According to @John_Hemming 's theory that means they’re working and sleep disturbance should stop after a few days or weeks.
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Yes, if they are causing additional autophagy that is expected to raise issues with sleep.
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Thank you for this explanation, John. I have had sleep disturbances with rapa and wondered if this was a negative, signifying that I was in the category of people who would not have benefits from Rapamycin. Given your theory about UA sleep disturbances being a sign of autophagy, would you extend that same theory to sleep disturbances with Rapamycin?
If so, is this mostly conjecture or is there data to support this theory?
Third question, how do you explain the many people who immediately have great sleep and energy with Rapamycin? Do you think that they have less cellular debris to auto phagocytose? And did I understand that eventually people will regain their sleep while taking the UA gummies (and/or Rapamycin)? Sorry to pepper you with so many questions, but I’m very interested to learn.
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There was paper that linked autophagy to the disruption of circadian proteins. I have had a quick search, but not found it. I have probably posted it previously.
It appears that this is temporary. Sleep is quite a complex process which can be affected in many different ways.
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Why would you think they increase autophagy? Have you seen any studies indicating that urolithin A can increase autophagy in vivo?
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Not sure what the “they” is here.
There was a paper (and I don’t mind trying to find it, but it is not that easy to find) which said autophagy caused the disruption of circadian proteins
I have done a bit of experimentation with high dose UA which seemed pretty futile unlike high dose rapamycin.
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Sorry for the confusion. “They” was not the best word, I should have said “it”. I was referring to Urolithin A since I took your comments above as if you think that increases autophagy and am wondering why.
Regarding autophagy disrupting circadian proteins, I’m not questioning that as being true.
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UA may help, but it is not on my list of autophagy agonists. I tried quite a high dose earlier this year and it did not seem to move the needle. Its one of those things that may be helpful, but not that useful.
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Plant-based phenolic components and their metabolites, such as ellagic acid (EA) and urolithin A (UA), possess a variety of biological activities. Here, we investigated the antiviral effect of EA and UA against HSV-1 infection, a virus that causes peripheral infection as well as brain inflammation. Both compounds demonstrated potent antiviral activity. Network pharmacology and molecular docking analyses identified protein kinase CK2 as a common target for their action. We showed that both EA and UA were direct CK2 inhibitors using an enzymatic assay, an observation substantiated in cell culture studies. The effect of EA and UA on HSV-1 infection through CK2 was confirmed in CK2 (CSNK2B) knockout cells. Finally, we demonstrated an antiviral effect using a murine model of herpetic stromal keratitis. EA or UA treatment reduced HSV-1 shedding and prevented viral neuroinvasion. CK2 is a critical enzyme involved in cell proliferation and the proinflammatory response. In addition to identifying CK2 as a putative target of EA and UA antiviral activities, this study also demonstrates that EA and its metabolite UA have the potential to reduce infection-associated neurodegenerative inflammation.
HSV-1 = Herpes Simplex Virus Type 1
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Urolithin A alleviates dopaminergic neurodegeneration and improves cognition in the sub-acute MPTP PD mouse model
Urolithin A alleviates neuronal injury and inflammatory responses within the hippocampal region in MPTP-treated mice
Urolithin A rescues synaptic damage and mitigates dendritic spine loss in the hippocampus of MPTP-treated mice
Urolithin A activates the AKT/CREB/BDNF signaling pathway in hippocampus
Urolithin A improves cognitive function in A53T α-synuclein transgenic PD mouse model.
It’s a mouse study but they used two different rodent models (one toxin and one transgenic alpha-syn), which strengthens the finding.
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Other recent UA papers (not of the highest quality):
UK preprint: The effects of urolithin A supplementation on muscle strength, muscle mass and physical performance in humans - a systematic review 2025
We identified 194 titles, of which three studies were eligible for inclusion. Included studies recruited 174 participants, and mean age ranged from 24 to 72 years. All studies were placebo controlled and examined doses of 500mg/d or 1000mg/d of Urolithin A. Overall risk of bias of included studies was low; urolithin was well tolerated with good adherence to therapy. Four of 12 included outcome measures showed a statistically significant positive effect of urolithin A on muscle strength and physical performance, with a further seven outcomes demonstrating non-significant improvements in muscle strength or physical performance. Pooled analysis of six-minute walk distance from two trials showed a non-significant improvement in walk distance with urolithin A (23m [95% CI −6m to 52m, p=0.12, I2=0%]). One study measured muscle mass but found no improvement in mass with urolithin supplementation.
Chinese paper + Mouse + MDPI: Urolithin A Exhibits Antidepressant-like Effects by Modulating the AMPK/CREB/BDNF Pathway 2025
Chinese paper + Mouse + Random journal: Methylated urolithin a attenuates lipopolysaccharide-induced memory impairment and behavioral disorders by inhibiting mitochondrial inflammation through the Drp1/HK1/NLRP3 pathway 2025
Indian paper + Mouse: Urolithin-A supplementation alleviates sepsis-induced acute lung injury by reducing mitochondrial dysfunction and modulating macrophage polarization 2025
Indian paper + Toxin model + Mouse: Urolithin improves α-synuclein aggregation and DNMT1 expression in rotenone model of Parkinson’s disease 2025
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These two posts are very compelling reasons to try urolithin A. I presume you’re taking it? What brand are you using?
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I tried it. It’s an interesting compound. I’m not sure it crosses the BBB well, though. That’s why I assume Timeline is developing Urolithin A-derivatives that cross the BBB. I’m not taking UA anymore. I might give it another try in the near future. The only “official” UA brand is Timeline.
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I haven’t managed to pull the trigger for Timeline’s $$$$ UA. @adssx do you have any idea when their new product might be available?
@AustraliaLongevity I don’t know if they ship to you, but I was told this stuff is legit, but I’m very very skeptical. Having said that, at 30% off, I did just order some this morning (see paste below for details… they have powder and capsules)
I was buying it from gethealthspan because I felt I could trust it being real (not cheap but much less than timeline).
@Joseph_Lavelle I thought you’d find it interesting that after your podcast with them, they no longer seem to be selling UA (I have emailed them to confirm this… probably because they are selling their new house brand supplements)
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Which new product?
I think that Timeline has many patents in UA so you’re unlikely to find good quality ones from other brands than Timeline (or related brands such as Solgar).
I appreciate that feedback. Hmmm, I wonder if I should try to cancel my order.
When you said
“ That’s why I assume Timeline is developing Urolithin A-derivatives that cross the BBB”, I mistakenly thought you were saying they have a new one in development.
Interesting! As you said, I see that Solgar contains the branded mitopure. I also see there is almost no savings through them, $50 for a 14 day supply (2 caps is 500mg and 28 in the bottle).
This will take years of development.
@Steve_Combi
Hi Steve,
It occurred to me that you offer UA, so perhaps you are familiar with Timeline’s UA patents and know what makes theirs a little different. Can you shed light on how others might also offer effective UA.
I doubt there is much (if any) difference as long as the purity of the compound is high.
Urolithin A CAS # 1143-70-0
Ours is 97% pure. This is a “research grade” level of purity, which anyone with commercial interest can purchase. Sigma sells small quantities of compounds for reference when testing.
If you need to get a compound tested by a 3rd party lab, they need to have a reference to compare the item to be tested to. If a lab has never tested a particular compound they need to buy a reference sample, or in my case they charged me for the reference sample. One place to get reference compounds from;
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AIUI and I have not checked the patents relate to what it is used for. Anyone can make it and sell it, but they must not market it for anything that conflict with the patent.
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