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- Another day, another potential mitochondrial enhancer! We just came across LOLA and now we have urolithin A – a most intriguing compound. Urolithin A (UA) is produced by the gut bacteria when they break down the substances found in foods like pomegranates, walnuts, strawberries and raspberries.
- it’s not new to science; it was discovered about 40 years ago, but more recent interest in its health-enhancing properties has resulted in hundreds of mostly lab and animal studies. UA’s great gift appears to be its ability to enhance mitochondrial production and muscle functioning across a wide range of species (worms, mice, and humans). Interestingly, it does this cleaning up of defective mitochondria (mitophagy, autophagy), a process studies suggest may be impaired in ME/CFS.
- UA supplementation has been shown to improve both muscle strength, improve mitochondrial efficiency, and reduce inflammation in middle-aged and older adults. Animal studies suggest it can increase lifespan as well.
- UA research appears to be booming. Just in the past 5 months, UA improved memory and learning in Alzheimer’s mice, suppressed colorectal cancer in the lab, reduced the toxicity of amyloid plaques in mice, reduced cognitive impairment in aging mice by increasing mitochondrial activity, reduced microglial activation in mice, and so on.
- It’s not all about mice and labs, though. Clinical trials are currently underway to assess UA’s ability to affect the immune system, enhance endothelial functioning, increase glucose metabolism, insulin availability, and energy production, alter the gut flora and boost mitochondrial production, assess skeletal muscle function and iron metabolism, and more.
- Studies suggest that only about 30-40% of people have the gut flora that produce enough urolithin A (UA) to make a difference. One review stated that only “a small percentage” of people get enough UA from food to get health benefits from it.
- Urolithin A supplements are readily available but, as with any supplement, it’s probably best to go with a reputable brand as one study found that some brands may not contain all the urolithin A they purport to. Mitopure by Timeline has been used in clinical studies and is surely safe, but at $2.08 pill on Amazon in the U.S., it’s also easily the most expensive source. Otherwise, UA is available from $0.33 to $1.28 per pill, and comes in powder form as well.
- Applying the Arsenau test regarding which treatments to try finds the source of the information regarding UA highly credible, the evidence of its effectiveness fair (a few good human studies have had positive results, the benefit appears to be moderate (but could hit a core problem in ME/CFS/FM), the cost runs from fairly low to fairly high depending on which brand you try, and the risk appears to be low. In other words, if you’re supplement inclined and you can afford it, urolithin A might be something to try.
- We, of course, don’t have a clue how well it would do in diseases like ME/CFS, FM and long COVID, but if mitophagy is a problem, and people with these diseases are aging more quickly, as some researchers recently suggested, UA’s mitochondrial and lifespan-enhancing possibilities might be helpful.
- No one supplement is going to do the trick with ME/CFS. With mitochondrial supplements popping up so much we’re going to try to use study results to dream up a possible mitochondrial supplement package for these diseases. If you have ideas please provide them!
- Thanks to the over 200 people who have contributed to Health Rising’s drive thus far!
Another possible mitochondrial enhancer shows up.
it’s not new to science; it was discovered about 40 years ago, but more recent interest in its health-enhancing properties has resulted in hundreds of mostly lab and animal studies.
Mitochondrial and Lifespan Enhancer
UA’s great gift appears to be its ability to enhance mitochondrial production and muscle functioning across a wide range of species (worms, mice, and humans). Interestingly, it does this cleaning up of defective mitochondria (mitophagy, autophagy), a process studies suggest may be impaired in ME/CFS. UA is so effective at this process that it’s been called a “first-in-class mitophagy enhancer“.
Reduced mitochondrial cleanup in the muscles (mitophagy) plays a role in the muscle weakening that occurs as we age. UA has been shown to improve both muscle strength and muscle endurance in both younger and older mice, improve mitochondrial efficiency, reduce inflammation, and improve muscle endurance in humans. It also appears to enhance cardiovascular health, improve T-cell functioning (reducing T-cell exhaustion – a problem in both ME/CFS and long COVID), and has neuroprotective and mitochondrial enhancing effects in the brain.
A 2022 study found that middle-aged adults taking two doses/day of Mitopure for four months showed significant improvements in muscle strength (∼12%) and “clinically meaningful” improvements in aerobic endurance (peak oxygen consumption [VO2]) and physical performance (6 min walk test) but no significant improvements on peak power output. Increased mitochondrial gene expression and reduced levels of acylcarnitines and C-reactive proteins suggested Mitopure had improved mitochondrial efficiency and reduced inflammation. The gene expression and proteomic analysis of muscle tissue confirmed that UA’s biggest effect was improved mitochondrial functioning.
