Impact of the Natural Compound Urolithin A on Health, Disease, and Aging

Urolithin A (UA) is a gut microbiome-derived natural compound that only 40% of people can naturally convert from dietary precursors at meaningful levels.Positive effects of direct UA administration in health, aging, and age-related conditions have been identified in several recent studies.Experimental models consistently show that UA increases mitophagy and mitochondrial function and blunts excessive inflammatory responses.UA increased biomarkers of mitochondrial function in preclinical models of aging and in healthy elderly people.UA is a promising strategy to target health and disease conditions of aging, especially those linked to mitochondrial and muscle dysfunction. Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranate, berries, and nuts. UA was discovered 40 years ago, but only recently has its impact on aging and disease been explored. UA enhances cellular health by increasing mitophagy and mitochondrial function and reducing detrimental inflammation. Several preclinical studies show how UA protects against aging and age-related conditions affecting muscle, brain, joints, and other organs. In humans, benefits of UA supplementation in the muscle are supported by recent clinical trials in elderly people. Here, we review the state of the art of UA's biology and its translational potential as a nutritional intervention in humans. Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranate, berries, and nuts. UA was discovered 40 years ago, but only recently has its impact on aging and disease been explored. UA enhances cellular health by increasing mitophagy and mitochondrial function and reducing detrimental inflammation. Several preclinical studies show how UA protects against aging and age-related conditions affecting muscle, brain, joints, and other organs. In humans, benefits of UA supplementation in the muscle are supported by recent clinical trials in elderly people. Here, we review the state of the art of UA's biology and its translational potential as a nutritional intervention in humans. UA belongs to the family of urolithins, characterized by a chemical structure containing an α-benzo-coumarin scaffold (Figure 1). Urolithins are produced in the colon following the microbiome-mediated transformation of the natural polyphenols ETs and EA, which are contained in dietary products, such as pomegranates, strawberries, raspberries, and walnuts [1.Espín J.C. et al.Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far.Evid. Based Complement. Alternat. Med. 2013; 2013: 270418Crossref PubMed Scopus (277) Google Scholar, 2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar, 3.González-Barrio R. et al.Bioavailability of anthocyanins and ellagitannins following consumption of raspberries by healthy humans and subjects with an ileostomy.J. Agric. Food Chem. 2010; 58: 3933-3939Crossref PubMed Scopus (180) Google Scholar]. (Figure 1 and Box 1).Box 1Conversion of Ellagitannins and Metabolism of UAThe complex natural polyphenols ETs and EA are present in a variety of plant products and foods and are the main dietary precursors of UA. ETs have a very low bioavailability and are either directly eliminated in the stool or converted into more bioavailable derivates [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar]. ETs are hydrolyzed into EA by gut bacterial enzymes called tannases. Further enzymatic reactions transform EA into UA and other urolithins (Figure 1) [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar]. UA and urolithin B (UB) are the most abundant final products, and UA is the most conserved and widely studied urolithin across species [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar].Ingesting ET-rich foods is not always enough to expose people to UA, as its formation depends on having the appropriate gut microbiome [10.Cortés-Martín A. et al.Where to look into the puzzle of polyphenols and health? The postbiotics and gut microbiota associated with human metabotypes.Mol. Nutr. Food Res. 2020; 64: 1900952Crossref Scopus (39) Google Scholar]. Of note, several efforts have been made to identify the bacterium, or bacteria, responsible for UA conversion. Although some species have been proposed based on ex vivo studies in feces [60.Selma M.V. et al.Gordonibacter urolithinfaciens sp. nov., a urolithin-producing bacterium isolated from the human gut.Int. J. Syst. Evol. Microbiol. 