Urolithin A (UA) One of 4 Promising Agents 2024 by Brian Kennedy of NSU

[AnUser]

I am suspecting right now it has to do with Pomella being standardized to 30% punicalagins and less than 5% Ellagic acid.

Punicalagin needs to be converted to EA first, so a supplement standardized to EA might be better.
Anyway reading this stuff confused me so much I am staying away for now from Pomella.

[desertshores]

A good video about urolithin A. Posted a few hours ago.

This Natural Molecule Removes Old and Generate New Healthy Mitochondria

[AnUser]

Buy Urolithin A Powder ≥98% pure - Liftmode

I think it’s likely this vendor is legitimate as it’s been long in the business on reddit with good reviews.

Discount code REDDIT10 might work for 10% off.

COA (Certificate of analysis)

lmurolithina20210706coa.pdf

LM-Urolithin-A-07231120-COA.pdf

30 grams is $79.68, so $40 a month at 500 mg a day.

@RapAdmin

Mitopure has a boatload of patents around the compound… so we’ll see how the competitive landscape develops … there are Chinese companies selling the raw material… but I wonder about the quality, and how long a company could be expected to resell supplements (in the USA) without legal challenges…

It is even possible to patent Urolithin A? Doesn’t seem possible to me.

[RapAdmin]

Patents like the ones Mitopure likely has are “use patents” - specific use cases, I think.

Obviously you can’t patent the molecule. I’m not a patent attorney, so I can’t comment on how defensible the patent cases are, but part of the benefit of Mitopure partnering with Nestle is that its a large company with deep financial resources, so small companies are going to have a tough time funding any litigation and hoping to win against Nestle. In a war of legal attrition, Nestle will win.

[John_Hemming]

I assume this therefore affects the advertising.

[adssx]

I think the patents are around the ways they found to make UA stable. Use patents are otherwise quite weak and often challenged.

Regarding UA and potential tiredness / sleep disruption: I think tiredness is okay, because as you said @John_Hemming it’s like exercise: as long as you don’t get injured, you can get tired, “bad” short term but long-term it’s better. The poor sleep though? I can’t see any analogy where poor sleep is good long term. That’s why people take rapa in the morning: to avoid sleep disruption. I’ll try again UA later this week with half the dose (250 mg instead of 500 mg) to see whether it still has adverse effects on my sleep. If it does, I’ll probably give up on UA until we have more data.

[John_Hemming]

I would personally expect something like UA to have a greater effect initially and then lesser effects. That means cycling it is quite likely to be a good thing. However, we shall have to see.

[RapamycinCurious]

@AnUser

The plasma levels of UA glucuronide (mean iAUC; p < 0.0001) as assessed by the 6 and 24 h time points (Fig. 5A) were six-fold higher in the Mitopure group than the PJ group.

So taking 500mg Mitopure resulted in somewhere between 2.4 and 6 times higher urolothin-A than drinking pomegranate juice. Pomella is going to give you a lot more punicalagins than drinking pomegranate juice would, so I would imagine UA levels would be higher than that. So the difference between Mitopure and Pomella should be <6X.

That’s not a crazy hypothesis, but it has some limits.

First, 20-40% of people drinking pom get no UA at all, so you have to assume you’re one of the lucky ones. (Yes, of course, your GI flora alters depending on what you feed it, but the right species of bacteria would have to be there in the first place: they don’t just evolve out of thin air once their food becomes available).

Second, it assumes that there is a linear response between increasing intake of UA precursors and UA production in the gut, which may not be the case: there could be an asymptote of some kind, whereby you get diminishing serum UA returns from increasing doses of precursors…

@AnUser

This is confusing, since this study showed 71 mg in 240 mL punicalagins in pomegranate juice, which increased [serum UA glucoronide levels to to 110 ng/mL]?

What is going on? 71 mg punicalagins in juice in this study had a larger increase than 300 mg punicalagins in the pomella study of 1 g pomella?

It would certainly depend on the microflora of the two testing groups, and probably other things in their diets; and, again, there could be an asymptote effect. Also, other compounds in the juice might affect UA production and/or absorption.