Urolithin improved muscle endurance and mitochondrial functioning in middle-age and senior adults.
Similar findings occurred in the double-blinded, placebo-controlled, randomized ENERGIZE clinical trial taking place at the University of Washington Medical Center and the Fred Hutchison Cancer Research Center in Seattle, Washington. Older adults (65-94) taking 1,000 mg in the morning on an empty stomach with a glass of water had a significant improvement in muscle endurance, reduced plasma levels of several acylcarnitines, ceramides (biomarkers of mitochondrial health), and C-reactive protein (inflammation).
UA research appears to be booming. Just in the past 5 months, UA improved memory and learning in Alzheimer’s mice, suppressed colorectal cancer in the lab, reduced the toxicity of amyloid plaques in mice, reduced cognitive impairment in aging mice by increasing mitochondrial activity, reduced microglial activation in mice, and so on.
It’s not all about mice and labs, though. Clinical trials are currently underway to assess UA’s ability to affect the immune system, enhance endothelial functioning, increase glucose metabolism, insulin availability, and energy production, alter the gut flora and boost mitochondrial production, compare Mitopure’s bioavailability with pomegranate juice, assess skeletal muscle function and iron metabolism, and more.
Dietary Urolithin A vs Supplements
Studies suggest that only about 30-40% of people sufficiently break down ellagitannins enough to produce urolithin A (UA) in their gut. One review stated that only “a small percentage” of people get enough UA from food to get health benefits from it. Attempts to identify the gut bacteria responsible for producing have failed thus far.
Buying Urolithin A
Urolithin A supplements are readily available but, as with any supplement, it’s probably best to go with a reputable brand. The news from a recent study that assessed UA levels in supplements was mostly good: of the 4 brands tested, two were very close to the manufacturer’s claims, while one exceeded it by almost 30%, and one was 16% lower. The names of the brands were not given. (The news regarding nicotinamide was worse with 8/16 brands containing less than 20% of the claimed levels and three containing none.)
Mitopure by Timeline has been used in clinical studies and is surely safe, but at $2.08 pill on Amazon in the U.S., it’s also easily the most expensive source. Otherwise, UA is available from $0.33 to $1.28 per pill, and comes in powder form.
Applying the Arseneau test suggested that if you’re into supplements and can afford it, urolithin A might be worth a try.
Applying The Arseneau Test
The Arseneau test assesses the factors below to help decide whether or not to try a new treatment. It comes from a presentation given by Dr. Ric Arsenau, a Canadian ME/CFS/FM doctor.
- The credibility of the source – with many studies and even a few human ones, the credibility of the source is good.
- The quality of the evidence – Pretty good – few human trials have been done, but a couple of high-quality trials have had good results in healthy humans.
- The benefit, cost, and the risk-benefit analysis – the benefit appears to be moderate (but could hit a core problem in ME/CFS/FM), the cost runs from fairly low to fairly high depending on which brand you try, and the risk appears to be low.
If you’re supplement inclined and you can afford it, urolithin A might be something to try.
Conclusion
UA might be the rare real deal. It’s been extensively studied – mostly in animal models and the lab for sure – but the few healthy human trials have gone well, and more are underway.
We, of course, don’t have a clue how well it would do in diseases like ME/CFS, FM and long COVID, but if mitophagy is a problem, and people with these diseases are aging more quickly, as some researchers recently suggested, UA’s mitochondrial and lifespan-enhancing possibilities might be helpful.
That said, UA does not appear to be a super supplement (is there one?). The increases in muscle endurance are generally around 15-20% – a nice increase but not staggering. It does appear, though, to be having a positive effect biologically.
Could urolithin A help with ME/CFS, FM and long COVID?
Thus far, though, we have one study that’s assessed autophagy in ME/CFS, three fibromyalgia mouse studies suggesting mitophagy / autophagy is a problem, and a couple of studies suggesting that impaired autophagy is in long COVID, as the virus appears to reduce autophagy. In other words, we have arrows pointing to autophagy/mitophagy being a problem but not a lot of solid evidence.
I never think that any one supplement is probably going to do it, and honestly, mitochondrial supplements have never done much for me. (Then again, I’m horrible at maintaining my supplement regimens).
