Urolithin A: Clinical Application Potential and Mechanism of Action

General Description

Urolithin A shows promising clinical application potential across various health conditions due to its anti-inflammatory, antiapoptotic, antioxidant, cardioprotective, and neuroprotective properties. It enhances mitochondrial health through mitophagy activation, improving cellular homeostasis and mitochondrial function. Urolithin A also exhibits potent anti-inflammatory effects by modulating inflammatory genes and proteins, reducing cytokine levels, and promoting M2 macrophage polarization. Additionally, Urolithin A protects against colitis, diabetes, and Alzheimer's disease by inhibiting inflammation and enhancing gut barrier integrity. Overall, Urolithin A's mechanisms of action involve activating mitophagy pathways and suppressing inflammatory signaling, offering therapeutic potential in age-related diseases and metabolic disorders.

Figure 1. Urolithin A

Potential of Clinical Application

Urolithin A has emerged as a promising compound with significant clinical application potential across various health conditions. Extensive research has highlighted its anti-inflammatory, antiapoptotic, and antioxidant properties, alongside cardioprotective and neuroprotective effects. Studies have demonstrated the beneficial impact of UA in aging, muscle dysfunction, inflammatory bowel disease (IBD), nervous system disorders, cardiovascular diseases, metabolic dysfunctions, and cancer. In both animal models and human trials, Urolithin A has shown remarkable outcomes. It has been linked to improvements in muscle strength, mobility, exercise performance, mitochondrial function, mitophagy, autophagy, and angiogenic pathways. Moreover, Urolithin A supplementation has been associated with enhanced mitochondrial health, reduced markers of metabolic disorders and inflammation, improved muscle endurance and strength, and enhanced vascular endothelial function. Furthermore, Urolithin A exhibits cardioprotective effects by reducing risk markers, improving cardiac function, and mitigating atherosclerotic lesions. It also shows promise in addressing metabolic dysfunctions like obesity, diabetes, and insulin resistance by enhancing insulin sensitivity, reducing triglyceride accumulation, and promoting thermogenesis. Additionally, Urolithin A demonstrates anticancer properties by inhibiting cell proliferation, promoting apoptosis, and suppressing angiogenesis in various cancer types. Its chemopreventive effects include anti-clonogenic activity, modulation of glycolytic potential, enhancement of autophagy and apoptosis, and protection against colitis by promoting gut barrier integrity. ¹

Mechanism of Action

Mitophagy and Mitochondrial Functions

Urolithin A plays a pivotal role in enhancing mitochondrial health through the activation of mitophagy, a process crucial for eliminating dysfunctional mitochondria. Mitophagy, a form of selective autophagy, ensures the quality of the cellular mitochondrial pool by removing damaged organelles, thereby promoting cellular homeostasis. Urolithin A administration has been shown to upregulate mitophagy-related genes, leading to decreased accumulation of damaged organelles and increased mitochondrial biogenesis in various animal models, including Caenorhabditis elegans and rodents. In nematodes, UA-induced mitophagy, mediated by the transcription factor skn-1, coordinates the regulation of mitophagy and mitochondrial biogenesis, resulting in improved mitochondrial respiratory capacity, extended lifespan, and increased mobility. Similarly, Urolithin A supplementation in aged rodents and models of Duchenne muscular dystrophy (DMD) enhances mitophagy, leading to greater skeletal muscle respiratory capacity, improved cell regeneration, and increased motility. Furthermore, UA administration stabilizes PTEN-induced kinase 1 (PINK1) in a mouse model of Alzheimer's disease (AD), highlighting its neuroprotective role by promoting mitophagy in neurons and microglia. Additionally, Urolithin A enhances pancreatic β-cell function in a mouse model of type 2 diabetes through the PI3K/Akt/mTOR-regulated autophagy pathway. Overall, Urolithin A's mechanism of action involves activating molecular pathways of mitophagy, thereby improving mitochondrial function, extending lifespan, and offering therapeutic potential in age-related diseases and metabolic disorders. ²

Anti-Inflammatory Activity

Urolithin A exhibits potent anti-inflammatory activity through a multifaceted mechanism of action. In various animal models and cell culture studies, Urolithin A has demonstrated the ability to modulate genes, proteins, and signaling molecules involved in the inflammatory response. Notably, Urolithin A administration has been shown to downregulate inflammatory cytokines and chemokines, as well as reduce the activity of immune cells implicated in inflammation. In conditions such as cisplatin-induced nephrotoxicity and obesity, Urolithin A administration has led to decreased levels of inflammatory markers and alleviated endoplasmic reticulum stress. Moreover, Urolithin A promotes the polarization of macrophages towards an anti-inflammatory M2 phenotype, thereby attenuating inflammation in high-fat diet-fed mice. In models of colitis, UA administration resulted in reduced inflammatory markers, inhibited neutrophil infiltration, and enhanced gut barrier integrity. Similarly, UA treatment has been associated with the improvement of intestinal barrier damage through the modulation of tight junction proteins. Furthermore, UA exhibits anti-inflammatory effects in diabetic and Alzheimer's disease (AD) mouse models, characterized by decreased levels of pro-inflammatory cytokines and enhanced anti-inflammatory cytokine production. Urolithin A also inhibits neuroinflammation and gliosis in AD mice, possibly through the restoration of neuronal mitophagy and enhanced phagocytic efficiency of microglia. The anti-inflammatory mechanisms of Urolithin A involve the suppression of various signaling pathways, including phosphatidylinositol 3-kinase (PI3-K)/Akt/NF-κB, JNK/AP-1, and aryl hydrocarbon receptor (AhR) pathways. By targeting these pathways, Urolithin A inhibits the production of pro-inflammatory mediators and modulates immune cell activation, thereby exerting its anti-inflammatory effects across different disease models. ²

Reference

1. Kothe B, Klein S, Petrosky SN. Urolithin A as a Potential Agent for Prevention of Age-Related Disease: A Scoping Review. Cureus. 2023; 15(7): e42550.

2. Wojciechowska O, Kujawska M. Urolithin A in Health and Diseases: Prospects for Parkinson's Disease Management. Antioxidants (Basel). 2023; 12(7): 1479.