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

[ORRAPA]

Is this a mispost? The medication being referenced seems unrelated to UA.

[Ulf]

Gemfibrozil was remarked on in the thread and I responded to that. Sorry for the confusion.

[adssx]

Targeting aging with urolithin A in humans: A systematic review 2024

Urolithin A (UA) is a gut metabolite derived from ellagic acid. This systematic review assesses the potential geroprotective effect of UA in humans. In five studies including 250 healthy individuals, UA (10 - 1000 mg/day) for a duration ranging from 28 days to 4 months, showed a dose-dependent anti-inflammatory effect and upregulated some mitochondrial genes, markers of autophagy, and fatty acid oxidation. It did not affect mitochondrial maximal adenosine triphosphate production, biogenesis, dynamics, or gut microbiota composition. UA increased muscle strength and endurance, however, had no effect on anthropometrics, cardiovascular outcomes, and physical function. Unrelated adverse events were mild or moderate. Further research across more physiological systems and longer intervention periods is required.

[sml491010]

Urolithin a Alleviates Schizophrenia-Like Cognitive Impairments in Male Rats Following Maternal Separation

UA treatment exerts anti-inflammatory effects by inhibiting microglial activation and the expression of proinflammatory cytokines TNF-α, IL-6, and IL-1β. The potential mechanism involves upregulation of BDNF protein expression and activation of the ERK signaling pathway.Conclusions: This is the first preclinical evaluation of the effects of UA on cognitive function in a schizophrenia model. Our results suggest that neuroinflammation, neurogenesis, and synaptic plasticity collectively contribute to cognitive changes in schizophrenia and that UA can reverse these processes. These insights open up new avenues for developing drugs to prevent and treat schizophrenia.

Urolithin a Ameliorates the TGF Beta-Dependent Impairment of Podocytes...

UA also reduced the typically elevated in HG expression of TGF-β receptors and activation of TGF-β signal transducer Smad2. Our results indicate that in podocytes cultured in conditions mimicking diabetic milieu, UA inhibits and reverses changes underlying podocytopenia in diabetic kidneys. Hence, UA should be considered as a po-tential therapeutic agent in podocytopathies.

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal...

UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA.

Urolithin A Targets Both PI3K/p-AKT/mTOR and p-c-RAF/MEK/p-ERK Signaling Pathways in Colorectal Cancer

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E–deficient mice

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@sml491010

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E–deficient mice | Acta Pharmacologica Sinica

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E–deficient mice

Interesting:

Apolipoprotein E-deficient (ApoE−/−) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg−1·d−1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization.

Thoughts on this @AnUser?

Also: does UA really increase nitric oxide production?

We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs.

[AnUser]

Mice model, about 90% of drug trials fail.
https://www.nature.com/articles/nrd.2016.136

Approximately 100 vaccines have been shown effective against an HIV-like virus in animal models, however, none have prevented HIV in humans.

Likewise, up to 1000 drugs have been shown effective for neuroprotection in animal models but none have been effective for humans.

…The success of the animal model in basic research can also be questioned based on the fact that, according to one report, only 0.004% of basic research papers in leading journals led to a new class of drugs.

For example, in part because the targets derived from animal models are not predictive for humans, the percentage of new drugs in development, after initial evaluation, that ultimately make it to market is somewhere in the area of 0.0002%.

Rapamycin and risk of cardiovascular disease

Because it is a different animal, you are not a rabbit, which is an entirely different complex system. What works in one tend to not work in another because there are so many different moving, causal parts. Here’s some examples and a good article on this topic: Approximately 100 vaccines have been shown effective against an HIV-like virus in animal models, however, none have prevented HIV in humans. Likewise, up to one-thousand drugs have been shown effective for neuroprotection in animal models but none have been effective for humans. Along the same lines, of twenty two drugs tested on animals and shown to be therapeutic in spinal cord injury, none were effective in humans. The success of the animal model in basic research can also be questioned based on the fact that, according to one report, only 0.004% of basic research papers in leading journals led to a new class of drugs. For example, in part because the targets derived from animal models are not predictive for hu…

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Thanks. Good to have in mind. So a mice model from an obscure Chinese paper…

[Steve_Combi]

We started our Max-5 experiment about 8 months ago and hope to see what the results are in our next DunedinPACE score.

It includes Urolithin A.

What is in the Max-5 experiment?

I based the dosing on the most current studies I could find. Very few are offering these interesting compounds in the doses used in the top studies due to cost. At retail, at these doses, it would cost $500 to $600 per month.

[adssx]

Any subjective / qualitative feeling so far?

[Steve_Combi]

It’s really hard for me to tell. I’ve felt pretty great for the past 15 months

I’d love to be able to say A is doing this, B is doing that but I can’t for sure, so I won’t. That’s why I’m anxiously waiting on our DunedinPACE and Symphony Age results from Tru…

I find that for most things I do, not a lot changes in how I “feel” except for the weight loss and the return to working out. Those 2 on top of everything else we do is a big factor. I think the “how” in the weight loss is quite important in the whole process.

