Urolithin A (UA) is a natural dietary, microflora-derived metabolite shown to stimulate mitophagy and improve muscle health in old animals and in preclinical models of aging1. Here, we report the results of a first-in-human clinical trial in which we administered UA, either as a single dose or as multiple 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 mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The gene expression data are deposited at the European Genome-phenome Archive under accession code EGAS00001003638 and can be accessed subject to signing a data access agreement.
Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016).
Choi, A. M., Ryter, S. W. & Levine, B. Autophagy in human health and disease. N. Engl. J. Med. 368, 651–662 (2013).
Drake, J. C. & Yan, Z. Mitophagy in maintaining skeletal muscle mitochondrial proteostasis and metabolic health with ageing. J. Physiol. 595, 6391–6399 (2017).
Coen, P. M. et al. Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. J. Gerontol. A 68, 447–455 (2013).
Zane, A. C. et al. Muscle strength mediates the relationship between mitochondrial energetics and walking performance. Aging Cell 16, 461–468 (2017).
Heilman, J., Andreux, P., Tran, N., Rinsch, C. & Blanco-Bose, W. Safety assessment of Urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins and ellagic acid. Food Chem. Toxicol. 108, 289–297 (2017).
Keefe, D. M. GRAS Notice No. GRN 000791 (Food and Drug Administration, 2018).
Yoshimura, Y. et al. Interventions for treating sarcopenia: a systematic review and meta-analysis of randomized controlled studies. J. Am. Med. Dir. Assoc. 18, 553 e551–553.e516 (2017).
Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products EMEA/CHMP/SWP/28367/07 (European Medicines Agency, 2007).
Yang, H. et al. Phase 1 single- and multiple-ascending-dose randomized studies of the safety, pharmacokinetics, and pharmacodynamics of AG-348, a first-in-class allosteric activator of pyruvate kinase R, in healthy volunteers. Clin. Pharmacol. Drug Dev. 8, 246–259 (2019).
Chandorkar, G., Zhan, Q., Donovan, J., Rege, S. & Patino, H. Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers. BMC Pharmacol. Toxicol. 18, 24 (2017).
Guideline on Bioanalytical Method Validation EMEA/CHMP/EWP/192217/2009 (European Medicines Agency, 2011).
Guidance for Industry: Bioanalytical Method Validation (US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research and, Center for Veterinary Medicine, 2001).
Tomas-Barberan, F. A. et al. Urolithins, the rescue of ‘old’ metabolites to understand a ‘new’ concept: metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol. Nutr. Food Res. 61, 1500901 (2017).
Schooneman, M. G., Vaz, F. M., Houten, S. M. & Soeters, M. R. Acylcarnitines: reflecting or inflicting insulin resistance? Diabetes 62, 1–8 (2013).
Mitochondrial Medicine Society’s Committee on Diagnosis et al.The in-depth evaluation of suspected mitochondrial disease. Mol. Genet. Metab. 94, 16–37 (2008).
Lum, H. et al. Plasma acylcarnitines are associated with physical performance in elderly men. J. Gerontol. A 66, 548–553 (2011).
Felder, T. K. et al. Specific circulating phospholipids, acylcarnitines, amino acids and biogenic amines are aerobic exercise markers. J. Sci. Med. Sport 20, 700–705 (2017).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
Mahoney, D. J., Parise, G., Melov, S., Safdar, A. & Tarnopolsky, M. A. Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise. FASEB J. 19, 1498–1500 (2005).
Lammers, G. et al. Expression of genes involved in fatty acid transport and insulin signaling is altered by physical inactivity and exercise training in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 303, E1245–E1251 (2012).
Robinson, M. M. et al. Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans. Cell Metab. 25, 581–592 (2017).
Andreux, P. A. et al. Mitochondrial function is impaired in the skeletal muscle of pre-frail elderly. Sci. Rep. 8, 8548 (2018).
Gong, Z. et al. Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice. J. Neuroinflammation 16, 62 (2019).
Fang, E. F. et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412 (2019).
Singh, R. et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun. 10, 89 (2019).
Olesen, J., Kiilerich, K. & Pilegaard, H. PGC-1alpha-mediated adaptations in skeletal muscle. Pflugers Arch. 460, 153–162 (2010).
Jeppesen, J. et al. Enhanced fatty acid oxidation and FATP4 protein expression after endurance exercise training in human skeletal muscle. PLoS ONE 7, e29391 (2012).
Laker, R. C. et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat. Commun. 8, 548 (2017).
Vainshtein, A., Tryon, L. D., Pauly, M. & Hood, D. A. Role of PGC-1alpha during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am. J. Physiol., Cell Physiol. 308, C710–C719 (2015).
Harrigan, J. A., Jacq, X., Martin, N. M. & Jackson, S. P. Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat. Rev. Drug Discov. 17, 57–78 (2018).
Spendiff, S. et al. Mitochondrial DNA deletions in muscle satellite cells: implications for therapies. Hum. Mol. Genet. 22, 4739–4747 (2013).
Milburn, M. V. & Lawton, K. A. Application of metabolomics to diagnosis of insulin resistance. Annu. Rev. Med. 64, 291–305 (2013).
Fried, L. P. et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 56, M146–M156 (2001).
We would like to thank the volunteers for their participation in the study and Eurofins Optimed study staff for subject recruitment, data collection and processing, and S. Houten for his insight on the acylcarnitine data. Grant support by the Fondation Suisse de Recherche sur les Maladies Musculaires and the Fondation Marcel Levaillant is acknowledged.
The authors declare the following competing interests: A.S., P.A.A., W.B. and C.R. are employees; P.A. and C.R. are board members; and J.A. and P.A. are members of the Scientific Advisory Board of Amazentis SA, the sponsor of this clinical study. The other authors declare no competing interests.
Journal peer review information: Primary Handling Editor: Christoph Schmitt.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Andreux, P.A., Blanco-Bose, W., Ryu, D. et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab 1, 595–603 (2019). https://doi.org/10.1038/s42255-019-0073-4
Korean Circulation Journal (2020)
BMB Reports (2020)
Frontiers in Cell and Developmental Biology (2020)
Frontiers in Cell and Developmental Biology (2020)