2014; 64: 2346-2352Crossref PubMed Scopus (69) Google Scholar,61.Selma M.V. et al.Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species.Food Funct. 2014; 5: 1779-1784Crossref PubMed Google Scholar], the UA-producing bacteria in the human gut are still unknown [10.Cortés-Martín A. et al.Where to look into the puzzle of polyphenols and health? The postbiotics and gut microbiota associated with human metabotypes.Mol. Nutr. Food Res. 2020; 64: 1900952Crossref Scopus (39) Google Scholar].After its production and absorption into the blood circulation, UA undergoes phase 2 metabolism to form UA conjugates, mainly UA-glucuronide and UA-sulfate. UA-glucuronide is the most abundant form of UA detected in the human plasma [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar]. The biological role of UA conjugates in vivo is still not clear. In vitro experiments suggest that UA conjugates have lower or no biological activity compared with UA [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar,70.Bobowska A. et al.Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions.European Journal of Nutrition. 2021; 60: 1957-1972Crossref PubMed Scopus (9) Google Scholar]. The complex natural polyphenols ETs and EA are present in a variety of plant products and foods and are the main dietary precursors of UA. ETs have a very low bioavailability and are either directly eliminated in the stool or converted into more bioavailable derivates [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar]. ETs are hydrolyzed into EA by gut bacterial enzymes called tannases. Further enzymatic reactions transform EA into UA and other urolithins (Figure 1) [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar]. UA and urolithin B (UB) are the most abundant final products, and UA is the most conserved and widely studied urolithin across species [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar]. Ingesting ET-rich foods is not always enough to expose people to UA, as its formation depends on having the appropriate gut microbiome [10.Cortés-Martín A. et al.Where to look into the puzzle of polyphenols and health? The postbiotics and gut microbiota associated with human metabotypes.Mol. Nutr. Food Res. 2020; 64: 1900952Crossref Scopus (39) Google Scholar]. Of note, several efforts have been made to identify the bacterium, or bacteria, responsible for UA conversion. Although some species have been proposed based on ex vivo studies in feces [60.Selma M.V. et al.Gordonibacter urolithinfaciens sp. nov., a urolithin-producing bacterium isolated from the human gut.Int. J. Syst. Evol. Microbiol. 2014; 64: 2346-2352Crossref PubMed Scopus (69) Google Scholar,61.Selma M.V. et al.Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species.Food Funct. 2014; 5: 1779-1784Crossref PubMed Google Scholar], the UA-producing bacteria in the human gut are still unknown [10.Cortés-Martín A. et al.Where to look into the puzzle of polyphenols and health? The postbiotics and gut microbiota associated with human metabotypes.Mol. Nutr. Food Res. 2020; 64: 1900952Crossref Scopus (39) Google Scholar]. After its production and absorption into the blood circulation, UA undergoes phase 2 metabolism to form UA conjugates, mainly UA-glucuronide and UA-sulfate. UA-glucuronide is the most abundant form of UA detected in the human plasma [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar]. The biological role of UA conjugates in vivo is still not clear. In vitro experiments suggest that UA conjugates have lower or no biological activity compared with UA [2.Tomás-Barberán 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. 2017; 61: 1500901Crossref Scopus (198) Google Scholar,70.Bobowska A. et al.Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions.European Journal of Nutrition. 2021; 60: 1957-1972Crossref PubMed Scopus (9) Google Scholar]. First identified as an EA metabolite in rats in 1980 [4.Doyle B. Griffiths L.A. The metabolism of ellagic acid in the rat.Xenobiotica Fate Foreign Compd. Biol. Syst. 1980; 10: 247-256Crossref PubMed Scopus (86) Google Scholar], similar gut microbiome (see Glossary) conversion of ETs to UA was later demonstrated across many species, including flies and mice [1.Espín J.C. et al.Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far.Evid. Based Complement. Alternat. Med. 2013; 2013: 270418Crossref PubMed Scopus (277) Google Scholar] . A pioneering study also showed the production of UA from ETs by the human gut microbiota [5.Cerdá B. et al.Identification of urolithin a as a metabolite produced by human colon microflora from ellagic acid and related compounds.J. Agric. Food Chem. 2005; 53: 5571-5576Crossref PubMed Scopus (191) Google Scholar], making UA the most common urolithin species produced in nature. Two clinical studies then measured UA in human plasma after consumption of pomegranate [6.Cerdá B. et al.The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans.Eur. J. Nutr. 2004; 43: 205-220Crossref PubMed Scopus (325) Google Scholar], berries, and nuts [7.Cerdá B. et al.Metabolism of antioxidant and chemopreventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans: identification of biomarkers and individual variability.J. Agric. Food Chem. 2005; 53: 227-235Crossref PubMed Scopus (318) Google Scholar]. Interestingly, the conversion of dietary precursors to UA does not occur in all individuals. The process is variable [8.Tomás-Barberán F.A. et al.Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status.J. Agric. Food Chem. 2014; 62: 6535-6538Crossref PubMed Scopus (184) Google Scholar] and takes place in only approximately 40% of the human elderly population [9.Cortés-Martín A. et al.The gut microbiota urolithin metabotypes revisited: the human metabolism of ellagic acid is mainly determined by aging.Food Funct. 2018; 9: 4100-4106Crossref PubMed Google Scholar]. Being a 'UA producer' requires an appropriate gut microbiome and varies with age, health status, and dietary intake [10.Cortés-Martín A. et al.Where to look into the puzzle of polyphenols and health? The postbiotics and gut microbiota associated with human metabotypes.Mol. Nutr. Food Res. 2020; 64: 1900952Crossref Scopus (39) Google Scholar]. Backed by growing interest in nutritional interventions to address the ever-increasing health problems of an aging population [11.Domingues-Faria C. et al.Skeletal muscle regeneration and impact of aging and nutrition.Ageing Res. Rev. 2016; 26: 22-36Crossref PubMed Scopus (50) Google Scholar,12.Kehoe L. et al.Nutritional challenges for older adults in Europe: current status and future directions.Proc. Nutr. Soc. 2019; 78: 221-233Crossref PubMed Scopus (21) Google Scholar], several research groups started to study the role and relevance of direct supplementation with UA instead of with UA precursors. This review outlines the most relevant in vivo preclinical studies that show positive impacts of UA on health conditions due to natural aging and on progressive diseases linked to aging. It describes the molecular mechanisms that explain how UA can counter the hallmarks of aging. Finally, this review explores the translational relevance and potential applications of UA as a nutritional intervention in humans. The most consistent effect of UA across species is the improvement of mitochondrial health, an effect observed in cells, worms, mice, and humans. This benefit is driven by the clearing and recycling of dysfunctional mitochondria, a selective autophagy process called mitophagy [13.Palikaras K. et al.Mechanisms of mitophagy in cellular homeostasis, physiology and pathology.Nat. Cell Biol. 2018; 20: 1013-1022Crossref PubMed Scopus (338) Google Scholar]. Mitophagy is impaired with increased age and in several age-related diseases [13.Palikaras K. et al.Mechanisms of mitophagy in cellular homeostasis, physiology and pathology.Nat. Cell Biol. 2018; 20: 1013-1022Crossref PubMed Scopus (338) Google Scholar,69.Diot A. et al.Mitophagy plays a central role in mitochondrial ageing.Mamm. Genome. 2016; 27: 381-395Crossref PubMed Scopus (68) Google Scholar]. Restoring correct levels of mitophagy is a promising strategy to counteract age-related decline of organ function [14.Ryu D. et al.Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.Nat. Med. 2016; 22: 879-888Crossref PubMed Scopus (368) Google Scholar,16.Fang E.F. et al.Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.Nat. Neurosci. 2019; 22: 401-412Crossref PubMed Scopus (396) Google Scholar]. Mitophagy occurs when mitochondria are damaged or following exposure to external mitophagy inducers (Figure 2). The process proceeds via several pathways that UA can activate. PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy starts with the stabilization of the kinase PINK1, which recruits and phosphorylates the ubiquitin-conjugating protein Parkin. Parkin in turn promotes ubiquitination of mitochondrial proteins, which are phosphorylated by PINK1 and serve as docking sites for adaptor proteins, such as the microtubule-associated protein LC3, and phagosome membranes. Once mitochondria are engulfed by the phagophore membrane, they merge with lysosomes for organelle clearance (Figure 2) [13.Palikaras K. et al.Mechanisms of mitophagy in cellular homeostasis, physiology and pathology.Nat. Cell Biol. 2018; 20: 1013-1022Crossref PubMed Scopus (338) Google Scholar]. Other PINK1–Parkin-independent mitophagy pathways activate mitochondrial proteins, such as BNIP3, NIX, and FUNDC1, which directly recruit LC3 to promote autophagosome formation (Figure 2) [13.Palikaras K. et al.Mechanisms of mitophagy in cellular homeostasis, physiology and pathology.Nat. Cell Biol. 2018; 20: 1013-1022Crossref PubMed Scopus (338) Google Scholar]. In the nematode Caenorhabditis elegans, UA increased the expression of mitophagy genes lgg-1 [14.Ryu D. et al.Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.Nat. Med. 2016; 22: 879-888Crossref PubMed Scopus (368) Google Scholar], pink-1, and pdr-1 [15.Luan P. et al.Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy.Sci. Transl. Med. 2021; 13eabb0319Crossref PubMed Scopus (9) Google Scholar], worm homologs of mammalian genes encoding for LC-3B, PINK1, and Parkin and autophagosome vesicle formation. The ablation of pink-1 and dct-1, the C. elegans ortholog of mammalian BNIP3, abolished the beneficial effects of UA on mitophagy [16.Fang E.F. et al.Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.Nat. Neurosci. 2019; 22: 401-412Crossref PubMed Scopus (396) Google Scholar] and lifespan [14.Ryu D. et al.Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.Nat. Med. 2016; 22: 879-888Crossref PubMed Scopus (368) Google Scholar]. PINK1 and phospho-ubiquitin accumulation was prominent in C2C12 mouse muscle myoblasts treated with UA. In vivo, higher levels of ubiquitinated and phospho-ubiquitinated mitochondrial proteins were observed in muscle tissues after administering UA in wild-type rodents [14.Ryu D. et al.Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.Nat. Med. 2016; 22: 879-888Crossref PubMed Scopus (368) Google Scholar] and in the mdx mouse model of Duchenne muscular dystrophy (DMD) [15.Luan P. et al.Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy.Sci. Transl. Med. 2021; 13eabb0319Crossref PubMed Scopus (9) Google Scholar]. PINK1 stabilization by UA was reported in human neuroblastoma SH-SY5Y cells and hippocampal neurons of an Alzheimer's disease (AD) mouse model [16.Fang E.F. et al.Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.Nat. Neurosci. 2019; 22: 401-412Crossref PubMed Scopus (396) Google Scholar]. Consistently, mitophagy events were increased in AD mouse brains. PINK1/Parkin mitophagy activation was also reported in pancreatic cells of diabetic mice [17.Tuohetaerbaike B. et al.Pancreas protective effects of urolithin A on type 2 diabetic mice induced by high fat and streptozotocin via regulating autophagy and AKT/mTOR signaling pathway.J. Ethnopharmacol. 2020; 250: 112479Crossref PubMed Scopus (15) Google Scholar] and in mouse nucleus pulposus cells in vitro [18.Lin J. et al.Urolithin A-induced mitophagy suppresses apoptosis and attenuates intervertebral disc degeneration via the AMPK signaling pathway.Free Radic. Biol. Med. 2020; 150: 109-119Crossref PubMed Scopus (23) Google Scholar]. PINK1/Parkin independent mitophagy is less explored in mammals; however, some data show activation of Bnip3 mRNA levels and mild accumulation of mitochondrial BNIP3 in the muscle of UA-treated mdx mice [15.Luan P. et al.Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy.Sci. Transl. Med. 2021; 13eabb0319Crossref PubMed Scopus (9) Google Scholar]. Mitophagy improves the quality of the cellular mitochondria pool and is tightly linked to the generation of new organelles, leading to improved mitochondrial respiratory capacity [19.Ploumi C. et al.Mitochondrial biogenesis and clearance: a balancing act.FEBS J. 2017; 284: 183-195Crossref PubMed Scopus (154) Google Scholar]. Mitochondrial abundance is reduced upon short-term treatment with UA in worms and C2C12 mouse muscle cells [14.Ryu D. et al.Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.Nat. Med. 2016; 22: 879-888Crossref PubMed Scopus (368) Google Scholar]. Conversely, muscle mitochondrial content is unchanged [14.Ryu D. et al.Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.Nat. Med. 2016; 22: 879-888Crossref PubMed Scopus (368) Google Scholar] or mildly increased in muscle [15.Luan P. et al.Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy.Sci. Transl. Med. 2021; 13eabb0319Crossref PubMed Scopus (9) Google Scholar] and increased in the liver [20.Toney A.M. et al.Urolithin A, a gut metabolite, improves insulin sensitivity through augmentation of mitochondrial function and biogenesis.Obesity. 2019; 27: 612-620Crossref PubMed Scopus (26) Google Scholar] in mice after longer UA exposure. This suggests that UA, at first, activates mitophagy and thereafter favors mitochondrial biogenesis. Consistent with this, UA induced mitochondrial oxidative phosphorylation (OXPHOS) proteins in muscle cells and tissue [14.Ryu D. et al.Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.Nat. Med. 2016; 22: 879-888Crossref PubMed Scopus (368) Google Scholar,15.Luan P. et al.Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy.Sci. Transl. Med. 2021; 13eabb0319Crossref PubMed Scopus (9) Google Scholar] and in the kidney of mice subjected to acute kidney injury [21.Zou D. et al.Oral delivery of nanoparticle urolithin A normalizes cellular stress and improves survival in mouse model of cisplatin-induced AKI.Am. J. Physiol.-Ren. Physiol. 2019; 317: F1255-F1264Crossref PubMed Scopus (11) Google Scholar]. Mitochondrial gene sets were also among the most upregulated in transcriptomic data of UA-treated HT29 colon cells [22.Singh R. et al.Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway.Nat. Commun. 2019; 10: 89Crossref PubMed Scopus (169) Google Scholar]. Mitochondrial functional readouts were measured in skeletal muscle, where UA elevated mitochondrial respiratory capacity in C2C12 cells [14.Ryu D. et al.Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.Nat. Med. 2016; 22: 879-888Crossref PubMed Scopus (368) Google Scholar] and Complex I- and II-mediated respiration in muscle tissues from mdx mice [15.Luan P. et al.Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy.Sci. Transl. Med. 2021; 13eabb0319Crossref PubMed Scopus (9) Google Scholar]. In humans, UA was shown to regulate mitochondrial function systemically and in skeletal muscle. Data from the first-in-human Phase I trial with UA administration showed a decrease in several plasma acylcarnitines [23.Andreux P.A. et al.The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans.Nat. Metab. 2019; 1: 595-603Crossref PubMed Scopus (108) Google Scholar], markers that reflect the efficacy of mitochondrial fatty acid oxidation at the level of the entire body [24.Schooneman M.G. et al.Acylcarnitines.Diabetes. 2013; 62: 1-8Crossref PubMed Scopus (338) Google Scholar], and an increase in the expression of mitochondrial gene sets in the muscle [23.Andreux P.A. et al.The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans.Nat. Metab. 2019; 1: 595-603Crossref PubMed Scopus (108) Google Scholar]. A common effect shared between preclinical models exposed to UA is the attenuation of detrimental inflammatory responses. This is particularly clinically relevant because aging and most age-related diseases are associated with chronic, low-grade inflammation. This process, recently named inflamm-aging [25.Franceschi C. et al.Inflammaging: a new immune–metabolic viewpoint for age-related diseases.Nat. Rev. Endocrinol. 