Orally available rapamycin: Don’t forget to take your pill

This isn’t exactly news, but it’s news to me: Rapamycin has an orally administered derivative, Everolimus, already in use as an anti-cancer and anti-rejection drug. (The two compounds are almost identical; Everolimus has one additional hydroxyethyl group on the protuberant cyclohexane ring, and apparently that’s enough to make the unwieldy rapamycin molecule orally bioavailable.)

This might be good news if it turns out that the longevity-enhancing qualities of rapamycin end up generalizing to humans: If you need to maintain constant levels of a chronically administered drug, t’s way easier to use timed-release oral capsules than injections. Also, as millions of diabetics will tell you, it’s just nice not to have to shoot up.

But the drug itself might be bad news, especially if it is taken over long periods of time: mTOR, the target of rapamycin, appears to be necessary for reconsolidation of long-term memory in mammals; inhibition of mTOR is efficacious enough at blocking fear memories that it’s discussed as a strategy for treating PTSD. The role of mTOR in memory appears to be general, i.e., in memories other than fearful ones, and it is evolutionarily ancient: TOR is important for long-term potentiation in the sea slug Aplysia, beloved model of scholars of learning and memory.

So, as I’ve commented before, I have this fear that rapamycin (or a derivative) will turn out to be a bona fide longevity enhancement drug, but one whose chronic use erodes long-term memory, which does defeat the purpose to some extent.

Then again, blood-brain barrier is an issue here: even though Everolimus can survive the stomach and pass through the gut into the blood, that doesn’t mean it will make it into the brain efficiently. Then again again, if the drug has a long half-life once it’s inside the brain, it might still accumulate there if one had to take it every day for the rest of one’s life.

On the happy side, if you find this possibility traumatic, the rapamycin will take care of that for you.

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  1. I am always afraid of making assumptions with evolutionary theories, but the trade off of memory for lifespan does seem to add support to antagonistic pleiotropy.

    I suppose that it is also worth considering that memory loss can tend to be a feature of growing old, thus making the trade off somewhat more reasonable.

    I wonder if there are not some legitimate memory enhancing therapies on the market? And how the two drugs might work in concert.

  2. Hopefully, mTOR inhibition does not impair human long term memory.

    A quick websearch uncovered a paper indicating that rapamycin had beneficial effects on memory and cognition in transplant patients.

    In Alzheimers-model mice, mTOR inhibition seems to improve memory:
    “Rapamycin rescues learning, memory in Alzheimer’s mouse model”

    Also, caffeine, another mTOR inhibitor seems to have beneficial effects on memory, and, perhaps, Alzheimers.

    Given the promise of this approach, I’d bet that quite a few volunteers could be recruited for human trials.

  3. I am interested in the use of Rapamycin in treating autism. I know some parents (outside of a clinical study)who already use it with interesting results (according with them).

  4. Ouroboros,

    I don’t believe this is the abstract I first saw, but here is another:

    “Immunosuppression Using the Mammalian Target of Rapamycin (mTOR) Inhibitor Everolimus: Pilot Study Shows Significant Cognitive and Affective Improvement”


    While searching for it, I also found another interesting result:

    “Rapamycin is a neuroprotective treatment for traumatic brain injury”

    Click to access 0413%20Clark.pdf

  5. Thanks, Lou.

    That immunosuppression article refers to a cognitive improvement after switching patients to rapamycin as a substitute for CNIs, which are known to cause psychiatric and cognitive side effects — i.e., one can conclude that rapamycin does less cognitive damage than CNIs, but not that rapamycin is generally good for you, cognitively speaking. The study doesn’t pertain to the baseline effects the drug might have on an otherwise intact patient.

    The traumatic brain injury article is interesting but I don’t think it pertains to memory. And like the other paper, its subjects have already received a significant insult – in this case, traumatic brain injury – and the data merely show that with rapamycin treatment they’re less badly off than with alternative treatment.

    Same for the Alzheimer’s paper: the mice are pretty sick already, but better off with rapamycin.

    So, this is an interesting situation: rapamycin treatment seems to be a good thing if your brain is already taking a major walloping for another reason – CNIs, Alzheimer’s, trauma – but seems to make things worse if you’re trying to build or reconsolidate normal memories, in the context of normal health.

  6. A study presented in this paper detected no memory impairment in transplant patients receiving rapamycin w.r.t. controls:

    “Memory and executive functions in patients after transplantation treated with different immunosuppressive drugs”


    No decrease of memory and executive function was found in patients after transplantation in comparison with the
    healthy control subjects.

  7. In the ‘Unfolding the role of the hypoxic response in aging’ post you discuss the idea of a naturally selected ‘sweet spot’. That makes a lot of sense (and not just for mTOR).

    Any chance of a vitamin D post, people are already taking that and in very considerable doses.

    Psychoneuroendocrinology (2009) Vitamin D, nervous system and aging

  8. funny ppl always talk about rapamycin as anti aging drug candidate. but one needs to be aware that it’s first an immuno-suppression drug used for organ transplant. I guess if it turns out to have an effect on anti-aging, people can always live in a bubble.

  9. The doses used for lifespan extension experiments are substantially lower than the ones used to suppress the immune system, but over the long term it may still be an issue.

  10. great you rake it to live longer, but forget where you live

    (well thats the way I read it)

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