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Complete Guide to Urolithin A

Every so often there are popular products that spread across the longevity community. One such compound is Urolithin A. You might have heard of this compound already, but whether you have or haven’t, this post is going to do a deep dive into Urolithin A, what the research tells us about its potential benefits, and my key take-aways on Urolithin A. 


TLDR

  • Urolithin A is a metabolite created by your microbiome mainly from consuming phenols in pomegranate, walnuts or almonds

  • Urolithin A has been shown to have a range of potential health benefits which seem to be mostly through modulation of mitochondria including mitophagy

  • There is enough research to warrant adding this into your health/longevity routine either through food or supplementation, however, much of the research is in rodent models

  • The easiest way to increase Urolithin A would be to add pomegranate or walnuts into your diet


What is Urolithin A

Urolithin A (UA) is a naturally occurring compound derived from the metabolism of gut microbiota (making it a postbiotic) in the class of molecules called Urolithins (Uros). It is created when microbes convert polyphenols Ellagitannins (ETs) and Ellegic Acid (EA) into UA. It has also recently been synthesised as a supplement that can be taken directly. This compound has been shown to potentially improve mitochondria, enhance autophagy, support muscle health and improve lifespan. Pretty significant claims, so let’s look at how UA is metabolised, what the research says and if UA is worth adding to your supplement regimen. 


Urolithin A Metabolism

Firstly, let’s look at Urolithin metabolism and how UA is produced. If you’re not interested in the nitty gritty science of UA metabolism, skip ahead to the benefits section. 


Metabolism and production mostly occurs in the colon. Uros occur naturally in the gut by the action of the gut microbiota on dietary ETs, but EA needs to be produced first. EA is then further metabolised and converted into Uros by specific gut microbes. There are specific metabotypes in individuals based on the species of microbes present and the type of Uros produced. Those who produce a significant amount of Urolithin A are classed as UM-A, those who produced Urolithin B UM-B and those who produce very little or no Uros UM-0. 


Proteobacteria, Clostridium, Bifidobacterium, Eubacterium, and Enterococcus faecium possess distinct metabolic functions that play a part in the production of Urolithin A (and other Uros) [R]. The genus Gordonibacter from the Eggerthellaceae family accommodates bacterial species that are part of the human gut microbiota and can metabolise EA into Uros Uro‐M5, Uro‐M6, and Uro‐C. Two other genera of the Eggerthellaceae family (Eggerthella and Adlercreutzia) predominate in UM‐A (characterised by Uro‐A production) versus UM‐B individuals (characterised by the production of Uro‐B and isoUro‐A in addition to Uro‐A) Ellagibacter, another genus from Eggerthellaceae family, can also convert EA into Uros (Uro‐M5, Uro‐M6, Uro‐C, and isoUro‐A)

metabolic pathways for urolithin a
urolithin A metabolism

It is then absorbed and transported throughout the body where it is further converted into other metabolites such as a mercaptan and sulphate form which enact various effects. Studies (mostly in rats) have shown variable uptake across a range of tissues including quadriceps muscle, adipose tissue, liver, pancreas, brain and more. Note that absorption and utilisation will be quite variable depending on the individuals age, sex, diet, microbiome, and genetics. Of note, a study by Zhang et al showed a reduced ability to convert polyphenols to Urolithins in individuals with prediabetes and insulin resistance (although this needs to be repeated and confirmed) [R]


A study in the elderly showed a Tmax (time to reach maximum concentration) of 6 hour and half life (time for half of it to exit your system) of a day [R].


What are the Benefits

Urolithins have been shown to have pleiotropic effects (meaning affecting many different things) [R], which sometimes makes it more difficult to understand the mechanism of effect. In saying that, Urolithin A has a growing body of literature to show benefits across different areas, specifically related to potentially improving lifespan/healthspan and athletic performance [R]. 


Organ system benefits of Urolithin A
Benefits of Urolithin A

Anti-Inflammatory 

Multiple studies in rodents have shown various anti-inflammatory affects, mainly in the colonic environment [R]. It possesses the ability to directly scavenge free radicals by capturing and neutralising reactive oxygen species, thus reducing cellular oxidative stress. It can also activate the Nrf2 antioxidant pathway and upregulate the expression of various antioxidant enzymes such as Glutathione peroxidase and superoxide dismutase, thereby enhancing cellular antioxidant defence capacity. Additionally, Urolithin A has been reported to inhibit enzyme activities involved in ROS generation, thereby reducing the occurrence of oxidative stress and protecting cells from oxidative damage [R,R,R].


Anti-Cancer 

Research has shown that Urolithin A can regulate the cell cycle and induce apoptosis preventing cancer growth by increasing the levels of cell cycle inhibitory proteins, such as p21 and p27. It has also been shown to induce cell death through multiple pathways, again preventing cancer growth [R].


Research has also shown anti-colon cancer findings in rodents [R]


Cardiometabolic

Those with UM-B subtype with high Coriobacteriaceae have been shown to have higher cholesterol and BMI which may be associated with high CVD risk [R].


Benefits in those with UM-B metabotype with highest CVD risk. These effects were partially correlated with urolithin production and the increase in Gordonibacter levels. Three (50%) nonproducers (UM-0) became producers following PE consumption [R], thus improving their risk profile with UA intake.


