Over the course of my postdoctoral fellowship at the University of Connecticut’s (UConn’s) Center on Aging, under the mentorship of Dr George A. Kuchel and Dr Phillip P. Smith, I studied several aspects of the intersection of aging and bladder dysfunction.¹ A couple of issues became very clear to me from our work and that of others: (1) the pathophysiology of bladder dysfunction is multifactorial and not well characterized, and (2) most drugs targeting different voiding disorders, such as the overactive bladder, aim to alleviate symptoms, perhaps by inducing detrusor relaxation, as opposed to targeting the primary underlying physiology. This has often led to poor outcomes for patients, and, combined with undesirable drug side effects, low adherence. Adding the fact that anticholinergics increase the risk of cognitive impairment in an already vulnerable older population,^2,3 it became obvious that novel, more precise targets for treating lower urinary tract dysfunction are needed.

Many studies, mostly done in rodent models of aging, have shown that the aged bladder exhibits many “biological hallmarks of aging.”^4-7 Biological hallmarks of aging (BHAs) are molecular and cellular changes that increase with advancing chronological age and have been shown to contribute to the pathophysiology of most chronic diseases that afflict humans, such as cancer, diabetes, cardiovascular disease, and Alzheimer’s. The observation that aging is the major risk factor for all these chronic diseases, far exceeding the traditional risk factors (for example, hypertension, smoking, diabetes, and cholesterol in cardiovascular disease), led scientists (called geroscientists) to hypothesize that slowing down the biological aging process would delay, prevent, alleviate, or cure several chronic diseases simultaneously (the Geroscience Hypothesis).⁸ Geroscience is a new field of study that arose from the Geroscience Hypothesis, and gerotherapeutics are interventions (pharmaceutical, behavioral, or other) that target BHAs to prevent, delay, alleviate, or cure 1 or more conditions.⁹ BHAs include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis.^10,11 Two well-established gerotherapeutic interventions in mammals are exercise and caloric restriction,^12,13 and some drugs (eg, metformin) have already been shown to have gerotherapeutic properties in preclinical models.¹⁴

Figure. Aging and the metabolic syndrome (MetS) share underlying biological mechanisms and are both risk factors for lower urinary tract symptoms (LUTS). These shared biological mechanisms, or biological hallmarks of aging, are targets of novel drugs called gerotherapeutics. Reproduced with permission from Iman M. Al-Naggar, PhD, copyright holder.

During my fellowship, I used several mouse models of aging, obesity, and accelerated aging to study bladder function: (1) naturally aged mice (18-26 months), (2) young mice fed a high-fat diet (a high-fat diet and obesity are models of accelerated aging and are commonly used in many studies, including studies of bladder function in rodents), and (3) young mice that had been intraperitoneally injected with senescent cells (cells that were damaged by irradiation and induced to enter into a state of cell cycle arrest that is characterized by the production of inflammatory molecules and growth factors, among other things, and is detrimental to cells and organisms). Interestingly, young mice that had been fed the high-fat diet or intraperitoneally injected with the inflammatory senescent cells (but not nonsenescent cells) exhibited the same changes on urethane-anesthetized mouse cystometry as those observed with natural aging in mice (I. M. Al-Naggar, PhD, unpublished data, November 2023). This suggests that systemic inflammation contributes to bladder dysfunction. Like aging, metabolic syndrome is a risk factor for cardiovascular disease, diabetes, and lower urinary tract symptoms (LUTS). This suggests that shared biological mechanisms exist between aging, conditions that accelerate biological aging such as the metabolic syndrome, and multiple chronic conditions and syndromes (eg, overactive bladder, LUTS; Figure).^15-17 Furthermore, longitudinal epidemiological studies done using data from the Study of Women’s Health Across the Nation showed that worsening incontinence is associated with aging, weight gain, and diabetes during midlife (www.swanstudy.org).

Although studies carried out in preclinical models such as rodents have been very useful for elucidating disease mechanisms, they are less useful for testing drugs to ameliorate LUTS. Besides obvious physical differences between humans and rodents, it is more difficult to interrogate rodents about their bladder symptoms: in all my years working with mice, none would tell me if they were experiencing urgency! Furthermore, it is well established that cystometric changes do not correlate well with symptoms. This motivated me to begin testing gerotherapeutic interventions using repurposed drugs or supplements with gerotherapeutic characteristics, whose safety profiles have already been well established, in human clinical trials. I hope to determine whether this novel approach could alleviate bothersome bladder symptoms that afflict a large proportion of older adults, greatly decreasing their quality of life. Moving to translational studies in humans is essential to discovering novel drugs for lower urinary tract dysfunction and bridging the gap between bench and bedside.

Making the jump from bench scientist to translational geroscientist, however, requires a lot of time and training. I am thrilled to be the recipient of the 2022 AUA New England Section Wyland F. Leadbetter, MD Award (AUA/Urology Care Foundation™ [UCF] Research Scholar Award), which will allow me to achieve this transition. Through this rigorous AUA mentored career development award, I am guaranteed protected time for executing all aspects of my proposed study and meetings with mentors, some tuition support towards a graduate certificate in clinical and translational research (at UConn Health), and some expenses for carrying out my clinical trial (eg, participant incentives, study supplies, lab tests, biomarker analysis, etc). A simultaneously awarded Scholar Award from the UConn Claude D. Pepper Older Americans Independence Center from the National Institute on Aging (P30AG067988) further provides me with the support, guidance, and services of experts from the recruitment and community engagement core, data resource core, and biomarkers and preclinical research core, ensuring the proper execution and completion of my study and analysis of my data. UConn Pepper Center cores have been crucial in guiding me to prepare my first Institutional Review Board application and submitting an Investigational New Drug application to the Food and Drug Administration for this clinical trial.

Obtaining one’s first grant as principal investigator is one of the most important yet often hardest parts of a research career. I attended several early career investigator talks both as a postdoc and faculty member, which all highly recommended applying for and getting any non-NIH funding, such as a foundation grant award, that would help me collect pilot data and establish feasibility of my study before applying for large research grants from the NIH. This was reiterated at the AUA’s Early Career Investigator Workshop that I attended in Linthicum, Maryland, in October 2022, a great workshop where I also learned about my eligibility for the AUA Research Scholar Award. I decided to submit my proposal and hoped that reviewers would see the potential of this novel geroscience approach for targeting lower urinary tract dysfunction. I am thrilled that the AUA and UCF appreciated the novelty and potential of this approach to the treatment of LUTS and the importance of supporting the training of translational researchers in urology to bring the dozens of promising discoveries from the bench to the clinic. I hope this study will serve as proof of concept that targeting BHAs is a promising approach in alleviating LUTS and bladder dysfunction, while training me in becoming a urological translational geroscientist! I hope to one day publish findings from my AUA/UCF-funded study in journals including Nature Medicine and The Journal of Urology^®.