#323

That + I think UA is unstable in its normal form and therefore useless (or at least that’s what Timeline claims) and Timeline developed a version that is stable. Is that true? I don’t know.

1 Like
#324

This is what chatGPT says: Q: how unstable is urolithin a?

Short version: as a dry powder, urolithin A is quite stable; in water it’s not. Heat and extreme pH speed its breakdown.

What’s known about stability

  • Solid state: Commercial specs list ≥4‑year stability at −20 °C for the neat powder; vendors also ship it at room temperature without loss of activity over short periods. (SelleckChem)
  • Solutions: It dissolves well in DMSO/DMF but is sparingly soluble in aqueous buffers. Suppliers advise dissolving in DMSO, diluting into buffer for use, and not storing aqueous solutions for more than one day (they even suggest purging stock solvents with inert gas). That’s a good practical indicator that urolithin A is unstable in water over time.
  • pH & temperature: Reviews note it is stable under physiological conditions but prone to degradation at extreme pH or at high temperatures—so avoid strong acid/base and heat. (PMC)
  • Formulation helps: Encapsulation (e.g., liposomes) has been shown to improve stability and bioaccessibility relative to the free compound. (ScienceDirect, ResearchGate)

Practical handling tips (lab or supplement prep)

  • Keep the powder sealed, cool, dry, and protected from light; −20 °C storage is standard.
  • Make fresh aqueous working solutions; for longer storage, keep concentrated DMSO stocks in small aliquots, minimize air exposure, and dilute right before use.
  • Avoid heat and extreme pH during processing. (PMC)

If you’re asking about consumer shelf life (capsules/powders) versus lab solutions/formulations, tell me which context you care about and I’ll tailor the specifics (e.g., expected shelf life, packaging, and handling steps).

2 Likes
#325

The correct word is probably not “stable” but if I remember correctly they were claiming something about their UA being superior to others. Might be total BS of course.

1 Like
#326

This is one of the hard things about the whole process. It is difficult to get really useful IP on things like UA. Hence if people are going to spend serious money on research they need to find some way of getting an extra marketing argument.

It may not be total BS. However, it may not be worth the price variation.

I am not persuaded by UA.

2 Likes
#327

We don’t know what UA does in the body. Without a clear understanding of the mechanisms involved, I am staying away from it simply because I take other agents, like rapamycin, and I don’t want any unexpected interactions. Even if it is shown conclusively that UA results in life/healthspan extension, with no clue about the mechanism I’d have no idea how to fit it into the rest of my health/longevity stack. And I’m not clearing the rest of my stack just to accommodate UA. Rapamycin is still the best validated drug in the ITP - I’m sticking with what’s proven and not risking undermining it with unknown interactions.

I’ll wait for science to tell me more about UA. Until then I’m not chasing dodgy supply sources at high cost and unknown effectiveness. Way outside of my risk/reward ratio at this point in time. YMMV.

#328

Is anyone who is taking Urolithin A cycling their administration? I see no clinical research on the topic but there is at least a theoretical case to be made, as well as some implications from animal research, to consider the possibility of adaptive downregulation.

#329

I took a large dose, but I didn’t notice anything to encourage me to buy any more.

#330

I don’t think one should expect to see primary benefits for a few months. Four weeks for measurable molecular effects; 8–12 weeks is typical for functional benefits. As I recall, steady state levels are more important than a peak/trough protocol.

1 Like
#331

Paper published by the Amazentis team (Timeline / Mitopure): Urolithin A abolishes high anxiety and rescues the associated mitochondria-related transcriptomic signatures and synaptic function 2025

