Orally administered Urolithin A is safe and modulates muscle and mitochondrial biomarkers in elderly
Pénélope Andreux1, William Blanco-Bose1, Dongryeol Ryu1,2,3, Frederic Burdet4, Mark Ibberson4,Patrick Aebischer5, Johan Auwerx2, Chris Rinsch1, Anurag Singh*1
1Amazentis SA, EPFL Innovation Park, Batiment C, CH-1015 Lausanne, Switzerland; 2Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; 3Current address: School of Korean Medicine, Pusan National University, Busan 46241, Republic of Korea; 4Swiss Institute of Bioinformatics, Quartier Sorge, Batiment Genopode, 1015 Lausanne, Switzerland; 5Neurodegenerative diseases laboratory, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
*correspondence: contact@amazentis.com
Age associated muscle decline that leads to frailty and sarcopenia has become a significant public health concern. Urolithin A (UA) is a natural gut metabolite derived from ellagitannins that improves mitochondrial function and enhance exercise capacity by stimulating mitophagy in models of age-related decline in muscle function. We performed a first-in-man clinical trial with UA during a single center, multi-part (single and multiple ascending doses) Phase I, double-blind, randomized, placebo controlled study in 60 healthy elderly subjects (NCT02655393). The primary endpoint of safety was successfully met as no serious or product related non-serious adverse effects were recorded, indicating a favorable safety profile for UA in humans. Several biomarkers related to mitochondrial function were measured in muscle and plasma of subjects who received a 4-week dosing of UA. Several genes related to autophagy, mitophagy, mitochondrial biogenesis and fatty acid oxidation were chosen based on preclinical studies and their expression level was determined by qPCR in muscle. There was a clear dose-dependent induction of these genes by UA, similar to what was observed in rats treated for 4-weeks at equivalent doses. These results were confirmed by a gene-set enrichment analysis of microarray data, which showed again a dose-dependent upgregulation of mitochondrial related genesets in muscle of subjects who received UA. Finally, acylcarnitines were found to be dose-dependently lower in plasma of subjects who received UA. Our results hold promise for the use of advanced dietary interventions involving UA to manage mitochondrial and muscle health during aging.
