1. 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).

2. Choi, A. M., Ryter, S. W. & Levine, B. Autophagy in human health and disease. N. Engl. J. Med. 368, 651–662 (2013).

3. Drake, J. C. & Yan, Z. Mitophagy in maintaining skeletal muscle mitochondrial proteostasis and metabolic health with ageing. J. Physiol. 595, 6391–6399 (2017).

4. 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).

5. Zane, A. C. et al. Muscle strength mediates the relationship between mitochondrial energetics and walking performance. Aging Cell 16, 461–468 (2017).

6. 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).

7. Keefe, D. M. GRAS Notice No. GRN 000791 (Food and Drug Administration, 2018).

8. 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).

9. 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).

10. 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).

11. 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).

12. Guideline on Bioanalytical Method Validation EMEA/CHMP/EWP/192217/2009 (European Medicines Agency, 2011).

13. 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).

14. 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).

15. Schooneman, M. G., Vaz, F. M., Houten, S. M. & Soeters, M. R. Acylcarnitines: reflecting or inflicting insulin resistance? Diabetes 62, 1–8 (2013).

16. Mitochondrial Medicine Society’s Committee on Diagnosis et al.The in-depth evaluation of suspected mitochondrial disease. Mol. Genet. Metab. 94, 16–37 (2008).

17. Lum, H. et al. Plasma acylcarnitines are associated with physical performance in elderly men. J. Gerontol. A 66, 548–553 (2011).

18. 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).

19. 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).

20. 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).

21. 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).

22. 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).

23. Andreux, P. A. et al. Mitochondrial function is impaired in the skeletal muscle of pre-frail elderly. Sci. Rep. 8, 8548 (2018).

24. Gong, Z. et al. Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice. J. Neuroinflammation 16, 62 (2019).

25. 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).

26. Singh, R. et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun. 10, 89 (2019).

27. Olesen, J., Kiilerich, K. & Pilegaard, H. PGC-1alpha-mediated adaptations in skeletal muscle. Pflugers Arch. 460, 153–162 (2010).

28. 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).

29. 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).

30. 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).

31. 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).

32. Spendiff, S. et al. Mitochondrial DNA deletions in muscle satellite cells: implications for therapies. Hum. Mol. Genet. 22, 4739–4747 (2013).

33. Milburn, M. V. & Lawton, K. A. Application of metabolomics to diagnosis of insulin resistance. Annu. Rev. Med. 64, 291–305 (2013).