Background: Peripheral nerve injury (PNI) often results in irreversible functional deficits due to incomplete regeneration, mitochondrial dysfunction, and chronic neuroinflammation. Current therapies insufficiently target mitochondrial stress and inflammasome activation. Urolithin A (UA), a gut microbiota-derived metabolite of dietary ellagitannins, possesses both anti-inflammatory and mitochondrial protective properties, but its efficacy in PNI is not well defined. Objective: To evaluate whether UA enhances peripheral nerve regeneration by activating TFEB-mediated mitophagy and inhibiting NLRP3 inflammasome activation.
Methods: Schwann cells (RSC96) were treated with UA (5ā20 Ī¼M) in vitro to assess mitochondrial function (JC-1, MitoSOX, ROS), NLRP3 activation (immunoblotting, immunofluorescence), and autophagy markers (LC3B, Parkin). In vivo, rats with sciatic nerve crush injuries received UA (1.0ā2.5 mg/kg), and effects on functional recovery (SFI), histology (HE, LFB), remyelination (TEM), and muscle preservation were evaluated. AutoDock Vina was used for molecular docking of UA with TFEB.
Results: UA improved mitochondrial homeostasis, reduced ROS, and suppressed NLRP3-driven pyroptosis in Schwann cells. In vivo, UA enhanced functional recovery, axonal regeneration, remyelination, and muscle preservation. UA promoted TFEB nuclear translocation, increased autophagy-related markers, and inhibited NLRP3 activation. Its effects mirrored those of the NLRP3 inhibitor MCC950 and were reversed by autophagy inhibition (3-MA).
Conclusion: UA serves as a dual-action therapeutic, coupling mitophagy induction with inflammasome inhibition, and effectively promotes peripheral nerve repair. Its natural origin, safety, and efficacy highlight its translational potential for PNI treatment.
Furthermore, while current preclinical research demonstrates that UA can cross the BBB [28], brain concentrations reach only approximately 10% of plasma levels, significantly limiting UAās therapeutic efficacy [27].
Citing:
Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging 2024: āMass spectrometry (UPLC-ESI-QTOF-MS) of perfused brains, and plasma samples as positive controls, showed that free UA crossed the blood-brain barrier and reached the central nervous system (Fig. 4a). Concentrations of conjugated UA-sulfate were much lower in the brains of UA-treated animals than in plasma samples (Supplementary Fig. 7a), while UA-3-glucuronide was detected only in plasma (Supplementary Fig. 7b), suggesting a possible in situ deconjugating mechanism from UA-sulfate to UA, and an inability of UA-3-glucuronide to cross the low-permeability blood-brain barrier. Since the perfused brain samples were not subjected to enzymatic hydrolysis, this is the first study showing unequivocally the precise Uro metabolic forms that reach the brain. Thus, these results support previous hypotheses suggesting the participation of free UA as a direct effector in brain tissues31.ā
In this research, we found that UA improved cognitive dysfunction and reduced AĪ² deposition in APP/PS1 mice. Furthermore, UA activated autophagy and upregulated the levels of autophagy-related proteins in both APP/PS1 mice and AĪ²1ā42-injured N2a and PC12 cells. At the same time, UA down-regulated the phosphorylation level of PI3K/AKT/mTOR and up-regulated the phosphorylation level of AMPK in APP/PS1 mice and AĪ²1ā42-injured N2a cells and PC12 cells. In addition, UA down-regulated VDAC1, consistent with the effect of VDAC1 antagonist DIDS (4ā²-diisothiocyano-2,2ā²-disulfonic acid stilbene). Importantly, the UA-induced activation of autophagy and modulation of the PI3K and AMPK pathways were reversed by VDAC1 overexpression.
Other labs found positive results on worms so I wouldnāt attach too much importance to one negative result on worms. SGLT2i failed on worms with Ora.
āIn terms of quality, tests in 2025 by the group SuppCo found that only four out of 10 products contained their claimed amounts (or somewhat more of urolithin A: CodeAge Liposomal Urolithin A capsules, Neurogan Health Pro+ Urolithin A, Pure Encapsulations Renual, and Timeline Mitopure Urolithin A. ConsumerLab analyzed the cost to get 500 mg (as listed) of urolithin A from these four products and Neurogan was, by far, the least expensive at just 83 cents (from one 500 mg capsule), while the cost was $3.33 from Codeage (two 250 mg capsules), $3.75 from Timeline (two 250 mg softgels), and $4.87 from Pure Encapsulations (four 125 mg capsules). Timeline and Pure Encapsulations were the only products to list Mitopure (see above) as their source of urolithin A and each included additional ingredients such as resveratrol and CoQ10. Five products were discovered to contain less than 0.1% of their listed urolithin A: Migcopat NAD+ Urolithin A, Pepeior Urolithin A+, Sundhedsliv Urolithin A 1500 mg, Totaria Health Urolithin A NAD+ CoQ10 Resveratrol PQQ, and CystoRebalance Urolithin A. One product, PureHealth Max Urolithin At, contained only 2% of its listed urolithin A. Contamination with heavy metals was found not to be an issue.ā
FWIW, I was using gethealthspanās UA, but recently switched to Aeternum for their better price
I read some comments on this forum saying they thought it was a legit brand, however it was only a handful of comments. (If anyone thinks differently, please chime in!)
I bought it during one of their many sales. Note, each serving is 1000mg, and each pill is 500mg, so itās a better value that it appears at first glance.
also, no fillers.
And, I see no evidence that Timeline contains CoQ10? I am curious because I need to take that and getting two things in one would be appealing.
Again: even assuming UA is all that, there are no studies that I am aware of which show what interaction, if any, there is between UA and rapa and/or SGLT2i or other drugs/supplements. Are you willing to take UA without any information regarding such potential interactions? I am not, because I have researched rapa and some of its interactions with some drugs (such as SGLT2i) that I also take, and since I like what I read about these, I donāt want to risk throwing UA into the mix potentially interfereing with them. I will wait for more information before even thinking of getting on UA. YMMV.
Excellent points, as always. And I always appreciate how exacting you are.
Because, as always, I have zero clue, I did run by the idea of taking it by a smart longevity doc, the one we all know and love, and he felt it was probably a worthwhile thing for me to add, and knows Iām on dapagliflozin and rapa.
Iām definitely not married to it and assumed it was a no harm and might possibly be beneficial proposition.
Iād want to be more convinced of benefits before spending $$$ on Time Line. Having said that, if it also contained the coq10 I need (Iām was shown to be deficient), Iād consider paying for the convenience of taking one thing vs two, especially because they have some new gummies that are supposedly yummy :).
Q10 might have other benefits. However, the paper you cited says: āPatients with heart failure were given coenzyme Q10 at doses ranging from 30 mg to 400 mg per day in the studies included. There was no determination of the minimum and optimal doses for coenzyme Q10 use, and further dose-response analyses will be required in the future.ā And we know that Q10 has a weird dose-response: Coenzyme Q10 (CoQ10) U-shaped dose-response relation with blood glucose and blood pressure