder contraction, increased bladder sensation, and increased detrusor excitability. 

Studies evaluating I/R noted that initial changes with ischemia were associated with bladder overactivity (e.g., increased micturition frequency, decreased bladder capacity due to increased contractility, increased micturition pressure) and later changes were associated with bladder underactivity (e.g., decreased micturition frequency, increased bladder capacity due to decreased contractility, decreased micturition pressure). This pattern of changes was accompanied by neural structural damage and muscarinic receptor expression, which may partially explain the impact of ischemia on the LUT [3].

The biomarker changes were evidence of oxidative stress induced molecular damage (ROS, MDA, 8-OHdG, IMA, N-(hexanoyl) lysine, 8-isoprostane, nitrotyrosine, AOPP, GRP75, NOS, Pb, and Cd), mechanisms to protect against oxidative stress (HIFs, PI3K/Akt, Hsp70, TAC, and SOD), neural changes (P2X, M1, M2, M3, and NGF2), and inflammation (NF-Kb, IL-8, IgE, and CRP). With the complex role oxidative stress plays in age-related LUT disorders, further research is needed to explore biomarkers in the context of demographics, pathophysiology, prognosis, and treatments.

With an increasing prevalence of LUT disorders in the aging population, there is a need to evaluate the pathogenesis by which aging leads to LUT disorders. Common manifestations of LUT and biomarker changes across studies suggest a strong role of oxidative stress, often linked to mitochondrial damage, in age-related LUT disorders. The data in this systematic review identifies prognostic markers and treatment opportunities; further investigation is warranted to examine the mechanisms by which these changes manifests in age-related LUT disorders.

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