Urolithin A: The Gut-Microbiome Metabolite Revolutionizing Anti-Aging—From Metabolism to Multidimensional Health Benefits

In the field of health and wellness, novel functional compounds consistently attract significant attention, and Urolithin A (UA) has emerged as a prominent "potential candidate" in recent years. Unlike many bioactive substances that are directly abundant in food sources, UA is a metabolite produced by the gut microbiota. Nevertheless, it exhibits remarkable potential in multiple domains, including antioxidant activity, anti-inflammatory effects, and anti-aging properties. This article aims to provide a comprehensive overview of Urolithin A, unraveling the unique characteristics of this specialized metabolite.

Urolithin A was formally identified and named in 2005, with a molecular formula of C₁₃H₈O₄ and a relative molecular mass of 228.2. From a physical property perspective, it appears as a yellow or pale yellow solid powder under normal temperature and pressure. Its solubility profile is notably distinctive: it dissolves readily in strongly polar organic solvents such as dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF), yet exhibits poor solubility in low-polarity solvents (e.g., petroleum ether, diethyl ether) and water. This characteristic directly results in extremely low natural abundance of Urolithin A in nature, making direct dietary intake an impractical means of obtaining it.

1. ET is hydrolyzed to form EA;

2. EA undergoes lactone ring cleavage and decarboxylation to generate Urolithin M5 (UM5);

3. UM5 undergoes dehydroxylation at different positions, producing tetrahydroxyurolithin isomers such as Urolithin D (UD) and Urolithin M6 (UM6);

4. Tetrahydroxyurolithins undergo another round of dehydroxylation, forming trihydroxyurolithin isomers including Urolithin C (UC) and Urolithin M7 (UM7);

5. Trihydroxyurolithins continue to undergo dehydroxylation, yielding dihydroxyurolithins such as Urolithin A (UA) and its isomer (isoUA);

6. A final dehydroxylation step produces the monohydroxy derivative Urolithin B (UB).

Ultimately, the generated urolithins are absorbed by intestinal epithelial cells, conjugated with glucuronic acid, and enter the systemic circulation to be transported to various target organs for biological activity.

• Individuals with Metabolizer Type A harbor microbiota capable of producing UA and its conjugates;

• Those with Metabolizer Type B have microbiota that primarily generate UB and its conjugates;

• Individuals with Metabolizer Type O lack microbiota capable of producing any urolithins.

This finding implies that the proportion of individuals who can naturally produce Urolithin A via gut microbiota metabolism through regular dietary intake is relatively small—estimates suggest only 40% of individuals can naturally convert polyphenolic precursors into UA. For the majority of consumers, direct intake of Urolithin A supplements represents a more direct and effective approach.

• In a study involving healthy volunteers, plasma oxygen radical absorbance capacity (ORAC) increased by 32% 0.5 hours after pomegranate juice intake;

• In vitro experiments using Neuro-2a cells demonstrated that UA effectively reduced reactive oxygen species (ROS) levels within cells;

• Additionally, Robuvit®—a compound with UA as its primary active metabolite—was shown to reduce oxidative stress levels in patients, thereby improving mood, alleviating fatigue, and addressing insomnia.

1. It inhibits the nuclear factor κB (NF-κB) and Akt/mitogen-activated protein kinase (MAPK) signaling pathways;

2. This inhibition further reduces the mRNA and protein levels of cyclooxygenase-2 (COX-2), thereby decreasing the production of inflammatory mediators;

3. Additionally, UA regulates cytokine balance by reducing the production of pro-inflammatory cytokines (e.g., tumor necrosis factor-α, TNF-α) while enhancing the synthesis of anti-inflammatory cytokines (e.g., interleukin-10, IL-10) and the expression of transforming growth factor-β1 (TGF-β1).

1. It induces autophagy, facilitating the clearance of abnormally accumulated proteins within cells;

2. It activates the deacetylation mechanism of sirtuin 1 (SIRT-1), mediating anti-inflammatory activity to inhibit neuroinflammation and neurotoxicity;

3. It directly scavenges free radicals, reducing oxidative stress-induced damage to nerve cells;

4. It inhibits oxidase activity, reducing the production of oxidative products at the source.

• Reduce oxidative stress in the aging retina;

• Decrease cytosolic cGAS levels in the aged retina;

• Reduce glial cell activation.

Owing to its strong antioxidant activity, Urolithin A ranks among the most potent antioxidants among all identified mammalian gut metabolites—second only to procyanidin oligomers, catechin, epicatechin, and 3,4-dihydroxyphenylacetic acid. This property endows UA with potential value in the skincare field, as it may help maintain youthful skin by combating oxidative damage.

According to projections from the World Health Organization (WHO), by 2030, 1 in every 60 people worldwide will be aged 60 years or older. The growing trend of population aging has fueled strong market demand for products that support healthy longevity. With its unique health benefits and exceptional anti-aging potential, Urolithin A aligns perfectly with consumer needs for aging intervention and health maintenance, positioning it as an ideal anti-aging supplement with broad market application prospects.

1. Microbiota dependence: Only a subset of the population can naturally produce UA via gut microbiota metabolism;

2. Long-term safety verification: Additional data on the long-term safety of UA supplementation are required;

3. Cost optimization: Developing cost-effective production and extraction methods to improve accessibility for a broader population remains an urgent task.

It is anticipated that with the advancement of research, these challenges will be gradually overcome. Urolithin A is poised to shine more brightly in the health sector, contributing significantly to human health and longevity.

Important Reminder：All content in this article is for general reference only and is provided solely to offer information support for practitioners in the nutrition and health industry. Descriptions related to efficacy are supported by corresponding data, but they do not represent claims or guidance for consumers. Content related to health, medical care, and technological applications is for reference only. For medical matters, please consult professional medical institutions and follow medical advice. This article does not provide any medical recommendations.