[RapamycinCurious]

@DrFraser

The other interesting thing has been the concern about Pomegranate constituents impairing rapamycin metabolism. I’m aware it isn’t exactly the same comparison, but I’ve found a couple of articles looking a this issue and it may not be that big of a worry. This article showed Grapefruit much more active.
https://cardiacos.net/wp-content/uploads/ArticulosMedicos/2007/2007-POMEGRANATE-JUICE-AND-CLEARANCE-OF-ORAL-OR-INTRAVENOUS-MIDAZOLAM.pdf

However other articles indicate area for concern with other drugs (in rats)
Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats - PubMed

Rapamycin is primarily metabolized by cytochrome P450 CYP3A4 - a recent article raises a bit of concern on this, likely with repetitive doses … Impact of Pomegranate Juice on the Pharmacokinetics of CYP3A4- and CYP2C9-Mediated Drugs Metabolism: A Preclinical and Clinical Review - PMC

The first study found no effects on midazolam PK in humans; the second study found an effect on carbamazepine AUC but not elimination half-life in rats; the third paper, a review, goes over 7 human studies on pom juice’s effects on the PK of several CYP3A4 -sensitive drugs, and found no effects on any of them. So this doesn’t seem to be a real concern, though it would be nice to see a repeat-dose study.

[AnUser]

@RapamycinCurious

Second, it assumes that there is a linear response between increasing intake of UA precursors and UA production in the gut, which may not be the case:

As shown in the study above, I think a 4x increase in pomella dose lead to a 2x increase in serum concentration. But yeah it might be capped. It is way too unreliable of a way to get UA imo.

@RapamycinCurious

Also, other compounds in the juice might affect UA production and/or absorption.

What about ellagic acid being the driver of EA production?

[tananth]

This product label does not even claim any Urolithin-A in the product: It is just Pomegranate extract labelled as “Urolithin-A production support”.

Correction: DrFraser correctly noted that the product label actually claims both 1000mg Urolithin-A + 1000mg Pomegranate extract. I assumed they were the same 1000mg, but the cover label says 2000mg, so they must be seperate items.

[AnUser]

Yeah, it contains compounds that are converted to Urolithin A by gut bacteria.
But it’s better to get UA directly, most likely, like from Liftmode.

[DrFraser]

That’s actually not what is claimed on the product label - it clearly states 1000 mg Urolithin A and in addition has 1000 mg of Pomegranate extract.

Now this is not brilliantly helpful, given that I’ve been unable to find any direct place to contact these folks for information on third party testing.

I thought I’d confirmed this one back some months ago - but realized I had not, and my attempts have been a failure; so I have no idea, it may have what it claims, or may not. The fact that this is widely sold through multiple countries and this group doesn’t have a website, and on their container there is absolutely none of the indications of any third party testing … bottom line … sorry I brought this one up.

The good news - it had me go through all the items I have on my list of sensible supplements, and I found one other that I had to remove as I couldn’t confirm third party testing.

[Jonas]

My general philosophy is if I can get it from healthy food, then I will skip the supplement as the industry is not regulated. Walnuts, almonds and berries are abundant in our diet, if one eats enough of those, would be a sufficient amount?

Here is a study about walnut and Urotithin A published in 2023:
“the polyphenolic ellagitannins (punicigalin) that are present in walnuts are converted by the microbiome to a panel of bioactive urolithin metabolites. In particular, urolithin A has been studied for its anti-inflammatory and anti-cancer properties.
In this pilot clinical trial, we evaluate the effects of walnut consumption (2-oz per day) on urinary urolithins and blood serum inflammatory markers, as well as on the transcriptome of normal colon and polyp tissue in 38 healthy obese and non-obese
subjects. Our in-depth computational analysis of metabolomics and proteomics data suggests that subjects with higher urolithin A formation show significantly lower levels of several key serological markers of inflammation, including C-Peptide, sICAM-1, sIL6-R, Ghrelin, TRAIL, sVEGFR2, MCP2, and Haptoglobin.”

[RapamycinCurious]

@Jonas

Our in-depth computational analysis of metabolomics and proteomics data suggests that subjects with higher urolithin A formation show significantly lower levels of several key serological markers of inflammation

Note the bolded phrase. They administered walnuts to 38 people, but only the subset with “higher urolithin A formation” got these benefits. We’ve already seen that the levels of UA in blood after pomegranate juice are far lower than after supplementing UA:

The plasma levels of UA glucuronide (mean iAUC; p < 0.0001) as assessed by the 6 and 24 h time points (Fig. 5A) were six-fold higher in the [500 mg] Mitopure group than the [one cup of pomegranate juice] group.
Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population | European Journal of Clinical Nutrition

… , and that there seems to be an asymptote in the rate at which UA precursors are converted to UA.

