TRANSLATING UROLITHIN A BENEFITS ON MUSCLE MITOCHONDRIA TO HUMANS

Urolithin A (UA) is a natural metabolite produced by the gut microflora upon ingestion of ellagitanins, a class of molecules that is abundant in pomegranates, nuts and berries. We have published a study demonstrating that UA induces mitophagy in vivo following oral consumption in worms and in rodents (Ryu et al., Nat Med 2016). In worms, UA extends lifespan, prolongs normal activity, including mobility and pharyngeal pumping, and maintains mitochondrial respiratory capacity during aging. These effects translate to rodents, where UA improves exercise capacity in two different models of age-related decline of muscle function. Recently, in a first-in-human randomized, double blind, placebo controlled study (NCT02655393), we have characterized the safety profile of UA in elderly, sedentary human subjects (n=60). UA was found to be safe across all oral dosing regimens and no serious adverse effects were recorded during the single and multiple ascending studies.. UA was bioavailable in human plasma and present in the skeletal muscle. In addition to safety and bioavailability endpoints, we have measured biomarkers linked to the mitochondrial function in the skeletal muscle, including mitochondrial gene expression profiles in skeletal muscle biopsies and plasma metabolomics. We will discuss these results clearly demonstrating the safety of UA in humans as well as the ability of UA to positively impact mitochondrial biomarkers following 28 days administration. Ongoing efforts continue to build on these findings and UA is being investigated in long term Phase 2 studies and in other experimental pre-clinical models where mitochondrial dysfunction(definition) is a hallmark feature.