Correlations between cardiometabolic factors and urolithins were found in overweight-obese individuals. Urolithin-A (mostly present in UM-A) was correlated with apolipoprotein A-I and intermediate-HDL-cholesterol (less atherogenic) while urolithin-B and isourolithin-A (characteristic from UM-B) were correlated with total-cholesterol, LDL-cholesterol, apolipoprotein B, VLDL-cholesterol, IDL-cholesterol, oxidised-LDL and apolipoprotein B:apolipoprotein A-I ratio (more atherogenic). 


Interestingly, in Metabolic Syndrome (MetS) patients, urolithin-A correlated inversely with glucose and statin-treated MetS patients with UM-A showed a lipid profile similar to that of healthy normoweight individuals while a poor response to lipid-lowering therapy was observed in MB patients. This shows that the UA metabotype seems to be protective [R]. 


Improved vascular endothelium mediated by microbiome [R].


Reduced UA is associated with metabolic syndrome and dysbiosis (which direction of causation still to be confirmed) [R]. 


Autophagy & Mitophagy

Various Mitochondrial, Mitophagy and Autophagy benefits [R,R].


Urolithin A activates the PINK1/Parkin signalling pathway, which is involved in mitochondrial quality control. Consequently, this activation promotes the selective aggregation, degradation, and removal of damaged mitochondria [R].


Enhance mitochondrial autophagy by activating the expression of glutathione S-transferases (GSTs). Urolithin A stimulates the Nrf2-ARE signalling pathway, subsequently upregulating the expression of GSTs, thereby enhancing cellular autophagy and mitochondrial quality control [R].


Mitophagy induced by Urolithin A
Mitophagy

Muscle 

There is a growing amount of data showing UA may have many benefits associated with muscle health, recovery and performance [R,R,R].


  • Evidence supports the potential of Urolithin A in facilitating muscle cell proliferation and augmenting muscle function . 

  • It can inhibit the inflammatory response and alleviate inflammation-induced damage. Moderate inflammation constitutes a natural process of the body’s repair, but excessive or prolonged inflammation may impair muscle recovery and growth. 

  • Able to promote mitochondrial function and muscle energy metabolism, which has a positive impact on muscle recovery and performance. 

  • It can also enhance mitochondrial function and activity (as above). It achieves this by activating gene expression similar to PGC-1α, regulating the quantity and quality of mitochondria. 

  • May have a positive role in improving endurance and delaying muscle fatigue, both of which are intricately linked to mitochondrial function.

  • May have a positive impact on muscle hypertrophy and maintenance of muscle mass but research is needed in humans


However, it should be noted that many of these findings are mostly in aged populations and may not have the same benefits for younger individuals. 


Cartilage & Arthritis

UA treatment significantly increased the quantity and quality of cartilage matrix deposition. Interestingly, UA also suppressed the senescence level induced by mechanical overloading, demonstrating its senomorphic potential. Mechanistic analysis confirmed that UA functioned partially by enhancing mitophagy [R].  


Anti-Aging & Lifespan

Research in the worm C. elegans has shown lifespan extensions [R,R]. 

Shown to improve symptoms of neurodegenerative disease in rodent models

Likely mechanism for many of these benefits is via mitophagy 


Gut Health

UA has been shown to create changes in the microbiome which may provide further health benefits such as cardiometabolic disease as noted above. There is also research to show a reduced colonic cancer risk [R].


Source & Dosing

Natural

Pomegranate, walnut, and almond stand out as the primary and richest dietary sources of Urolithin A. Certain other fruits and nuts such as strawberries and peanuts may also be a source. [R,R]


Pomegranate is likely the best source for natural UA [R,R]


Blueberry, recognized for its antioxidant-rich content, including various polyphenolic compounds, may also include Urolithin A [R].


Note, some people may have issues with phenols that can cause other symptoms such as inflammation or gut disruption.


Supplemental

UA has been marked as Generally Recognised Aa Safe by the FDA. 


Currently the best and clinically tested product is MtioPure 


Seed Probiotic also contains Indian Pomegranate which can allow your microbiome to produce UA if it has the appropriate species. 


Food vs Supplement

Recent research has shown higher concentrations of UA with direct supplementation vs pomegranate [R,R]. Obviously supplementing bypasses the need for UA to be produced by your microbiome, so if by chance you don’t have the specific species to produce UA, it wont matter.


Dosing

500-1000 mg UA per day


Testing

If you want to see which Urolithin species you might have to gauge your potential Urolithin A capacity, Microba does check for some species like Gordonbacter



Take Away

UA sounds like a promising compound for health and longevity. However, a lot of data is in rodent models or in elderly populations, so it may not have the same affects for a younger or healthier human.


Majority of the benefits are likely due to improvements in mitophagy which can have pleitropic affects across the body.


There are apparent benefits in overweight/obese individuals to improve CVD, but other more important strategies like diet and exercise still outweigh the signal with UA.


Ultimately. you can probably save yourself the money and get the benefits by consuming Ellagitannin and Ellegic Acid rich foods like Pomegranates. But if budget isn't a constraint, there seems to be ample data for the additional of UA to your regimen.


As usual, it's important to actually test to confirm if it makes any difference for you by tracking bloods and potential via Microba.



Other References

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