UA produced a robust anxiolytic effect in both high-anxiety models, in both sexes, without altering behavior in low-anxiety animals. High-anxiety MSNs displayed coupled dysregulation of mitochondrial and synaptic gene pathways that UA normalized to low-anxiety levels across MSN subtypes. These changes were accompanied by structural and functional rescue of MSN dendritic architecture, spine density, and excitatory synaptic transmission. Notably, UA also restored expression of mitofusin-2 (Mfn2), a mitochondrial protein causally involved in the regulation of anxiety-related behavior and circuit dysfunction in the NAc, further supporting a mechanistic link between mitochondrial remodeling and UA’s anxiolytic efficacy.
These findings position UA as a mechanistically informed intervention in preclinical models of heightened anxiety and provide systems-level insights into how mitochondrial pathways interface with synaptic function and circuit regulation in anxiety states.
To determine which mitochondrial pathways were affected in HA rats and modulated by UA, we examined four primary MitoPathway classes (Figure S2E): ‘Mitochondrial central dogma’, ‘Metabolism’, ‘OXPHOS’, and ‘Mitochondrial dynamics and surveillance’. Among these, ‘Mitochondrial central dogma’ was downregulated in HA but restored to LA-like levels following UA treatment. ‘Mitochondrial dynamics and surveillance’ also increased with UA. Focusing on specific MSN subtypes, we identified dysregulated pathways in HA animals in mitochondrial DNA/RNA/protein biogenesis and maintenance (e.g., ‘mtDNA repair’, ‘mitochondrial ribosome’), mitochondrial dynamics and energy metabolism (e.g., ‘mitophagy’, ‘autophagy’, ‘OXPHOS’, ‘TCA cycle’), as well as other metabolic pathways (e.g., ‘itaconate metabolism’, ‘carnitine shuttle’, ‘carnitine synthesis and transport’) (Figure 2F, Figure S2D, Table S2). Notably, UA normalized all these pathways to LA-like levels in at least one MSN subtype (Figure 2F, grey rectangles). Pathways were considered normalized if they were significantly different in HA vs. LA but not in HA-UA vs. LA (padj>0.1).

Interesting link between stress/anxiety and mitochondrial function @John_Hemming. Urolithin A might be irrelevant in low-anxiety people but beneficial in high-anxiety ones?

#332

Stress increases cortisol which drives higher glucose which causes more ROS.

#333

Having, at best, guarded interest in metabolic generalizations from rodent studies, I have even less confidence when the dependent variable we are tacitly asked to generalize to is the human construct of anxiety, the operational definition of which is entirely different for rats; and – if is it possible – even less confidence when the study animals have been bred to display an analog of this human construct.

3 Likes
#334

Do these (and other studies referenced above in mouse models) imply that UA crosses the BBB in mice? Does that translate to humans?

#335

I don’t think UA crosses the BBB well; otherwise, Amazentis would not have started a spin-out dedicated to creating BBB-crossing UA derivatives (see discussion on that somewhere above).

2 Likes
#336

Actually, it wasn’t posted before: Vandria announces first subjects dosed in its first-in-human Phase 1 clinical trial of VNA-318 brain-penetrant mitophagy inducer - BioSpace

Vandria is a clinical-stage company at the vanguard of mitochondrial therapeutics. It is developing first-in-class mitophagy inducers that rejuvenate cells to treat age-related diseases. Its lead program, VNA-318 is a brain-penetrant, patent-protected, mitophagy inducer which has been shown to improve memory and learning and to have strong disease-modifying effects in models of neurodegenerative disease such as Alzheimer’s and Parkinson’s disease. The company is also developing mitophagy-inducing small molecules to address muscle, lung, and liver diseases.
Based at the EPFL Innovation Park in Lausanne Switzerland, Vandria was spun out of Amazentis SA in 2021 by its founders Patrick Aebischer, Chris Rinsch, and Johan Auwerx. The company has raised $32M (CHF28M) in venture finance from ND Capital, Hevolution Foundation, Dolby Family Ventures and private investors.

VNA-318 is a urolithin derivative: Urolithin A (UA) One of 4 Promising Agents 2024 by Brian Kennedy of NSU - #283 by adssx

If UA was so good for AD and PD then I guess Amazentis would work on UA instead of spin out a new company and creating a derivative? Unless it’s just to be able to patent it?

2 Likes
#337

I would assume this is a big part of it. In theory they can argue it is in some way better, but it may not be that much better.

ChatGPT says UA can cross the BBB.