[Ericross2]

It’s interesting that you mention that autophagy disrupts your sleep. Ive done a number of four-day water fasts (autocorrect almost changed “four” to “dour” which changes the meaning a bit) and i sleep like a baby every time. There’s a small “community” of fasting aficionados and they seem to mention that sleep while fasting is very good. Maybe there are many other things beyond autophagy when fasting that other “autophagy-only” interventions don’t provide.

I’m curious to try Urolithin A but the mitopure cost seem prohibitive.

[Neo]

@Ericross2 Water only fast for me seems to lead to high quality and more (remembered) dreams. But I sleep less (while waking refreshed) during such fasts…

[L_H]

Interesting, thank you. In your opinion what could be behind the “Urolithin a formation” variation?

Are we just talking akkermansia levels or are there other factors we know about?

[adssx]

I’ve just had the call with the Mitopure “nutrition expert”. Useless. tl;dr:

• Fatigue and sleep concerns: “I’ve never heard that before. Usually, people report more energy.” “Mitophagy happens instantly; there’s no lag in the creation of new mitochondria.”
• Pulsing or not: “You can take it every other day, but every day is better.”
• How can I tell if it is working? “Subjective, more energy, better skin, gut health and cognition.”
• UA blood test: “It’s not offered anymore.”

I also emailed the above questions to the Mitopure team (care@timelinenutrition.com): they didn’t answer. (I know they got my email as they almost instantly answered a previous email to that same address about a bug on their website).

[Acarb]

I don’t believe they never heard that before. Fatigue is the well-known side effect of UA…

Urolithin A/Mitopure Released - Supplements

The next day I did feel overwhelmed with fatigue and had more muscle soreness than normal. Obviously, it could have been due to the harder training and but I am wondering if the supplement itself was the main reason for this.

Important question for Urolithin A: If your product promotes mitophagy, how can you be certain that it’s clearing out damaged mitochondria only and not healthy ones, as well? I would point out the following study:

Not surprisingly, mitophagy is closely coupled to mitochondrial biogenesis. Studies have demonstrated that mitophagy has the capacity to clear most of the mitochondria in cells. In fact, cells overexpressing PINK1 or Parkin can degrade all their mitochondria within 24-96 h in response to treatment with mitochondrial uncouplers 86, 92. It is therefore important for the cell to quickly replace the mitochondria that have been removed by mitophagy. Mitochondria have a significant reserve capacity that can be utilized upon demand 122. In response to modest mitophagy, myocytes can utilize their mitochondrial reserve to maintain energy production without affecting contractility. However, excessive mitophagy in the absence of mitochondrial biogenesis will result in the depletion of the bioenergetic reserve in the remaining mitochondria and subsequent cell death.

Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control - PMC

This is concerning. It’s interesting that it took about 3 days for the extreme fatigue to set in for both me and my mother, which is inline with the 24-96 hours noted in this study.

Do you know which pathway/s urolithin a works through? Would you agree that it might be overstimulating PINK1 and causing an excessive purge of mitochondria from the cells? That seems to be the most sensical explanation.

I want to clarify, this isn’t slight fatigue. This is “I need to find the nearest place to lie down and go to sleep immediately” fatigue. Until I am convinced otherwise, I am going to assume that, at least in my body, urolithin a is causing mitochondria, both healthy and unhealthy, to be expelled from my cells at such a high rate that mitochondria biogenesis can’t keep up and thus causes extreme fatigue.

purchased Mitopure softgels from Timeline Nutrition website and they included a free sample of their Mitopure + Protein packet (https://www.timeline…rotein-powder).I first tried this free sample on a Sunday, about 2 weeks ago from today.

The next morning, I woke up as though I didn’t sleep for a week and that I was hungover. It has been 2 weeks since then and I’ve been extremely fatigued, yawning all the time, and even persistent low grade headaches. I’ve never felt like this in my life. I could crawl into bed all day every day, and I’m normally and extremely active person. It takes all my will power to stay alert and focused for normal tasks, and the two times I attempted to go to the gym, with 10 mins I just want to go lay down in the corner and sleep. I think you get the idea…