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

[SNK]

@JuanDaw

There is also the libidinal effect posted about earlier.

Yes it turns you into a “horse” lol

[Neo]

@Jonas

It has a similar lifespan increase to Rapamycin (Brian Kennedy, NSU). One of 4 promising agents that he is working on (Dec 23)

@John_Hemming what is your perspective on this - it’s seems like the company who has invested like crazy in this and has many of the patents - is primarily arguing that it supports healthy mitochondria and that it helps with needed mithophagy

They say there are hundreds of papers on this:

And link to many of the key ones here - that seem to be in high impact journals

Our studies

[Neo]

@Lowroad

Is there a more affordable source than Mitopure?

1. Given the clinical study that shows that a daily dose of Mitopure leads ~6x more UA than the subset of the population that can get UA from pomegranate after drinking a full glass of 100% pomegranate juice I wonder if we would be find by just taking a quarter or even a sixth of the dose of this? (Could be done by taking on of the two “daily pills” every other day or every third day).

2. Or given that much of the mithophagy happens during the first month or two (see their web page, we should see if the papers back that up) if might be bought one takes it everyday day for a month or two and then wait another 4-6 months before doing it again (kind of like senolytics or how some of us do fasts now and then, but not all the time).

3. Or perhaps we could even combine some version of (1) and (2) above?

—-

Does anyone know if we can do any of the blood tests they did in the human studies to check our levels?

[John_Hemming]

I looked a buying some at one stage. I coyld not then get it. Hence it remains in maybe.

[Neo]

@Neo

• Or given that much of the mithophagy happens during the first month or two (see their web page, we should see if the papers back that up) if might be bought do so this day for a month or two and then wait another 4-6 months before doing it again (kind of like senolytics or how some of us do fasts now and then, but not all the time).

Re above cost saving strategy, some form of intermittent dosing does seems to have some merit based on this paper and post that I just saw on a different thread (though I have not read the paper yet, one of the forum said it was independent without conflicts of interest).

Does anyone know how to think about the one week on, one week off in mice could/should be translated to humans:

@Vlasko

In the newly published study linked to below from the journal Geroscience, researchers Josué Ballesteros-Álvarez et al, found that Urolithin A can reduce amyloid beta levels and improve cognition in a rodent Alzheimer’s model. But they also tested the compound’s effects on lifespan in normal mice, finding that it substantially increased lifespan. They found that, “UA, likely via its actions as a autophagy inducer, is capable of removing Aβ from neurons and its dietary administration prevents the onset of cognitive deficits associated with pathological Aβ deposition in the 3xTg-AD mouse model as well as extending lifespan in normal aging mice.” […]

[W]e investigated whether long-term intermittent administration of the compound would be able to enhance lifespan in normal aging mice. For this purpose, we fed UA on alternate weeks (1 week on, 1 week off) to a cohort of male C57BL/6 mice starting at 3 months of age. We found that dietary supplementation of UA significantly increased survival. The median lifespan at 80th percentile mortality was extended 18.75% from the UA feeding start point. (emphasis added)

[Neo]

@John_Hemming

I coyld not then get it. Hence it remains in maybe.

The more I look into it the more promising it seems!

See here - It may be marketed by Nestle under a different name in the UK instead of as Mitopure

Urolithin A Extends Lifespan in Mice

I think that as part of the partnership between Nestle and Amazentis, Amazentis perhaps focuses on the NA market, and Nestle the rest of the world?

[Neo]

For those in the US it looks like Mitopure can be bought via one other route - via the Nestle related product, Solgar brand family - @John_Hemming and others outside of US perhaps you can find that brand

https://cellularnutrition.solgar.com/cellular-strength

[John_Hemming]

I have found Aeternum powder on Amazon. I will give it a shot. I am planning on taking Rapaycin on Tuesday so I won’t take the Urolithin A for a bit of time. I would like to see if it has any measurable impact.

[adssx]

@Joseph_Lavelle

Interesting that the lower dose of Urolithin A was better for flies.

Interesting

Amazentis has two ongoing trials of Mitopure

• “Urolithin A Supplementation to Boost Immune Health”: “Softgel containing 250mg of Urolithin A (Mitopure) Single oral dose administration (4 softgels) to be orally administered daily according to the randomization for 28 days”
• The Mitopure Challenge to Detect Levels of Urolithin A in Dried Blood Spots: comparing 100% Pomegranate juice to Mitopure

The US National Cancer Institute (NCI) is also running a trial Placebo-Controlled Trial of Urolithin A Supplementation in Men With Prostate Cancer Undergoing Radical Prostatectomy, URO-PRO Trial.

