#81

I tried Mitopure 500 mg on 3 separate days, and it made me quite tired, and I had poor sleep on these days. So I stopped. I’ll try again later. Does it mean autophagy is kicking off? Should I lower the dose?

#82

I think poor sleep is a symptom of autophagy. Personally I am inclined to cycle autophagy. I would not necessarily lower the dose simply because it causes one night of bad sleep, but I would cycle it so that it does not do too much harm to sleep.

I don’t think we are yet at a stage where we know what the ideal levels of autophagy/mitophagy are.

I started on the biohacking thing because my sleep was awful and I now generally get enough sleep for me to function without being tired during the day. Ideally I want to be tired when I want to go to sleep.

However, I use Melatonin to extend my natural periods of sleep.

I have also ordered some Mitopure and may be able to compare Aeturnums version to that of TimeLine.

5 Likes
#83

Thanks a lot. It’s interesting because I clearly felt this tiredness and insomnia after taking Mitopure. I initially wanted to post it here but I refrained from doing so as I thought these were maybe random occurrences. Anyway, that’s another good reason to cycle Mitopure.

2 Likes
#84

I’ve taken Mitopure 4 or 5 times in the past month and that’s been my experience as well. An almost euphoric sedation the day of dosing. No trouble sleeping that I recall, but it seems to make me less motivated for a couple days afterward. I’ll try to monitor it more carefully in the future, but going forward I probably won’t take it more than once every couple weeks.

1 Like
#85

I have no idea what you should do in response to this symptom. It’s curious that you say you are both tired (fatigued? sleepy?) and get poor sleep — that’s incongruous.

I note that others are also reporting tiredness or fatigue, including people on Reddit as you noted in an earlier post. It also reminds me of the “euphoric fatigue” reported by @DeStrider when he takes rapa. This would make sense if they were both similarly autophagy inducers, but it’s my understanding from limited reading that UA is specificallly a mitophagy inducer and rapa induces macroautophagy; these two systems are regulated very differently, although of course macroautophagy sweeps up some mitos as the autophagosomes roam around the cell.

2 Likes
#86

I would expect mitophagy to reduce energy supplies in the short term potentially causing fatigue . If also melatonin production is reduced then sleep will be disrupted. This appears to be my situation.

2 Likes
#87

I don’t think we can say unhealthy life choices help anyone - we can say that some elderly people live lifestyles that would be expected to diminish their own length of life and that of others - but due to unclear factors, as everything is a statistical bell curve, some beat the odds. Those individuals shouldn’t be the example, but should be the exception. Where we are really interested is groups of people who are genetically diverse who live a similar lifestyle and have excellent outcomes outside of the population norm. Right now, I think, only Loma Linda meets this criteria as the rest of the blue zones are failing due to western lifestyle influences. I grew up around Loma Linda and my father ran the health study there until a year ago … for over 40 years. The lifestyles of those individuals are worth looking at, and considering what to mimic and what to pass on.
For anyone interested in the diet and lifestyle that generates best outcomes (without the addition of all the clever things we do here) - here is a great video of Simon Hill and my Dad …

5 Likes
#88

On the Gemfibrozil - mentioned in the video - I know the focus has been the Urolithin A (which incidentally, I’m not sure if anyone mentioned it has a cost effective option in the U.S., 240 capsules of 500 mg each for $72 in the Pepeior brand. Amazon.com

So back on Gemfibrozil - looked pretty interesting on his mouse model … but the human data not looking so brilliant: JAMA article on Gemfibrozil Outcomes

This is our challenge, what to act on … including Urolithin A. I doubt it is harmful … it might be helpful - but we don’t have outcome data.

2 Likes
#89

This might be a chicken or the egg situation, as consuming certain foods, including pomegranates can increase akkermansia too. My theory is as long as there is some akkermansia there to work with, it is possible to increase it–which should in turn increase Urolithin-A.

I went from very low akkermnsia to above average after ~6 months of taking pomella, a standardized pomegranate extract. This is per the Gut Zoomer stool test.

The akkermansia from pendulum seems to be transient and does not colonize unfortunately.

1 Like
#90

I would be careful of cheap Urolithin A on Amazon. I always like to see a certificate of 3rd party testing for my supplements. See here:
https://www.nutraingredients-usa.com/Article/2023/08/30/Timeline-raises-questions-about-Urolithin-A-supplements-on-Amazon

2 Likes
#91

Totally, 100% agree. (I think you might have misunderstood how I was using the point I made).

1 Like
#92

Whatever I took and it probably was about 500mg of urolithin

a) I started off mildly fatigued and got tired reading 1 chapter of Philip Ball’s book.

b) i fell asleep about 8.45pm then woke about every hour, but fitbit has not yet managed to analyse my sleep

c) I got back to sleep quite easily each time until 0.50 when i spent an hpa cycle awake before resleeping

I am now on the melatonin

1 Like
#93

Thanks, Dr. Fraser. This is a brand with next to no track record, and they don’t post COAs or have any QC certifications (such as with NSF or USP). Do you have some reason to believe that they are selling genuine urolithin-A?

