Regarding polyphenolic supplements as mTOR and CYP3A4 inhibitors

#1

I used perplexity with the question “Name the most promising natural polyphenolic mTOR inhibitors.”. And this is a summary of what I got. When using a multitude of supplements, I think it is easy to venture into a territory where we inhibit mTOR 2. And some commonly used supplements also inhibit CYP3A4. This made think even more about how to not inhibit mTOR 2. I see a real risk of doing so when I use to many supplements, even if most of them have rather weak effects on mTOR 2. Some of them inhibit CYP3A4 to. This makes calculating the risk even more difficult.

Summary Table

Compound mTORC1 Inhibition mTORC2 Inhibition Mechanism of Action
Curcumin Yes Yes (at high doses) Reduces phosphorylation of S6K1/4E-BP1; affects Akt
EGCG Yes Possibly Suppresses phosphorylated S6; neuroprotective
Fisetin Yes Yes Downregulates Raptor/Rictor
Quercetin Yes Yes Blocks PI3K/Ras; activates AMPK/TSC1
Resveratrol Yes Indirectly Inhibits PI3K/Akt; activates AMPK-TSC
Myricetin Yes Less defined Inhibits PI3K/Akt/mTOR pathway
Kaempferol Yes Less defined Modulates upstream signaling
Apigenin Yes Less defined Affects PI3K/Akt/mTOR pathway

These compounds demonstrate promising potential as natural inhibitors of the mTOR pathway, with varying degrees of efficacy against both complexes. Further research is needed to fully elucidate their specific mechanisms and therapeutic applications.

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#2

Interesting. More herbals.

I don’t think I want longer time of mTOR inhibition on top of my 1x/14-21 day rapamycin dosing. Is the idea to dose along with rapamycin to get a bigger effect than just taking more rapamycin (If that is possible)? I only seek a hit and run effect.

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#3

Even though these compounds are weaker mTOR inhibitors than rapamycin, it is hard to get a clear view of what happens in our bodies when you combine them with rapamycin. Especially since some of them, are known inhibitors of CYP3A4. This indicates that when using herbal supplements, we can’t foresee the effect we get on mTOR 2. I should add that follow-up questions to perplexity or to consensus gave similar but far from identical information on the effect polyphenols have on mTOR 2. Curcumin in low doses seems to be safe when it comes to avoiding mTOR 2 activation.

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