With UA and LOLA popping up recently, though, I’m wondering what the studies suggest the best mitochondrial supplement package for these diseases might be. That will be coming up in a future blog but first, please offer your ideas. (Thanks to Neilly for the urolithin A tip.)
Health Rising’s Quickie Summer Donation Drive
We are on the lookout for new treatment possibilities for these disease.
Thanks to the 235 people who have helped bring Health Rising get to about 75% of the way to its goal of $20,000. Because Health Rising is almost entirely (as in like 97%) community supported thanks to everyone who helping keep us online and spreading the news.
Urolithin A, LOLA, methylene blue, oxaloacetate, a new anaerobic exercise program, rapamycin, Putrino’s autonomic rehabilitation program, Tomnya, Copaxone, Baritcinib, monoclonal antibodies… it goes on and on. We are committed to keeping up with new treatment possibilities that have been showing up for these diseases.
If learning about new treatment possibilities floats your boat please support us in a manner that works for you.
Does it have immunodulatory effects? Does anyone know?
It appears to have anti-inflammatory properties if that fits.
That helps. Thanks!
Does anyone have any suggestions for how to get mitropure in Australia? I looked at the timeline website And they don’t ship here
Karen, try this:
https://mitorenewal.com/products/mito-renewal-complete-urolithin-a-500mg-90-capsules
I have ordered some for myself off of Amazon.ca in powder form. I will load it into delayed release capsules.
Thankyou so much! I was reading somewhere that many other sources are not pure and do not have real Urolithin A
Do you know whether this is a good brand ? Have you seen any difference?
I have no idea if this is good or not. I haven’t tried urolithin A yet, but I ordered pure powder from Amazon.ca and I will give it a try.
Maybe you could order pure powder from Amazon.ca and they would ship it to you in Australia. I often order stuff from Amazon.uk and they ship it to Canada for me.
Hello everyone, I am reporting back on two of my trials. If T Allen is reading, I tried high dose thiamine and it did not work for me, plus it gave me diarrhea even at low doses. Darn, I had hope on that one.
The other trial is the peptide NACE2i. Remember the study?
https://www.nature.com/articles/s41467-023-39341-4
and the lay explanation?
https://www.youtube.com/watch?v=JTYVd9daLAo
I think Giis also posted this. It is supposed to reverse the epigenetic changes that the covid virus causes, resulting in reversed symptoms.
I contacted one lab in Canada, two in the U.S. and one in the UK. None would synthesize it for me.
I found two in China that would. One was extremely expensive, and one was very expensive. I could only afford a small amount, and not even the full dose of 100mg/kg IV per day for six days.
But I bought some anyway and put the powder into delayed release capsules, and also put some under my tongue.
I have to say, even though it was a very low dose, that I felt better. More energy, less pain. The effect wore off when I ran out.
I really think this may help, but I cannot afford to buy more. We should track the research on this. They are beginning trials for blood markers. If you want to join the trials, here is the link:
https://www.qimrberghofer.edu.au/participate-in-the-trial/
I wish them success.
Urolithin A is confirmed as an important research target for ME/CFS and LongCOVID for amelioration of symptoms with Artificial Intelligence methods : https://x.com/lifeanalytics/status/1808582440761634903
Ha! This is what Efthymios wrote a couple of days before this blog
If I had to pick a compound for further investigation for #MECFS and #LongCOVID, this would be ellagic acid and its metabolites. Strong & coherent “signals” from this research target : Mitophagy, microbiome, activation of LXR, ABCA1 , PGC1a, NRF2. Many more associations.
I saw your post and thought that this is spot on Cort ! Actually, the first mention for Urolithin A was in October 2023 but some days ago I confirmed that Ellagic acid and its metabolites (one of them being Urolithin A) could be very important compounds for further investigation. Here is the older post : https://x.com/lifeanalytics/status/1710651896233447708
I tried Mitopure for a full year and could not detect any real improvement. My belief is that the effect is strong enough in healthy people (which were used in the tests of the paper), but does not move the needle enough if you are sick.
Unfortunately this was my experience with it as well.
have you perhaps looked into oxaloacetate?
https://pubmed.ncbi.nlm.nih.gov/35764955/
I’ve been taking Ultrapome for some time now (I live in the UK) and it was the most reasonable Urolithin A supplement I found that I felt I could trust. It helps with my energy levels and I have slightly less gut issues. Like all supplements I’ve tried though, it only helps a bit. Still that’s better than nothing and I continue to take it because I think it’s worth the cost.
