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

#238

I dug more on UA. Here are some interesting 2024 papers, not of the highest quality though:

  • Chinese preprint on mice: Urolithin A improves motor dysfunction induced by copper exposure in SOD1 G93A transgenic mice via activation of mitophagy 2024: “Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1G93A mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1G93A mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.”
  • Japanese paper, on mice: Urolithin A-mediated augmentation of intestinal barrier function through elevated secretory mucin synthesis 2024: “We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function.” (@Joseph_Lavelle @DrFraser for gut health?)
  • Chinese paper, on mice: Urolithin A Ameliorates Athletic Ability and Intestinal Microbiota in Sleep Deprivation from the Perspective of the Gut-Muscle Axis 2024: “UA is gavaged to C57BL/6 mice (50 mg kg−1 bw) before 48-h SD. The results indicate that pretreatment of UA significantly enhances motor ability and energy metabolism. The inflammation is suppressed, and intestinal permeability is improved after prophylactic treatment with UA. The decreased level of serum lipopolysaccharide (LPS) is concomitant with augmentation of the intestinal tight junction proteins. 16s rRNA analysis of colonic contents reveals that UA significantly reduces the abundance of Clostridia_UCG-014 and Candidatus_Saccharimonas, and upregulates Lactobacillus and Muribaculaceae. UA probably influences on gut microbial functions via several energy metabolism pathways, such as carbon metabolism, phosphotransferase system (PTS), and ATP binding cassette (ABC) transporters.”
  • German-Swiss RCT by the Mitopure team, 1,000 mg UA/day: Impact of urolithin A supplementation, a mitophagy activator on mitochondrial health of immune cells (MitoIMMUNE): A randomized, double-blind, placebo-controlled trial in healthy adults. 2024: “Intake of UA was safe and well-tolerated in the intervention cohort of 25 participants. After the study period, total peripheral lymphocytes and circulating NK cells were expanded in the UA group. Performing a complete immunophenotyping via spectral flow cytometry, we found that UA elicits immune remodeling characterized by broad changes of immune surface markers and mitochondrial measurements. CD8+ cells of participants in the intervention arm displayed greater mitochondrial mass, while preferably taking on a naive phenotype and expressing more Ki67. In addition, circulating monocytes exhibited a less inflammatory signature. UA intake reduced plasma levels of several proinflammatory cytokines. […] Collectively, our study constitutes an unprecedented intervention-based assessment of immune aging that globally characterizes the effect of UA on the immune system, proposing validation in future confirmatory studies and potential combination with cancer immunotherapy.” (@Neo wdyt?)
  • Small (n=10) short (10 weeks) Iranian RCT, 1,000 mg/day: Evaluation of Urolithin A Efficacy in Heart Failure Patients with Reduced Ejection Fraction: A Randomized, Double-blind, Crossover, Placebo-controlled Clinical Trial 2024: “All patients completed the study. The results failed to reveal any significant effect of UA supplementation on echocardiographic measures (LVEF, LVEDD, LVESV, and TAPSE). Plasma concentrations of pro-BNP, glucose, and CRP (p >0.05) were also not altered. Serum HDL-C levels were increased with UA compared with placebo (+6.46 ± 2.33 mg/dL, p =0.026), whereas other lipid indices (LDL-C, triglycerides, total cholesterol, and VLDL-C) remained unchanged (p >0.05).” => At least it’s safe? :man_shrugging:
  • Chinese paper, on mice: Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice 2024: “Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases.”

The Mitopure RCT looks quite good to me. It seems to confirm the Chinese studies on rodents (see also those: Urolithin A (UA) One of 4 Promising Agents 2024 by Brian Kennedy of NSU - #220 by sml491010 ).