Over all I do feel pretty amazing though my wife and I talk about that almost every day the past 15 months. We both amazed and “feel” better than we did when we were 50 and that was 18 years ago for me. I was in great shape then, walking miles a day, working out 4 days a week and ready for pretty much anything (had my last bar fight then LoL). I “feel” the same way today but with less effort and more calmness.

One of the things that has amazed me in the past 7 months is how rapid our recovery is from any extended, hard physical effort. I attribute that primarily to the other peptides we take.

My new motto is “better living through biochemistry” LoL!

[adssx]

Amazing to read this, contrats!

@Steve_Combi

That’s why I’m anxiously waiting on our DunedinPACE and Symphony Age results from Tru…

When will you receive them?

[Steve_Combi]

I ordered the kits Sept 5th and they have not arrived yet. Once I have the kit and send our samples back it usually take 3 to 4 weeks.

I think they are getting a bit swamped after the Kardashian bump

[Thiago]

I was lucky to have 12 months to try. I cannot say that I felt anything different. My Lactate threshold stayed quite similar on the bike (3,1 Watts/Kg) and my VO2 was also 62 on average.

I know this sounds very unbelievable, and I am a physician, but only in 2 weeks on rapamycin, my shoulder pain diminished by about 90%…

I don’t think we have enough data in humans to be paying 120 euros a month, investing your money on better quality food, a gym subscription it will give you much more

[Thiago]

@adssx

UA increased muscle strength and endurance, however, had no effect on anthropometrics, cardiovascular outcomes, and physical function.

if you read the studies, the lower dose in some endpoints was better than the 1g. I asked this to them, but they did not have an answer. also the gains were quite small

[Neo]

May I asked what the % next to each compound stands for

[helenas]

Matt Kaeberlein had a similar shoulder pain healing anecdote. Perhaps it’s time we do a clinical trial on shoulder pain and rapamycin.

[Steve_Combi]

The % indicates how much of the active ingredient is present.

Very few compounds are 100% of the active “ingredient”. Especially if it’s an extract. Extracts run anywhere from 5% to 50%. So it depends on how a compound is produced as to the % of the active ingredient. The other % 100 - 99 = 1% is of little concern in dietary supplements if you are getting it from a reputable mfg.

Also once a compound is made into a pill or put in a capsule various other things are added to allow the machinery to function properly. So no drug or dietary supp is 100% pure

[Jonas]

@Steve_Combi

What kind of blood markers you will be measuring for effects?

[Steve_Combi]

Getting blood work done here is not inexpensive if it’s outside the health care system and not prescribed by a Doc. So the only testing I do is the Trudiagnostic Complete test. Which I have done 4 in 3 years and will be doing our 5th soon.

We do get annual blood panels done but they are not “longevity” oriented, just the standard stuff. My last one was the best it’s been in 15 years. I’ll be getting that done again in January.

I’ve posted some of my results in my intro thread.

[adssx]

These Iranian meta-reviews found −5 to –8 mmHg reduction in systolic BP:

• The effects of pomegranate consumption on blood pressure in adults: A systematic review and meta-analysis 2024: “Our meta-analysis of the pooled findings showed that pomegranate consumption significantly reduced SBP (WMD: −7.87 mmHg; 95% CI: −10.34 to −5.39; p < 0.001) and DBP (WMD: −3.23 mmHg; 95% CI: −5.37 to −1.09; p = 0.003). Individuals with baseline SBP > 130 mmHg had a significantly greater reduction in SBP compared to individuals with baseline SBP < 130 mmHg. Also, there was a high level of heterogeneity among studies (SBP: I2 = 90.0% and DBP: I2 = 91.8%).”
• Impact of pomegranate juice on blood pressure: A systematic review and meta-analysis 2023: “Meta-analysis of 14 clinical trials (n = 573 individuals) demonstrated a reduction in systolic BP (SBP) with pomegranate juice (MD: −5.02 mmHg, 95% CI: −7.55 to −2.48, p < 0.001).”
• Effects of pomegranate juice on blood pressure: A systematic review and meta-analysis of randomized controlled trials 2017: “Quantitative data synthesis from 8 RCTs showed significant reductions in both systolic [weighed mean difference (WMD): −4.96 mmHg, 95% CI: −7.67 to −2.25, p < 0.001) and diastolic BP (WMD: −2.01 mmHg, 95% CI: −3.71 to −0.31, p = 0.021) after pomegranate juice consumption. Effects on SBP remained stable to sensitivity analyses.”

So, I would expect similar results with urolithin A. However I can’t find any evidence for hypotensive properties of UA in humans.