The Science Behind Urolithin A: What You Need to Know

 Urolithin A (UA) is a compound produced by the metabolism of intestinal flora in foods rich in ellagitannins (such as pomegranates, raspberries, etc.). It is considered to have anti-inflammatory, anti-aging, antioxidant, induction of mitophagy, etc., and can cross the blood-brain barrier. Many studies have confirmed that urolithin A can delay aging, and clinical studies have also shown good results.

What is urolithin A?

Urolithin A (Uro-A) is an ellagitannin (ET)-type intestinal flora metabolite. It was officially discovered and named in 2005. Its molecular formula is C13H8O4, and its relative molecular mass is is 228.2. As the metabolic precursor of Uro-A, the main food sources of ET are pomegranates, strawberries, raspberries, walnuts and red wine. UA is a product of ETs metabolized by intestinal microorganisms. UA has broad application prospects in the prevention and treatment of many diseases. At the same time, UA has a wide range of food sources.

Research on the antioxidant effects of urolithins has been carried out. Urolithin-A does not exist in the natural state, but is produced by a series of transformations of ET by intestinal flora. UA is a product of ETs metabolized by intestinal microorganisms. Foods rich in ET pass through the stomach and small intestine in the human body, and are eventually metabolized mainly into Uro-A in the colon. A small amount of Uro-A can also be detected in the lower small intestine.

As natural polyphenolic compounds, ETs have attracted much attention due to their biological activities such as antioxidant, anti-inflammatory, anti-allergic and anti-viral. In addition to being derived from foods such as pomegranates, strawberries, walnuts, raspberries and almonds, ETs are also found in gallnuts, pomegranate peels, myrobalan, Dimininus, geranium, betel nut, sea buckthorn leaves, Phyllanthus, Uncaria, Sanguisorba, In Chinese medicines such as Phyllanthus emblica and Agrimony.

The hydroxyl group in the molecular structure of ETs is relatively polar, which is not conducive to absorption by the intestinal wall, and its bioavailability is very low. Many studies have found that after ETs are ingested by the human body, they are metabolized by intestinal flora in the colon and converted into urolithin before being absorbed. ETs are hydrolyzed into ellagic acid (EA) in the upper gastrointestinal tract, and EA is passed through the intestines. The bacterial flora further processes and loses a lactone ring and undergoes continuous dehydroxylation reactions to generate urolithin. There are reports that urolithin may be the material basis for the biological effects of ETs in the body.

What is the bioavailability of urolithin related to?

Seeing this, if you are smart, you may already know what the bioavailability of UA is related to.

The most important thing is the composition of the microbiome, because not all microbial species can produce. The raw material of UA is ellagitannins obtained from food. This precursor is easily available and almost ubiquitous in nature.

Ellagitannins are hydrolyzed in the intestine to release ellagic acid, which is further processed by intestinal flora into urolithin A.

According to a study in the journal Cell, only 40% of people can naturally convert urolithin A from its precursor into usable urolithin A.

What are the functions of urolithin A?

Anti-aging

The free radical theory of aging believes that reactive oxygen species generated in mitochondrial metabolism cause oxidative stress in the body and lead to aging, and mitophagy plays an important role in maintaining mitochondrial health and integrity. It has been reported that UA can regulate mitophagy and thus exhibit the potential to delay aging. Ryu et al. found that UA alleviated mitochondrial dysfunction and extended lifespan in Caenorhabditis elegans by inducing mitophagy; in rodents, UA can reverse age-related muscle function decline, indicating that UA improves mitochondrial function by enhancing Muscle mass and extending body life. Liu et al. used UA to intervene in aging skin fibroblasts. The results showed that UA significantly increased the expression of type I collagen and reduced the expression of matrix metalloproteinase-1 (MMP-1). It also activated nuclear Factor E2-related factor 2 (nuclear factor erythroid 2-related factor 2, Nrf2)-mediated antioxidant response reduces intracellular ROS, thereby showing strong anti-aging potential

Antioxidant effect

At present, many studies have been carried out on the antioxidant effect of urolithin. Among all urolithin metabolites, Uro-A has the strongest antioxidant activity, second only to proanthocyanidin oligomers, catechins, epicatechin and 3,4-dihydroxyphenylacetic acid. The oxygen radical absorbance capacity (ORAC) test of the plasma of healthy volunteers found that the antioxidant capacity increased by 32% after 0.5 h of ingestion of pomegranate juice, but the level of reactive oxygen species did not change significantly, while in Neuro- In vitro experiments on 2a cells found that Uro-A can reduce the level of reactive oxygen species in cells. These results indicate that Uro-A has strong antioxidant effects.

03. Urolithin A and cardiovascular and cerebrovascular diseases

The global incidence of cardiovascular disease (CVD) is increasing year by year, and the mortality rate remains high. It not only increases the social and economic burden, but also seriously affects people's quality of life. CVD is a multifactorial disease. Inflammation can increase the risk of CVD. Oxidative stress is related to the pathogenesis of CVD. There are reports that metabolites derived from intestinal microorganisms are associated with the risk of CVD.

UA has been reported to have powerful anti-inflammatory and antioxidant effects, and relevant studies have confirmed that UA can play a beneficial role in CVD. Savi et al. used a diabetic rat model to conduct in vivo studies on diabetic cardiomyopathy and found that UA can reduce the initial inflammatory response of myocardial tissue to hyperglycemia, improve the myocardial microenvironment, and promote the recovery of cardiomyocyte contractility and calcium dynamics, indicating that UA can It can be used as an auxiliary drug to control diabetic cardiomyopathy and prevent its complications.