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#239

Sorry I don’t, more than thst overall healthier immune system may help in cancer treatment and they seems to see some improvements along those lines :frowning:

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#240

A summary of some Longecity user experiences with fatigue when taking Mitopure:

Longecity user Decimus and his mother took MitoPure (urolithin-A). After a big increase in energy after taking it for the first time, he experienced extreme fatigue. His mother subsequently had the same experience. Longecity user genereader, who posted later in the same thread, wrote that Decimus’s sudden onset fatigue sounded like low potassium.
Subsequently, in a post on 26 December 2021, Decimus found that he indeed had a potassium deficiency and that when he resolved it, he had no more extreme fatigue issues after taking MitoPure. Some posts are reproduced and further discussed here:

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#241

If you are in an autophagic state you should expect to feel fatigue.

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#242

Yes. Good point. I should have added that to my post.

#243

Korean paper: Urolithin A prevents age-related hearing loss in C57BL/6J mice likely by inducing mitophagy 2024

Urolithin A (UA) prevents hearing decline with aging and preserves mitochondria in the auditory system.
UA effectively induces mitophagy and preserves molecules associated with mitochondrial metabolism in the auditory system.
UA can be used as a potential preventive agent by activating mitophagy against age-related hearing loss.

Are rodent models good for hearing loss?

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What is the highest frequency sound you can hear?
#244

Urolithin A has been very helpful to me. At the end of last year, I experienced sudden hearing loss in my right ear, with low-frequency hearing impairment. Although I later recovered, the sounds I heard remained distorted. After taking Time line Urolithin A for two months, I have almost fully recovered

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#245

Incredible! Did you take it for this purpose? Is it known to improve hearing (besides the recent article shared)? How much did you take? Daily?

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#246

I take 500mg of Urolithin A on an empty stomach every morning. In the first month, I often felt fatigued around noon and in the afternoon, so I would lie down to rest for a while. However, after about two months, that fatigue disappeared, and now I feel great. Due to work, my sleep time is often shortened, but whenever I wake up, I feel energized throughout the entire day.

#247

Ah I experienced this whenever I tried Urolithin A. That urge to have a nap around 2 pm was weird. So I stopped taking it. But it might be that it is doing its work as suggested earlier by @John_Hemming :thinking:

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#248

I think it is a timing of autophagy. I think autophagy has two effects that can be felt
a) Less energy whilst it is happening (not surprising as the recycled mitochondria will not be replaced immediately)
b) A disruption of sleep. (in that it disrupts circadian proteins).

As an interesting test I have just taken two mitopure UA sachets with a total of 1g of UA. Making reasonable assumptions about the half life and effect of GFJ I am perhaps in a state equivalent to taking 20mg of Rapamycin (enteric coated, but without accelerator) today.

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#249

By the way, why on an empty stomach? Mitopure recommends with the first meal: Timeline Longevity on Instagram: "When’s the best time to take Mitopure®? 🕕 ⁠ ⁠ Digestion slows down at night to give your body a chance to repair itself from the day’s stress. Taking Mitopure® with your first meal of the day ensures maximum absorption. (We like ours with a breakfast smoothie or cup of coffee. 😉)⁠ ⁠ When do you take Mitopure®?⁠ #timelinelongevity #longevity #healthyaging #mitopure #cellularhealth #wellnesstips"

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#250

Thank you for providing this information. I indeed take it on an empty stomach in the morning and have achieved the expected results. I will consider the suggestion provided by the official source to take it with food. Thank you!

#251

If it is good for hearing loss, it can probably be good for tinnitus as well. Many people complain of tinnitus and unfortunately there is no known effective cure.

#252

It’s still questionable and very very expensive. I was lucky enough to be able to test for almost 12 months. What did I feel? … Nothing. No difference also in my blood test.
I consider myself a healthy person, so maybe this is the point. It’s probably very low gains.

But I do see and read several good papers about it.

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#253

After researching UA and seeing how costly Mitopure was i purchased UA made by Neurogan in the USA… 700 mg per serving… 42,000mg per bottle. It gave me incredible energy but I had to stop taking it because of incredible insomnia. I felt like i never had to sleep again! Not good for me and i wanted to see if it could stave off dry macular degeneration. I am going to try rapa next since it has good results in mouse studies. There is only recently approved injections for dry AMD turning into geographic atrophy and doctors are reluctant to give them since the side effects are numerous and could cause total blindness.

