LETTERS https://doi.org/10.1038/s42255-019-0073-4 1 Amazentis SA, EPFL Innovation Park, Bâtiment C, Lausanne, Switzerland. 2 Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 3 Vital-IT Group, SIB Swiss Institute of Bioinformatics, Quartier Sorge, Bâtiment Génopode, Lausanne, Switzerland. 4 Neurodegenerative Diseases Laboratory, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 5 Present address: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea. 6 These authors jointly supervised this work: Anurag Singh, Chris Rinsch. *e-mail: contact@amazentis.com Urolithin A (UA) is a natural dietary, microflora-derived metabolite shown to stimulate mitophagy and improve mus- cle health in old animals and in preclinical models of aging 1 . Here, we report the results of a first-in-human clinical trial in which we administered UA, either as a single dose or as mul- tiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochon- drial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regu- lar oral consumption in humans. During aging, there is progressive decline in the cell’s capacity to eliminate its dysfunctional elements by autophagy 2 . Accumulating evidence has highlighted the decrease in the specific autophagy, or recycling, of dysfunctional mitochondria, known as mitophagy, in aging skeletal muscle 3 . This can result in poor mitochondrial function in the skeletal muscle, and has been closely linked to slow walking speed and poor muscle strength in elderly individu- als 4,5 . Consequently, improving mitochondrial function in elderly people by restoring levels of mitophagy represents a promising approach to halt or delay the development of age-related decline in muscle health. UA is a first-in-class natural food metabolite that stimulates mitophagy and prevents the accumulation of dysfunctional mito- chondria with age, thereby maintaining mitochondrial biogenesis and respiratory capacity in cells, and, in the nematode Caenorhabditis elegans, improving mobility and extending lifespan 1 . In rodents, UA improves endurance capacity in young rats and in old mice either fed a healthy diet or placed under conditions of metabolic challenge 1 . Recently, UA was shown to have a favourable safety profile following a battery of standardized toxicological tests, including subchronic exposure for 90 d in rodent models 6 , and received a favourable review by the US Food and Drug Administration under the agency’s generally recognized as safe (GRAS) notification program 7 . In this report, we detail the outcome of a first-in-human, ran- domized, double-blind, placebo-controlled clinical study with UA in healthy, sedentary elderly individuals, and describe its safety, bioavailability and beneficial impact on key biomarkers of mito- chondrial health (NCT02655393). Physiological endpoints were not evaluated as part of this study, as the 4-week intervention was considered too short in comparison to the extended protocols (min- imum 3 months) deemed necessary to improve muscle strength or physical performance parameters in elderly individuals 8 . This phase 1 study was a two-part study, with a single ascend- ing dose (part A) followed by a multiple ascending dose (part B). As the first objective of the study was safety assessment, the dose escalation was designed to progress from the lowest to the highest UA dose investigated in both parts of the study. Dose escalation to the next higher UA dose was always twofold higher than the previ- ous dose (see Methods and Supplementary Table 1 for the decision tree and stopping rule criteria to advance to the next higher UA dose). During part A of the study, three cohorts of eight subjects each (24 subjects) received either placebo or UA in a two-period design separated by a minimum 3-week wash-out period and at single ascending doses of 250, 500, 1,000 or 2,000 mg, either in soft gels or admixed with food (Fig. 1a, also the CONSORT diagram in Supplementary Fig. 1). In part B of the study, three cohorts of 12 elderly subjects were given either placebo or UA at 250, 500 or 1,000 mg once daily in soft gels for 28 d (Fig. 1a and Supplementary Fig. 1). The lowest dose of 250 mg was chosen on the basis of preclinical studies, where the equivalent daily dosing of 50 mg per kg (mpk) of body weight in mice demonstrated efficacy on mito- chondrial and muscle function after a 6-week oral intervention 1 . Clinical study treatment groups were evenly matched for age, sex and body mass index, and all of the subjects were sedentary at the time of inclusion in the study (Supplementary Tables 2 and 3). All enrolled subjects completed the study, there were no major devia- tions in the clinical protocol or in product intake, and no subjects were excluded in the final analysis for the main study endpoints (Supplementary Fig. 1). As the study was a single and multiple dose escalation phase 1 study, designed according to guidelines and recommendations for first-in-human studies 9 and following standard dose escalation safety trial design 10,11 , it was powered to meet the primary outcome of safety and tolerability of UA in elderly humans to provide sufficient infor- mation on human safety and pharmacokinetic profile and to allow dose selection for future phase 2 efficacy trials (see also Methods). The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans Pénélope A. Andreux 1 , William Blanco-Bose 1 , Dongryeol Ryu  1,2,5 , Frédéric Burdet 3 , Mark Ibberson 3 , Patrick Aebischer 4 , Johan Auwerx 2 , Anurag Singh 1,6 and Chris Rinsch  1,6 * NATURE METABOLISM | VOL 1 | JUNE 2019 | 595–603 | www.nature.com/natmetab 595