Vibegron: A Novel Treatment for Multisystem Functional Decline in Aging and Obesity - PROJECT SUMMARY Aging is characterized by the gradual loss of physiological integrity, and this process may be accelerated in the presence of obesity, increasing susceptibility to disease, frailty, and death. Although the shared molecular pathways involved have not been fully elucidated, adipose tissue dysfunction is likely a key contributor to multisystem functional decline in aging and obesity. Despite growing evidence that β3 adrenergic receptor {β3AR) mediated activation of brown adipose tissue {BAT) may alter pathophysiological pathways implicated in various aging-related diseases including metabolic, cardiovascular, and neurodegenerative diseases, BAT has been largely ignored in aging research. In this highly innovative study, we propose to conduct a randomized, double-blind, placebo-controlled trial to investigate whether treatment with a β3AR agonist (vibegron) can improve energy metabolism, cardiometabolic risk factors, and physical and cognitive function. Vibegron {Gemtesa) was FDA-approved in 2020 for the treatment of overactive bladder and has greater selectivity, potency, and activity at the β3AR than other agonists studied to date. This presents a timely opportunity to explore pharmacological activation of β3ARs as a way to improve multiple health outcomes relevant in aging and obesity. To test our hypothesis, 40 middle-aged and older adults {45-75 yrs) with obesity will be randomized to vibegron {75 mg/day) or placebo for 12 weeks to compare their effects on various bioenergetic, cardiometabolic, physical function, and cognitive outcomes. Specifically, in Aim 1 we will assess the effects of vibegron vs. placebo on energy expenditure, core body temperature, mitochondrial bioenergetics, and thermogenic protein expression. In Aim 2 we will assess the effects of vibegron vs. placebo on glucose and insulin indices, lipid levels, body composition, and body fat distribution. In Aim 3 we will assess the effects of vibegron vs. placebo on self-report and objective measures of lower extremity function, muscle strength and pOY1er, global cognition, memory, executive function, quality of life, and depression. Notable innovations include blood-based bioenergetic profiling to assess systemic mitochondrial function, isolation and characterization of adipose tissue-derived small extracellular vesicles to assess target engagement, and continuous monitoring of core body temperature to assess circadian thermoregulation. In exploratory analyses we will compare the effects of vibegron vs. placebo on the accumulation of health deficits {i.e., frailty) and the preservation of physical and mental abilities {i.e., intrinsic capacity), two integrated measures of phenotypic aging that will provide estimates of the potential for vibegron to impact multisystem functional decline. This unique study will be the first clinical trial to explore the potential to repurpose vibegron for the treatment of aging-related obesity and associated comorbidities. If successful, the results of this study will be used to inform the design of a larger, longer trial to confirm the efficacy of vibegron as a novel treatment to IOY1er risk for multisystem functional decline in both aging and obesity.