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#254

UA is thought to be an mTOR inhibitor. It has a half life of 17-22 hours. I wonder, therefore, if it causes similar effects to Rapamycin on blood glucose, lipids and the immune system. I am tempted to try this out using a highish dose of UA whilst wearing a CGM to see if anything shifts. If its mode of action is via mTOR it is clearly quite a bit weaker given dosing, but it is probably synergistic.

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#255

I’m always looking for more energy, so I’m going to give the Neurogan version a shot. Thanks for the referral.

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#256

Chinese paper: Assessment of Urolithin A effects on muscle endurance, strength, inflammation, oxidative stress, and protein metabolism in male athletes with resistance training: an 8-week randomized, double-blind, placebo-controlled study 2024

We recruited twenty male individuals for this study (average age: 24.1 ± 1.59 years, average height: 177.4 ± 5.92 cm, average weight: 84.55 ± 2.72 kg, average training experience: 4.40 ± 1. 07 years), all of whom had engaged in long-term resistance training.
Participants were instructed to consume two capsules of UA(Mitopure, USA) daily(1 g/ day), each containing 250 mg of UA, after both breakfast and dinner on a daily basis.
After 8 weeks of UA supplementation, compared to baseline measurements, the UA group exhibited increases in 1RM bench press and squat, although these changes were not statistically significant (Δ = 3.00 ± 0.17 kg, p = 0.051, Δ = 1.35 ± 2.73 kg, p = 0.499). However, significant improvements were noted in Maximum Voluntary Isometric Contraction (MVIC) and repetitions to failure (RTF) performance (Δ = 36.10 ± 0.62 NM, p = 0.000; Δ = 2.00 ± 0.56, p = 0.001). When compared to the placebo group, the UA supplementation for 8 weeks led to an increase in 1RM bench press and squat, although statistical significance was not reached (Δ = 3.50 ± 0.79 kg, p = 0.462; Δ = 2.55 ± 1.36 kg, p = 0.710). Furthermore, the group receiving UA supplementation, compared to the placebo group, showed significant improvements in MVIC and RTF (Δ = 43.50 ± 0.77 NM, p = 0.048; Δ = 2.00 ± 1.22, p = 0.011), indicating that the UA group exhibited superior performance enhancements in these metrics compared to the placebo group. After 8 weeks of UA supplementation, the UA group showed a significant decrease in 3-methylhistidine (3-MH) compared to baseline measurement (Δ=-2.38 ± 1.96 μmol/L, p = 0.049). Additionally, the UA group exhibited a significant increase in C-reactive protein (CRP) compared to baseline (Δ = 0.71 ± 0.21 mg/L, p = 0.001). However, there was no significant changes observed in Interleukin-6 (IL-6) (Δ=-1.00 ± 1.01 pg/mL, p = 0.076), or superoxide dismutase (SOD) (Δ=-0.004 ± 0.72 U/mL, p = 0.996) compared to baseline in the UA group. When compared to the placebo group, there was no significant difference observed in 3-MH in the UA group (Δ=-3.20 ± 0.31 μmol/L, p = 0.36). In terms of inflammation markers, the UA group exhibited a significant decrease in CRP (Δ=-0.79 ± 0.38 mg/L, p = 0.032) compared to the placebo group, whereas there was a decrease in IL-6 without statistical significance (Δ=-1.75 ± 0.45 pg/mL, p = 0.215). Furthermore, the UA group showed a significant decrease in SOD compared to the placebo group (Δ=-4.32 ± 0.90 U/mL, p = 0.041).
After 8 weeks of UA supplementation at 1 g/day, resistance-trained male athletes showed improvements in muscle strength and endurance. Additionally, UA supplementation was also associated with reduced oxidative stress levels and a decrease in inflammation response levels.

So CRP increased in both groups but more so in the placebo? :thinking:

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#257

The problem with CRP as a measurement is that infection causes it to jump. Hence you need to identify what the uninfected value is by doing a number of measurements.

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