Hi Cort, do you know if Hwang, Nath et al are following up on their findings of high WASF3 from their 2023 research? For me this was one of the more elegant and interesting research findings from the past 5 years, and I am interested in whether they are taking it further. In particular it offered a nice potential explanation for PEM.
It would be really nice to see these sorts of leads followed up by researchers.
Yes, they have said they are. Not sure what they’re doing, though.
Have you looked at nicotinamide riboside, NAD, or other NAD precursors?
I went into research mode after reading this latest blog. Found this article (although a bit heavy technically) which has a nifty Table 2 which lists all the most well known mitophagy promoting supplements including Urolithin.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657188/
I found it interesting that it lists Metformin as something that could inhibit muscle formation (see Table 2). What else I found interesting is that balancing mitophagy (cleaning up old damaged mitochondria) with biogenesis (the formation of fresh, new mitochondria) is necessary for this to work properly. That’s a bit simplified, but this subject is very complex so I digressed to that generalization.
And as an aside, I have been taking LOLA for over a week and have noticed an increase in stamina–small, but noticeable. Also a bit of loose bowels but am not sure they are from County Fair Food (4th of July) or the supplement. Will report back later.
I’m due to see Bonilla again after a failure of Ketotifen. He told me it was for neuroinflammation but as near as I can figure out it is usually used as a mast cell stabilizer. When I inquire about other drugs/supplements I am told to ‘stick to the program’ which irritates me. I’d rather have more personalized treatment. Anybody else get this drug?
We are hopefully getting our LOLA order in a day or so. All the way from USA to New Zealand
Who has tried mitochondria enhancing peptides like ss-31 and MOTS-C?
Metabolism and mitochondria are a very difficult areas of research. The mitochondria are not damaged in ME/CFS patients. The ‘substances and oxygen’ are sufficiently present in the blood. This means 1. these are not properly absorbed and/or processed 2. there is a low blood volume so we have less of everything. That is why I do not believe that you can solve this problem with just one solution. We suffer from multiple systems that are dysfunctional. It seems that 1 chain is causing everything to collapse.
Back to rapamycin, I asked my CFS doctor about it and she said she’s very familiar with it and I’m not a good candidate because it can lower white blood cell count. I don’t know if low WBCs is a factor for most ME/CFS patients or not.
I’m willing to test new supplement ideas on myself. I am taking coq10+ PQQ (1000mg coq10 and 20mg pqq, twice daily) and it seems to be having a positive effect over time, ie. since February, in minimising the frequency and severity of PEM (I have severe CFS and homebound).
Improvement is slow but my sense is that severity overall is lessening.
I’ve ordered Lola and am curious, and obviously hopeful, to see if there are any benefits for me.
I’m also very interested to hear of other people’s experiences with these supplements.
Our order of LOLA is taking a while. Might also try TUDCA as that reduces ER stress.
Higher levels of ER stress increase WASF3
Matthias, what are ER and WASFS?
Thanks.
Hi cassy. EE is endoplasmic reticulum stress and WASF3 is a protein which hinder muscle energy production. TUDCA is bsslieved to amoreeliate it but it didn’t worked for mr
Thank so much for explaining, Anish!
Here you go Cassy:
https://www.nih.gov/news-events/nih-research-matters/protein-may-be-linked-exercise-intolerance-me-cfs#:~:text=References%3A%20WASF3%20disrupts%20mitochondrial%20respiration,Disorders%20and%20Stroke%20(NINDS).
I have not been able to source Urolithin A in Canada yet so if anyone knows where to get it here, please share. Also, the ‘Arseneau Test’ is quite a helpful and well articulated decision making tool. A nice contribution from this Dr 🙂
Geoff,
I am in BC, and I bought urolithin a (pure powder) on amazon.ca and have been on it at 1500 mg per day for two weeks. I find I am significantly better on this. I think it works better with low dose naltrexone on board, but I’m not sure why. Give it a try!
Thanks for the tip Ann1! I generally steer clear of powders, as we never quite know for sure what we’re getting. But if it comes with an endorsement like that from a pwME I’m way more partial to giving it a try. Can you share the name of the company who supplied it on amazon so I know what to look for. Glad it seems to be helping you, and thanks again.