1 Like
#94

Aeturnum UA on Amazon in the UK is GBP 59 for 30 grams. (On Amazon they claim a price reduction from GBP93.59 to GBP59)

Say USD 2.50 per gram.

The cited example is USD 0.60 per gram.

Timeline/Mitopure is USD 175 (including shipping and taxes) for about 15 grams. Say USD 12 per gram.

I would be concerned to get some confirmation at 0.60 per gram. I have bought some Timeline and will see what effect that has. It strikes me that Urolithin A is not something to take daily hence the Timeline price might be worth paying for certainty as quality, but I definitely had sleep disruption from Aeternum. (Which IMO is a good thing - because it implies something is happening).

With my experience last night (yesterday I tried Urolithin A and Citrulline both as additions to my stack) I am not intending to take any version of Urolithin A daily. It seems to sensibly fit into a cycling routine. I do need first to ensure that the sleep disruption was not caused by Citrulline, but it looks a reasonably good assumption that UA caused my sleep disruption. In the end because I went to bed early and read another chapter of Phillip Ball’s book during the night and took some melatonin I managed to get probably a total of 6 hours sleep which for me is sufficient to be fully functional (and to build a sleep reserve).

Because this was the first time of taking UA (if UA was the cause) although I have eaten Pomegranates before it may be the next time does not have such a big effect. However, I am going to stop Citrulline and UA and then try Citrulline to ensure that it is not citrulline that is part of the effect.

2 Likes
#95

I agree. Weird.

Similar experience. Again, only took it 4 times, with one or two days off in between but the same thing happened each time I took it:

  • 500 mg Mitopure in the morning
  • Then I was quite good. Until after lunch when I suddenly felt super tired. I had to do a 10-minute micro nap at 4 pm! I had never felt like this before in my life.
  • Went to bed at 10 pm. Fell asleep instantly (as usual) but then woke up regularly during the night. I had no difficulties going back to sleep each time I woke up though.

The day after taking it: totally normal. Potentially a bit better Zone 2 performance (as measured by my heart rate being a bit lower while biking to work in the morning and back home in the evening). Again n=1, 4 doses only.

I don’t get the point with melatonin. How would it interact with UA?

1 Like
#96

I don’t think Melatonin directly interacts with UA. However, I am working on the assumption that autophagy disrupts sleep at least initially. However this happens the form of mitophagy encouraged by UA also seems to disrupt sleep (on the basis of a number of N=1 experiments - none of which are placebo controlled). It appears to me by the symptoms that it is a lower production of pineal melatonin that is behind this.

The fatigue people get I think is from low ATP production (possibly also in the brain). That would not be surprising if a proportion of mitochondria were destroyed. Obviously as AMPK comes into play and gets new mitochondria created there is an improved outcome hopefully with more efficient mitochondria.

4 Likes
#97

I thought they had third party testing - but they clearly don’t. I’ll back away from the low price bargain on this one, as I agree, they should have such testing clearly evident. This brand is sold in a lot of markets. The number of options for Urolithin A on Amazon is impressive now. I went through >10 brands, and not a single one has anything better than being manufactured in a cGMP facility - which as far as I can tell solely has to do with a certain standard of manufacturing, and doesn’t seem to in any way relate to whether what is stated on the package is present. So I guess the best option is nothing or mitopure until there is a decent third party tested option.
Has anyone located a non-mitopure brand that has credible 3rd party testing. I’m not finding one.

3 Likes
#98

I wonder if simply eating pomegranate juice daily like Bryan Johnson, maybe having some pomella extract as well, will change the gut microbiome to produce Urolithin A over time from it in large amounts.

From Nootropicsdepot CEO:

Yeah, that’s the problem with urolithin-A. It costs a ton. We considered offering it, but it would be one of the most expensive products we offered. It’s hard to say how much urolithin-A you will get with a big dose of Pomella. It’s going to depend on the person. If you go by Mitopure’s data, it doesn’t seem a massive amount higher.

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

The analysis showed that circulating levels of UA glucuronide were significantly higher (p < 0.0001; 2.4-fold higher mean level) with Mitopure supplementation compared with drinking PJ (Fig. 4B).

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. I’d love to see a pharmacokinetic study comparing 500mg of Mitopure with one capsule of Pomella and six capsules of Pomella.

https://www.reddit.com/r/NootropicsDepot/comments/w9j9b2/comment/ii78gcw/?utm_source=share&utm_medium=web3x&utm_name=web3xcss&utm_term=1&utm_content=share_button

6 capsules a day here (900 mg a day) is about $40 a month:

1 gram a day powder is about $27 a month:

1 Like
#99

a) in terms of creating fatigue and then disrupting sleep Aeturnum works
b) i dont think it is best as an every day molecule.
C) when i get timeline i will report on any effects.

2 Likes
#100

I would think it is a quantity thing.