Rapamycin and the brain - any potential side effects to be aware of?³

shc · February 18, 2022, 1:35pm

Many folks these days seem to be increasing the dosage and duration between doses to get a high peak blood concentration of rapamycin which could then cross the blood-brain barrier, etc. I’m not sure if this has been well studied, but let’s assume this is true. Rapamycin is hypothesized to have various benefits for the brain that are being investigated – e.g. prevention of Alzheimer’s, vascular benefits in the brain, etc.

Now, what are potential downsides of high or frequent rapamycin administration w.r.t the brain? It seems like most side-effects people focus on tend to be related to the immune system, to glucose sensitivity, or concerns about muscle-wasting (though anecdotal and scientific reports seem to disagree about this).

Barring these, are there any neural side effects one may want to keep an eye on? This barely seems to be discussed. Would frequent high doses or mTORC2 inhibition be a cause for concern? I can imagine that persistent mtor downregulation can cause depression (even though it helps make ketamine work better). Apart from this, is it all fine and dandy w.r.t the brain, with only the other side effects being something to be concerned about in adults? I have doubts that this would be the case.

Guywholikessleep · February 18, 2022, 1:38pm

https://www.nature.com/articles/s41467-021-22908-4

https://journals.sagepub.com/doi/full/10.1177/1535759720905835

Agetron · August 3, 2022, 3:17pm

Without a doubt my memory, recollection ability… vivid dreams, articulation of thoughts has improved back to my level when much younger.

Information is there and ready. It’s great.

tongMD · August 3, 2022, 3:44pm

There is a very big difference between high pulse dose and frequent dosing.

mTOR plays a central role in many cellular processes, so there is a wide range of potential mechanisms and complexity involved. I’m not going to go over them. I invite you to read the entire process because it’s a very important node of aging with a lot of reproducibility in literature. I find most people tend to read only abstracts. Very bad idea!

I do have high confidence in replicating the ITP results in mice and dogs though. The unknown is whether it translates for humans.

desertshores · August 3, 2022, 5:20pm

May I please ask your thoughts on dosing for the elderly, given that mouse studies indicate high doses for older mice? In animal studies, it looks like results are dose-dependent according to the age when rapamycin is first started.

MAC · August 3, 2022, 5:42pm

As far as I know, no powered RCT in dogs/rapamycin proving longevity, so TBD.

Mechanistically, metabolically or other science, why the “high confidence” in dogs?

I have summarized some dog studies below.

Dog comorbidity and mortality, more similar to humans than mice? Appears much closer indeed.

Common Causes of Death in Dogs - World Small Animal Veterinary Association World Congress Proceedings, 2011

https://www.vin.com/apputil/content/defaultadv1.aspx?pId=11343&meta=Generic&id=5124261

Of the small initial dog trials, have any studies done full biometric workup similar to rapamycin treated mice…tissue, gene expression, inflammation, glucose, lipids, western blots, pMTOR, autophagy, etc? Having this data set would give me some confidence too re translation scaling.

This small study (2016) just looked at pharmacokinetics, which is a promising data point…kinetics not too unlike humans, so big metabolic translation positive.

MK also did a small study, of two doses rapamycin, but very little metabolic insight (2017)

This study was very in depth, dogs with cancer, IM rapamycin delivery. Evaluated pharmacokinetics and tissue mTOR inhibition. Excellent translation study akin to a human cancer trial.

“Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. In this short-term study of rapamycin exposure in dogs with osteosarcoma, there was no evident lymphopenia, increased. post-operative infection rate, nor surgical incision healing delays reported. However it is likely that longer-term exposure would be necessary to cause clinical immunosuppression. This work validates dogs with cancer to be relevant models in researching rapalog drug development”

Early days, but seems “promising” so far. We might not have to wait 40 yrs with the dogs trial, hopefully a longevity signal will come within the next decade.

Rapa dogs could indeed prove to be “mans best friend”.

tongMD · August 3, 2022, 7:53pm

There is unpublished data for early results that provides suggestive evidence of increased lifespan in dogs. I’ve also mentioned this before - I tested them on my own set of dogs, albeit open-label. I don’t jump from rat studies for most interventions I test on myself without a very good rationale even if there’s basically a decently sized “case series”.

As far as visible data goes - you’ve nailed it. I’d also note TRIAD cohort had improved cardiac function. You’re welcome to wait years for published data, but I simply have different risk tolerance.

I take the same approach for interventions like acarbose (which as you already may know, rapa+acarbose had the best possible results in the ITP, also unpublished). Spermidine and astaxanthin would be an exception, but it’s from food only (this doesn’t mean it’s inherently better or “safer” - but it’s enough for me to skip a few steps at the rough dosing I use if a ton of people have taken it for many decades at those doses).

I’m still waiting on an indirect path to Urolithin A. Just not too keen on taking from supplement companies (with some minor exceptions) unless they can prove USP. Even though the dosing gets a bit wonkier with food - it can end up being better if you read a ton of truly independent third-party testing results for the supplement industry.