I am not really a fan of UA or C Elegans. Because of the paucity of results for IPAM I thought this would be interesting, but C Elegans is not that comparative to mammals.
Mitophagy is about improving mitochondria systematically and IPAM is about propping up dysfunctional mitochondria (and possibly improving well functioning ones, but I am not so sure about that). They are likely to be synergistic, but I would not test the synergy in C Elegans.
I was just asking in general. Do you have any particular mitophagy activators you are a fan of?
Rapamycin is I think the best. I don’t know what melatonin does in this aspect, it may help and it may not. Obviously exercise has a role as does HIF 1 alpha.
Rapamycin does appear to be the best option and it fits with the overall goal of longevity.
There is a mediation called roxadustat that activates HIF 1 alpha but it likely has higher side effect profile than rapamycin. Can increase malignancy of tumors, best to avoid.
Apparently urolithin A and spermadine can also activate mitophagy through different pathways.
Hypoxic exercise can also activate HIF 1 alpha, without the risks of roxadustat.
So a potential strategy might be to utilize IPAM throughout the week and take a day off on rapamycin dosing day. Once every 2-4 weeks you could choose to do a higher dose pulse of urolithin A and/or spermadine for 2 days.
I’m going to wait until most of my kids are in summer camp, a couple of weeks from now. I want less on my plate when I get started. It is absolutely a black box according to my own research and ChatGPT. Typically I don’t react much to pharmaceuticals but just in case….
I found some interesting information in regards to IPAM recently as I’ve gone through more research. I posted about it here for anyone who is interested: The four best longevity interventions? - #179 by AustraliaLongevity
To summarize IPAM is an endogenous molecule and there are things we can do upstream from this to increase endogenous production.
Very interesting! I’ve read recently that with a combo of arginin / citrullin and exercise, you can basically rejuvenate your heart.
Seems we are finding a lot of really useful health information by looking deeper into indolepropionamide.
I have started taking citrulline daily in my electrolyte drink. I’m going to buy either L-arginine or L-arginine alpha-ketoglutarate.
Since IPAM is a gut metabolite I’m aiming to optimize gut health as well. I’ll be adding in inulin, resistant starch in addition to psyllium husk.
When we know that citrullin / arginine raises IPAM and exercise further strengthens the effect, we can assume that directly supplementing IPAM with exercise would also be very powerful. It’s really exciting! 
Poeggeler replied to an email I sent him! (translated with ChatGPT)
The different species occupy specific niches and can therefore also differ in their signaling and response.
Perhaps IPA triggers a toxic effect here that does not occur in the other species.
This is supported by the protection through EUK-8.
You have searched the literature very thoroughly.
In fact, I am also not aware of any further findings on this topic.
It remains exciting. Presumably, C. elegans will react differently, as there are specific adaptations here.
Wishing you much luck and success with your investigations. I am very curious about the outcome.
Is he mixing up IPA with IPAM?
Good work getting a response.
Nope. This was my email for context:
Dear Dr. Poeggeler,
Your message made me very curious: Do you have findings from further investigations or a hypothesis as to how this strong difference in effect between different species comes about?
Regarding IPAM, we have not found any additional data on lifespan, except for one study in which the life-extending effect of IPA was investigated: Antioxidants can extend lifespan of Brachionus manjavacas (Rotifera), but only in a few combinations - PMC
This study was apparently later mistakenly cited in another paper as results relating to IPAM (even though IPA was used instead of IPAM), which caused some confusion during our research. 
Warm regards,
Katrin
The most interesting thing is that he doesn’t have seem to have tested IPAM in c. elegans so he doesn’t have data. The test will create new information
I’m glad to hear.
Do you know what this means?
Quick check with ChatGPT:
EUK‑8 becomes protective under conditions of elevated oxidative stress, mimicking SOD and catalase within mitochondria and cytoplasm. This aligns well with Poeggeler’s hypothesis: EUK‑8 shields one species from IPA-induced ROS toxicity but may not protect another one where IPA doesn’t trigger ROS—or where ROS pathways differ due to species-specific physiology.
I’m not sure if ChatGPT can be trusted here, didn’t research this carefully. I really like that Poeggeler is so open about sharing is knowledge.
Yea I like him. Seems like a good guy that really does care about longevity and health from what I’ve read of his other work.
I’m making a number of changes to my routine based on a study he worked on “Nitric Oxide as a Determinant of Human Longevity and Health Span” as mentioned in that post I made today.
I have to read that study tonight! Yes, he seems so friendly and he has done such important work.
Wanted to expand a bit on my experience with IPAM (same one posted earlier). Additional (potential) side effects have emerged: mouth ulcers and constipation. The mouth ulcers are especially of interest, I can’t think of a reason besides IPAM for having them, but who know. When asking chatGPT for possible reasons, it responded with:
| Mechanism | Description |
|---|---|
| Redox imbalance | Overactivation of mitochondrial ROS buffering could cause local oxidative damage. |
| Immune modulation | Immune overactivation or T-cell hypersensitivity response in mucosa. |
As a potent antioxidant, it’s possible that IPAM creates rebound oxidative stress. The immune modulation reason has several potential mechanisms, which I don’t understand.
| Mechanism | Explanation |
|---|---|
| T-cell hypersensitivity (Type IV) | IPAM may trigger CD4+/CD8+ mucosal response against epithelial tissue. |
| Neoantigen formation | IPAM or its metabolite binds to host proteins → modified self → immune attack. |
| Cytokine skewing (Th17/IL-17) | IPAM may promote mucosal inflammation by enhancing pro-inflammatory cytokines. |
| Aryl hydrocarbon receptor (AhR) | Indole core may activate AhR → immune imbalance, barrier disruption. |
| Microbiome-immune disruption | Alters immune tolerance via changes in microbiota → mucosal inflammation. |
I’m not done with IPAM yet, but when these ulcers go away completely, I will start very low, probably 0.5mg, and see how it goes. This is just to bring awareness of other potential side effects, and to show that for some of us, this stuff have very potent impacts.
That’s interesting. Similar side effect to rapamycin.
Did you put the powder directly in your mouth? Maybe try putting in a capsule next time.