ORALLY ADMINISTERED UROLITHIN A IS SAFE AND MODULATES MUSCLE AND MITOCHONDRIAL BIOMARKERS IN ELDERLY

Abstract

Background: Age associated muscle and physical decline that leads to frailty and sarcopenia has become a significant public health concern. This has fueled a growing interest to identify novel interventions that can mitigate the process of muscle aging. Urolithin A (UA), is a natural metabolite derived from ellagitannins, compounds found in pomegranates, nuts and berries. UA has been shown to improve mitochondrial function by stimulating mitophagy, resulting in enhanced exercise capacity that was observed in two separate models of age-related decline in muscle function (Nature Medicine 22, 879–888 (2016). Objective: To investigate the safety of UA and its impact on biomarkers in a first-in-human Phase 1 clinical trial in elderly. Methods: A single center, multi-part (single and 4-week multiple ascending doses) Phase I, double-blind, randomized, placebo controlled study in 60 healthy elderly subjects was conducted (NCT02655393). All of the subjects were between 61 to 85 years of age and sedentary with a BMI range of 18–32 kg/m2. The subjects modified their diet to exclude pomegranates, berries and nuts as well as dietary supplements for the duration of the study. Plasma samples and muscle biopsies from the vastus lateralis muscle were collected to investigate the effects of UA on the plasma metabolomics profile and the skeletal muscle transcriptome.. Results: The primary endpoint of safety was successfully met as no serious or product related non-serious adverse effects were recorded. No clinically significant changes were observed in a battery of safety tests (vital signs, physical examination, ECG, serum biochemistry, haematology and urinalysis), indicating a favourable safety profile for UA in humans. The impact of UA on plasma and muscle biomarkers following a 4-week dosing were assessed, and this revealed that UA modulated both genes and metabolites linked to mitochondrial and muscle function. Conclusion: UA is well tolerated and has an attractive safety profile when orally administered in single and multiple doses to elderly. Importantly, UA is bioavailable in both human plasma and muscle and modulated biomarkers of muscle and mitochondrial function. Our results hold promise for the use of advanced dietary interventions involving UA to manage mitochondrial and muscle health during aging.