UA can improve mitochondrial function and muscle function by inducing mitophagy. Heart mitochondria are key organelles responsible for producing energy-rich ATP. Mitochondrial dysfunction is the root cause of heart failure. Mitochondrial dysfunction is currently considered a potential therapeutic target. Therefore, UA has also become a new candidate drug for the treatment of CVD.

 Urolithin A and neurological diseases

Neuroinflammation is an important process in the occurrence and development of neurodegenerative disease (ND). Apoptosis caused by oxidative stress and abnormal protein aggregation often triggers neuroinflammation, and the pro-inflammatory cytokines released by neuroinflammation then affect neurodegeneration.

Studies have found that UA mediates anti-inflammatory activity by inducing autophagy and activating the silent signal regulator 1 (SIRT-1) deacetylation mechanism, inhibiting neuroinflammation and neurotoxicity, and preventing neurodegeneration, suggesting that UA is an effective Neuroprotective agent. At the same time, some studies have found that UA can exert neuroprotective effects by directly scavenging free radicals and inhibiting oxidases.

Studies have shown that pomegranate juice plays a neuroprotective role by increasing mitochondrial aldehyde dehydrogenase activity, maintaining the level of the anti-apoptotic protein Bcl-xL, reducing α-synuclein aggregation and oxidative damage, and affecting neuronal activity and stability. Urolithin compounds are the metabolites and effect components of ellagitannins in the body and have biological activities such as anti-inflammation, anti-oxidative stress, and anti-apoptosis. Urolithin can exert neuroprotective activity through the blood-brain barrier and is a potentially active small molecule for intervening in neurodegenerative diseases.

Urolithin A and joint and spinal degenerative diseases

Degenerative diseases are caused by multiple factors such as aging, strain, and trauma. The most common degenerative diseases of the joints are osteoarthritis (OA) and the degenerative spinal disease intervertebral disc degeneration (IDD). Occurrence can cause pain and limited activity, resulting in loss of labor and seriously endangering public health. The mechanism of UA in treating spinal degenerative disease IDD may be related to delaying nucleus pulposus (NP) cell apoptosis. NP is an important component of the intervertebral disc. It maintains the biological function of the intervertebral disc by distributing pressure and maintaining matrix homeostasis. Studies have found that UA induces mitophagy by activating the AMPK signaling pathway, thereby inhibiting tert-butyl hydroperoxide (t-BHP)-induced apoptosis of human osteosarcoma cell NP cells and reducing intervertebral disc degeneration.

Urolithin A and metabolic diseases

The incidence of metabolic diseases such as obesity and diabetes is increasing year by year, and the beneficial effects of dietary polyphenols on human health have been confirmed by many parties and have shown potential in the prevention and treatment of metabolic diseases. Pomegranate polyphenols and its intestinal metabolite UA can improve clinical indicators related to metabolic diseases, such as lipase, α-glucosidase (α-glucosidase) and dipeptidyl peptidase-4 (dipeptidyl peptidase-4) involved in glucose and fatty acid metabolism. 4), as well as related genes such as adiponectin, PPARγ, GLUT4 and FABP4 that affect adipocyte differentiation and triglyceride (TG) accumulation.

In addition, some studies have also found that UA has the potential to reduce symptoms of obesity. UA is a product of intestinal metabolism of polyphenols. These metabolites have the ability to reduce TG accumulation in liver cells and adipocytes. Abdulrasheed et al. fed high-fat diet to Wistar rats to induce obesity. UA treatment not only increased fat excretion in feces, but also reduced visceral adipose tissue mass and body weight by regulating genes related to lipogenesis and fatty acid oxidation. Reduces liver fat accumulation and its oxidative stress. At the same time, UA can increase energy consumption by enhancing the thermogenesis of brown adipose tissue and inducing browning of white fat. The mechanism is to increase triiodothyronine (T3) levels in brown fat and inguinal fat depots. Increases heat production and thereby antagonizes obesity.

In addition, UA also has the effect of inhibiting melanin production. Studies have found that UA can significantly weaken melanin production in B16 melanoma cells. The main mechanism is that UA affects the catalytic activation of tyrosinase through competitive inhibition of cell tyrosinase, thereby reducing pigmentation. Therefore, UA has the potential and efficacy to whiten and lighten spots. And research shows that urolithin A has the effect of reversing the aging of the immune system. The latest research found that when urolithin A is added as a dietary supplement, it not only activates the vitality of the lymphatic area of ​​the mouse immune system, but also enhances the activity of hematopoietic stem cells. The overall performance demonstrates the potential of urolithin A to combat age-related immune system decline.

To sum up, UA, as an intestinal metabolite of natural phytochemicals ETs, has attracted much attention in recent years. With the research on the pharmacological effects and mechanisms of UA becoming more and more extensive and in-depth, UA is not only effective in cancer and CVD (cardiovascular diseases). It has a good preventive and therapeutic effect on many clinical diseases such as ND (neurodegenerative diseases) and metabolic diseases. It also shows great application potential in the fields of beauty and health care such as delaying skin aging, reducing body weight and inhibiting melanin production.

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