Geoff,
Here’s the direct link:
https://www.amazon.ca/Akersunder-Urolithin-Purity-1143-70-0-Grams/dp/B0CX1CBLX6/ref=sr_1_2?crid=3B838JMYQ0C46&dib=eyJ2IjoiMSJ9.wTGXioK58EGWJuo0uxnLxZrwCwCro6IZfMyGrFeImmwa_xD1B2SwXNYgOCRwmTm7tPVooBFtAZFGV6fDEiCcqg.tbGTBoVSkPJ2z37IBj4HKXhlm8fgXq2ACZ-K0vMJbGg&dib_tag=se&keywords=urolithin+a+powder&qid=1721681523&sprefix=urolithin+a+%2Caps%2C1327&sr=8-2
This includes the analysis reports as seen in the left column. I am way more partial towards buying the powder direct from China when the analysis is clear. ALL of the combination capsules (like Mitopure) that say “Made in USA” are actually put together from ingredients imported from China. No one makes these powders in the U.S. because the feed stock doesn’t grow in the U.S. I have never seen 1400 acres of pomegranate trees growing in Iowa. It’s much cheaper to buy it from China, the contacts are in my experience nice people, the shipping is dirt cheap, and I have never had a bad experience. YMMV.
Well, the other feedstocks would be Walnuts or Almonds so at least there’s the potential for a domestic supply. Also I’m not familiar with either SGS or Shimadzu, or whether they would qualify as true third party quality control testing bodies in North America, but will look into it. If it’s helping you feel better, and you feel worse when you stop, that’s definitely a good sign. Personally though I like to be very confident that an overseas bulk supplement is free from contaminants. We each have our own standards. Glad it’s helping 🙂
I have had medium grade long Covid symptoms for 2 years. Been taking 500mg Urolithin a powder per day for three weeks now and… Hesitate to say but…. Symptoms markedly improved. Still get tired after exercise but the inflammation is gone. Generally feeling way clearer and less foggy.
I do take blood pressure pills and read somewhere that UA can interfere with some of these drugs… And my bp has definitely gone up, as well as probably being responsible for a constant and quite strong headache, which is unusual for me.
I’m sure everyone will find a different set of solutions but thought I’d pass on my experience with UA. The more I read about it the more it makes sense that it MIGHT help all manner of illnesses. Simon
FWIW – Case Study of one….
I have been struggling with long covid for years now. Recently came across UA from Timeline. It certainly works for me, and I crash badly if I do not take it. As everybody says, very expensive though. (Taking 500mg per day).
Good on you Piet. I’m about to try a cheap supply from China via Aliexpress. Suspicious but gotta try it.
3 Weeks of 1 g urolitin a/ Day from hansen Supplements.
I have me cfs bell 10.
Know it is bell 20 up to Even 30( half days .)
This is very very expensive supplement.
But i am happy to have something that Helps.
I am able to talk longer louder and even Listen to music and able to stand up from wheelchair an walk few steps.
Sure far away from health but with mire hope nearer to it.
Just writing to share that I immediately started this supplement after reading about it here in the beginning of July. I am a homeschooling mom of four boys, and have been fighting through a resurgence of ME/CFS over the past two years (the first happened in 2015-2018). I believe mine is viral related/triggered in both instances.
I have had incredible success supplementing with urolithin-A. Thank you so much sharing this study!! I have felt my energy grow steadily (doubling every couple of weeks) over the past two months while taking this supplement.
I will say that I have also previously implemented by trial and error nearly all of the non-medicated treatment options listed in the recent study on treatment for the two day exercise study follow up – much of which I learned during my first bout with this horrible illness. And had experienced an extremely slow but steady recovery from about January to July of this year. However, while I had managed to control the chronic pain, my energy had stayed extraordinarily low, requiring me to make daily, careful accommodations and plans. This past month has been wildly different.
If you can afford it, I highly encourage trying this supplement!
I tried this supplement (via Neurogan as it was a bit less expensive and published their 3rd party tests) after finding your blog the day you published this study to it.
This has been my second major flare up of ME – the first lasted about 1.5 year and the more recent about the same. I believe both were triggered by viruses combined with ill timed stress.
None of the things that had worked the first time were working. And with four boys to raise – I was desperate! I felt my muscles literally waste away from my body, struggled with constant brain fog, ever increasing weakness and sensitivity to seemingly any level exertion (ie washing my hair).
I’m sorry others haven’t had luck with the supplement – but thank you SO much for sharing it. It has transformed my life and energy levels since I started taking it 2 months ago! Honestly, I feel like a new person, and am moved to tears daily with gratitude over finally feeling my strength return bit by bit. I would say my experience exceeds the typical 15-20% strengths gains and my energy levels have doubled every 1-2 weeks. Truly life changing.
Anyone know what probiotics I take to help my microbiome produce this successfully in my gut?