2018; 14: 576-590Crossref PubMed Scopus (603) Google Scholar], contributes to age-related decline in cellular and organismal function. The anti-inflammatory effect of UA was reported for the first time as a decrease in mRNA and protein levels of the inflammatory marker cyclooxygenase 2 (COX2) in the colon of a dextran sulphate sodium (DSS)-induced rat model of acute colitis [26.Larrosa M. et al.Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism.J. Nutr. Biochem. 2010; 21: 717-725Crossref PubMed Scopus (309) Google Scholar]. Further studies showed a consistent reduction in plasma of proinflammatory cytokines interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFα) in both acute, trinitrobenzenesulfonic acid (TNBS)-induced and chronic, DSS-induced mouse models of colitis [22.Singh R. et al.Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway.Nat. Commun. 2019; 10: 89Crossref PubMed Scopus (169) Google Scholar]. The same cytokines were reduced in the plasma of UA-treated streptozotocin-induced diabetic mice [17.Tuohetaerbaike B. et al.Pancreas protective effects of urolithin A on type 2 diabetic mice induced by high fat and streptozotocin via regulating autophagy and AKT/mTOR signaling pathway.J. Ethnopharmacol. 2020; 250: 112479Crossref PubMed Scopus (15) Google Scholar], where an increase in anti-inflammatory IL-10, was also noted [17.Tuohetaerbaike B. et al.Pancreas protective effects of urolithin A on type 2 diabetic mice induced by high fat and streptozotocin via regulating autophagy and AKT/mTOR signaling pathway.J. Ethnopharmacol. 2020; 250: 112479Crossref PubMed Scopus (15) Google Scholar]. IL-1β was reduced by UA in the livers of high-fat diet (HFD)-fed obese mice [20.Toney A.M. et al.Urolithin A, a gut metabolite, improves insulin sensitivity through augmentation of mitochondrial function and biogenesis.Obesity. 2019; 27: 612-620Crossref PubMed Scopus (26) Google Scholar] and in the kidneys of mice subjected to cisplatin-induced nephrotoxic injury [27.Guada M. et al.Urolithin A mitigates cisplatin-induced nephrotoxicity by inhibiting renal inflammation and apoptosis in an experimental rat model.J. Pharmacol. Exp. Ther. 2017; 363: 58-65Crossref PubMed Scopus (20) Google Scholar]. Lower levels of fractalkine, a proinflammatory cytokine that influences myocardial function [28.Taube D. et al.Fractalkine depresses cardiomyocyte contractility.PLoS ONE. 2013; 8e69832Crossref PubMed Scopus (15) Google Scholar], were measured in a streptozotocin-induced rat model of diabetic cardiomyopathy (DCM) after treatment with UA [29.Savi M. et al.In vivo administration of urolithin A and B prevents the occurrence of cardiac dysfunction in streptozotocin-induced diabetic rats.Cardiovasc. Diabetol. 2017; 16: 80Crossref PubMed Scopus (55) Google Scholar]. In neuronal tissues, UA treatment reduced levels of IL-1β, IL-6, and TNFα in the brains of the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD [16.Fang E.F. et al.Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.Nat. Neurosci. 2019; 22: 401-412Crossref PubMed Scopus (396) Google Scholar,30.Gong Z. et al.Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice.J. Neuroinflammation. 2019; 16: 1-13Crossref PubMed Scopus (49) Google Scholar]. These studies suggested that promotion of the phagocytic activity of microglia, cells that are crucial to clean up cellular debris from the central nervous system (CNS) and to control inflammatory responses, contributes to UA's protection against neuroinflammation [16.Fang E.F. et al.Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.Nat. Neurosci. 2019; 22: 401-412Crossref PubMed Scopus (396) Google Scholar,30.Gong Z. et al.Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice.J. Neuroinflammation. 2019; 16: 1-13Crossref PubMed Scopus (49) Google Scholar]. Notably, knockdown of Pink1 in microglia ablated UA-mediated reduction of TNFα and increased IL-10 secretion, indicating that UA reduces neuroinflammation via the induction of mitophagy [16.Fang E.F. et al.Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.Nat. Neurosci. 2019; 22: 401-412Crossref PubMed Scopus (396) Google Scholar]. A reduction in inflammatory cell infiltration was recently reported when analyzing white matter tissue in a mouse model of inflammatory experimental autoimmune encephalomyelitis (EAE) treated with UA [31.Shen P.-X. et