[adssx]

Those who tried Mitopure (@Walter_Brown @Financial_Term_Struc @tananth and maybe others?): what were your conclusions?

@Neo: have you tried it? “given that much of the mithophagy happens during the first month or two” Do you say this based on this page and their claim “Day 30: New Healthy Mitochondria”? We need to look at research papers indeed, and most of them are published by Amazentis… I’d like to see independent studies on rodents or humans.

[Walter_Brown]

Didn’t feel any noticible difference but I found a cheaper generic available in the UK available on amazon: Aeternum UA - Urolithin A Powder - 15g : Amazon.co.uk: Health & Personal Care

Taking 500mg per day. Rather safe than sorry (as the saying goes )

Also - import duties were a killer.

[adssx]

Thanks. Ah, I didn’t think about import duties; I might wait for Mitopure to be available in the UK then…

[Neo]

@adssx

have you tried

I’d like to see independent studies on rodents or humans.

Not yet, I just started really looking into it this week a little bit

This paper was said to be independent and may be one place to start and see what literature they cite:

Urolithin A Extends Lifespan in Mice

In the newly published study linked to below from the journal Geroscience, researchers Josué Ballesteros-Álvarez et al, found that Urolithin A can reduce amyloid beta levels and improve cognition in a rodent Alzheimer’s model. But they also tested the compound’s effects on lifespan in normal mice, finding that it substantially increased lifespan. They found that, “UA, likely via its actions as a autophagy inducer, is capable of removing Aβ from neurons and its dietary administration prevents the onset of cognitive deficits associated with pathological Aβ deposition in the 3xTg-AD mouse model as well as extending lifespan in normal aging mice.” […] [W]e investigated whether long-term intermittent administration of the compound would be able to enhance lifespan in normal aging mice. For this purpose, we fed UA on alternate weeks (1 week on, 1 week off) to a cohort of male C57BL/6 mice starting at 3 months of age. We found that dietary supplementation of UA significantly increased su…

[adssx]

@Neo

This paper was said to be independent and may be one place to start and see what literature they cite:

This follow-up preprint from last month is very good as well: Amyloid β accelerates age-related proteome-wide protein insolubility.

In their previous rodent study, they used 25 mg/kg of UA in alternate weeks (1 week on, 1 week off) in males. ChatGPT tells me it would be about 120 mg for a 60-kg human. According to ChatGPT, humans should keep the 1-week cycle. So that’s about one Mitopure pill (250 mg) every other day for a week, then off. So about 90 Mitopure pills per year. So $125 to 200/y (as they sell by 60 and not by 90). However, in the rodent study, they started UA supplementation at 3 months of age, that’s 9 yo for a human. So this low dose may only work if started super early. Maybe you can do a first “big boost” of daily high-dose of Mitopure for one to three months and then keep the low “maintenance dose” every other day with one week on, one week off. Alternatively, ~2 Mitopure pills weekly. Or ~4 every two weeks.

[Neo]

@adssx Good find on that new paper.

Yes, something like this sounds interesting.

For me I’ll have to figure out how to combine the “waves” with my fasting periods.

Re the scaling from rodent to human - might be good to do the math outside of AI as they still can hallucinate / make things up. There are a couple of places on the forum that discuss how one can do those calcs.

I’d also triangulate it from the other direction - how much do we think should be safe and cost acceptable - and if that is higher than the rodent scaling calculation perhaps choose to dose somewhere in between the two levels.

[Neo]

Is the Nestle/Solgar version not available in the UK?

[Neo]

@adssx

Detect Levels of Urolithin A in Dried Blood Spots: comparing 100% Pomegranate juice to Mitopure

Does anyone know any way to test these levels - either via blood spot or normal blood testing somewhere?

[adssx]

@Neo

Re the scaling from rodent to human - might be good to do the math outside of AI as they still can hallucinate / make things up. There are a couple of places on the forum that discuss how one can do those calcs.

I just used Table 1 here. 25/12.3*60 = ~120. I mentioned ChatGPT about the one-week on/one-week off schedule, as I thought that because one week of a mouse is like 4 months of a human, we would need longer periods of pause. But ChatGPT said no (without much reasoning).

@Neo

I’d also triangulate it from the other direction - how much do we think should be safe and cost acceptable - and if that is higher than the rodent scaling calculation perhaps choose to dose somewhere in between the two levels.

