Rapamycin and autophagy

Could you point out that podcast?

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Yes, that’s the one I was thinking about, thank you. I think the Matt K podcast is this one, but not 100% sure -

#175 - Matt Kaeberlein, Ph.D.: The biology of aging, rapamycin, and other interventions that target the aging process - Peter Attia (peterattiamd.com)

Additionally, Joan Mannick (a noted Rapa researcher) states that “rapalogs don’t consistently induce autophagy” and in many cell lines (that she presumably studied) “there was no induction of autophagy”.

#123 - Joan Mannick, M.D. & Nir Barzilai, M.D.: Rapamycin and metformin—longevity, immune enhancement, and COVID-19 - Peter Attia (peterattiamd.com)


Popular science report:

scientific report:

We don’t want dysfunctional autophagy in the brain. And this knowledge makes it important that, when we age, we make sure that our NAD levels isn’t to low in the brain.


Is low dose rapamycin more beneficial than high dose?

I think generally no. The mouse studies do not indicate so. They show greater benefits at higher doses, and the most effective doses are pretty massive compared to what humans normally use. I think one reason for this is that rapamycin only inhibits mTOR partially. Even massive doses do not fully inhibit mTOR.

Is the combination of CR, and even fasting, with rapa excessive?

Possibly but I would think not unless we’re talking about moderate to large CR which is very uncommon for humans to practice. The reason I think this is because rapamycin appears to mainly inhibit mTOR when it’s moderate or elevated. When mTOR is already low such as during fasting, it doesn’t seem to reduce it any further.

Do we need to be careful combining rapa with autophagy inducing supplements and phytochemicals?

I don’t think so. The reason I don’t think so is that there aren’t any supplements that are well proven to induce autophagy in humans in vivo. If such supplements existed, then it would be logical to be careful combining them with rapamycin. But no such supplements exist. The supplements you hear about that are claimed to increase autophagy most likely do not inhibit it vivo in humans to any significant degree. An example is spermidine. It may increase autophagy in vitro but in vivo it appears to be not effective at all. Note that in the ITP studies, they tried giving spermidine to mice but found out that none of it was found in the blood after ingestion so they abandoned it.


BTW I have been on the lookout for interventions that increase autophagy for 15 years. I’m not aware of any supplements that are likely to increase it significantly upon ingestion of reasonable doses in humans.

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I believe tempeh is relatively high in spermidine.