Urolithin A, a Gut Microbiome Derived Metabolite Improves Mitochondrial and Cellular Health: Results from a Randomized, Placebo-controlled, Double-blind Clinical Trial (FS09-06-19)

Abstract

Abstract Objectives Muscle health declines with aging and is accompanied by impairment of skeletal muscle mitochondrial function. Strategies targeting improvements in mitochondrial health are being pursued. One such novel nutritional intervention that has recently been identified is Urolithin A (UA), that is a metabolite produced by the gut microflora upon ingestion of ellagitannins that are abundant in pomegranates, nuts and berries. UA induces mitophagy in vivo following oral consumption (Ryu et al., Nature Medicine 2016) and improved exercise capacity in different models of age-related muscle decline. Methods The safety and bioavailability of UA and its impact on mitochondrial biomarkers was evaluated in a placebo controlled, double-blind, randomized study (NCT02655393). This was a 2-part study: single ascending dose Part A and a 4-week multiple ascending dose Part B. In Part A, 24 healthy elderly male and female volunteers were randomized (6 subjects/group) to consume UA in single doses of either 250 mg, 500 mg, 1000 mg, 2000 mg or placebo. In Part B, 36 healthy elderly male and female volunteers were randomized (9 subjects/group) to receive 250 mg, 500 mg, 1000 mg of UA or placebo daily for 28 days. UA was administered orally, in fasting condition. Subjects were monitored for adverse events and safety parameters. Plasma and muscle biopsies were collected to investigate the effects of UA on the skeletal muscle transcriptome and on the metabolomics profile. Results In both phase's there were no serious adverse events (SAE) recorded. No clinically significant changes were reported in a battery of safety tests. UA was bioavailable in human plasma and in the skeletal muscle. UA administration significantly up-regulated mitochondrial gene expression in the skeletal muscle and lowered plasma acylcarnitines. There was a dose-dependent up-regulation for the expression of mitochondrial pathway genes after 28 days of UA treatment with a FDR <0.25 and in the plasma a dose-dependent decrease of acylcarnitines levels (C8 to C14 and <C20) was observed with UA treatment. Conclusions UA is safe and bioavailable in humans. These results demonstrate a successful translation of the effects of UA on muscle mitochondria in elderly, and open the door to a new nutritional solution for managing age-related muscle decline. Funding Sources Amazentis SA sponsored the clinical study.