Safety: no idea at all. We have almost zero long-term data on UA. Maybe we have long-term data on pomegranate juice consumption, or pomegranate supplement use.

@Neo

Is the Nestle/Solgar version not available in the UK?

Nothing on their website: https://solgar.co.uk

I emailed them.

Still good to know for Americans that Mitopure is a bit cheaper on Nestle’s website: https://www.nestlenutritionstore.com/shop-by-categories/adults/cellular-nutrition.html

Also, for anyone interested: BREW30 gives 30% discount on Mitopure Softgels | Timeline Nutrition (not promoting it, just saying)…

[adssx]

A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer’s Disease 2022

I don’t know if this is a good journal or team but this paper argues that Urolithin A + green tea extract EGCG is even better than UA alone.

EDIT: the same authors made the same claim one year earlier in a way better journal (Pharmacological Research): Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease 2021

We recently optimized the doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. […] Further, urolithin A showed strongest protective effects among all enhancers tested in AD. Our combination treatments of urolithin A + EGCG, addition to urolithin A and EGCG individual treatment revealed that combination treatments approach is even stronger than urolithin A treatment. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with AD.

[adssx]

As UA inhibits mTOR, is it better to cycle it? How often? Is it better to take it in the morning? In the evening? With or without food?

In terms of half-life, I found this:

• “The washout period was considered effective and not to have influenced the results during the crossover design, as UA has a half-life of ~24 h with elimination following a single oral dose occurring after between 3 and 4 days” (Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population 2021)
• “It showed a relatively long-half life (t1/2 = 17–22 hours), most likely due to an active enterohepatic recirculation.” (Impact of the Natural Compound Urolithin A on Health, Disease, and Aging 2021)
• “The biphasic kinetics was shown for metabolites, probably due to enterohepatic circulation. The half-life (t1/2) ranged from 17 to 22 hours for the parent compound and urolithin glucuronide, while it was slightly longer (25-58 hours) for urolithin A sulfate.” (Ellagic Acid-Derived Urolithins as Modulators of Oxidative Stress 2020)

(to compare: “The half-life of rapamycin is 58–63 hours (~ 3 days).”)

@adssx

A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer’s Disease 2022

In this mice study they use 2.5 mg/kg UA (that’s 10x less than in the 2023 Buck Institute paper that showed life extension) + 25 mg/kg green tea extract EGCG. The UA+EGCG combination seems about 15% more potent than UA alone looking at figures and tables (guesstimate). Interestingly, they still cycled UA even with this low dose: “3 times per week for 4 months.” And they still had good results.

If my above reasoning is correct (maintenance dose of 90 Mitopure pills per year), then with EGCG, you can instead use only 77 pills. You can probably even decrease to 60 pills/y, meaning one Mitopure Softgels sachet ($125 to which you need to add the cost of EGCG). Of course, we don’t have evidence yet evidence this dosing regimen in human adults would have any benefits.

I don’t know how to make sense of the 10x difference in terms of dose between the two studies. The authors of the 2022 paper (that used the lowest 2.5 mg/kg dose) wrote: “We recently optimized doses of mitophagy enhancers urolithin A, actinonin, tomatidine and nicotinamide riboside in HT22 cells” and they cite this paper: Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease 2021. They only tested 0, 2, 5, and 10 μM of UA directly on cells, and there was a quasi-linear dose-response relationship. Would 100 μM be even better?

In the Mitopure study on middle-aged humans, they compared 500 mg (the commercial Mitopure dose) to 1,000 mg, and found that 1,000 mg was better.

In this 2023 study (by Amazentis) they even “supplemented with UA oral targeting 50mg/kg/day” on mice (Study 2)! Urolithin A induces cardioprotection and enhanced mitochondrial quality during natural aging and heart failure (preprint)

Anyway, I bought one Mitopure pack (60 pills). I’ll see what I do. I’m hesitating between (with or without EGCG in each case, TBD):

• Following the recommended Mitopure regimen (500 mg/d = 2 pills) for a month then see or,
• 1 pill (250 mg) every other day, one week on, one week off,
• 2 pills (500 mg) per week.

Feedback welcome

Also, Solgar UK answered my email regarding Mitopure:

Unfortunately we don’t sell this product here in the UK. It sells well abroad but there isn’t enough demand for it in this country at the moment.
A lot of our products are available to buy from reputable online retailers such as Amazon, or from specialist import/export retailers.

If other UK residents email them we could maybe convince them that there’s enough demand. poke @Walter_Brown