Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?

@morlock mentioned that he’s using everolimus instead of sirolimus / rapamycin, which I’m finding really interesting because its the first time I’ve heard of a person using everolimus. How is it going? How does it compare to rapamycin / sirolimus (have you tried both?).

For those new to the topic - everolimus is a rapalog that Novartis developed to compete against rapamycin. It is almost identical to rapamycin, but slightly different so that they could patent it and sell it in competition with rapamycin (Pfizer Rapamune). It should operate and provide the exactly the same lifespan benefits as rapamycin - though it has not been proven or used in these studies yet - perhaps primarily because it was still on-patent until a few years ago.

He mentioned in another post:

Another option is to use Everolimus from Indian sources as 10mg doses are much easier to obtain. From my reading Everolimus seems to dose 1:1 with Rapamycin.
I’ve just received my first 10mg x10 box manufactured by Glenmark which was $60 +ship. I have no purity data though, so I’m reluctant to call it a perfect option.

This is really interesting from two points - the price is really good - Morlock, correct me if I’m wrong, but it sounds like you got 10mg X 10, for $60, which would work out to $0.60 per mg, a pretty good price - especially for everolimus, which is much more recently off-patent than sirolimus / rapamycin.

Also - I’ve read that everolimus is interesting also because the 1/2 life of the drug is much shorter than rapamycin - about 28 hours for everolimus, vs. 62 hours (typical in transplant patients) to 82 hours (in healthy younger patients) typical for rapamycin.

I’ve seen scientists argue that this could be useful and allow higher dosing of the drug, for better anti-aging effects because you don’t have to worry as much about the higher trough levels over the long term that can cause mTORC2 inhibition. So the strategy might be to dose it higher, and a little more frequently than rapamycin / sirolimus which could theoretically result in better life extension effects.

Here is the 1/2 life blood sirolimus levels you see with rapamycin vs. what you would see in everolimus.

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BloodEverolimus1

Has anyone else tried everolimus? Any comments on your experiences with it?

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Unfortunately I have only a single week experience with Everolimus, so nothing really to report.

I have a 6mg Rx for Sirolimus that I’ve been dosing once a week for the past 12 months with no side effect. My drive to find a less expensive rapalog is primarily due to cost. After listening to Peter Attia’s podcast with Matt Kaeberlein I felt more confident to pursue Everolimus.

I didn’t realize that there is a half-life difference between the two, so now I will have to re-evaluate my dosing strategy. My plan was to move to 10mg once a week.

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I haven’t done the research on what the equivalent dosing is for everolimus as compared to rapamycin. I think the dosing may be a little different, not due to any specific thing I’ve read - just because we see the higher dose tablets - e.g. the 10mg tablets, that you never see in rapamycin. That suggests to me that the dosing is not entirely equivalent…

A quick search suggests this is true - let us know if you find out more on this issue, as I’m sure more people will be trying everolimus in the future for anti-aging.

and

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Interesting. I appreciate the data on this.

Was just reviewing an interview with the Novartis exec Lloyd Klickstein who was involved with the everolimus tests and the research papers related to this topic. In the interview they mention what they believe is the dose equivalency of everolimus to sirolimus / rapamycin - see below:

In one experiment. Patients with polycystic kidney disease that were otherwise healthy, took the rapalog (RAD001) and a substantial fraction saw these biochemical changes in their blood

  • The dose was 5 to 10 mg a day (equivalent to 2-8 mg of rapamycin)
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Perfect. Thanks for the followup with those numbers. It gives me a good comparison to start at.

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This just in today from one of the leaders in rapamycin research - no preference for rapamycin or everolimus (see tweet below). I’m going to a more in-depth analysis on the dosing and pricing comparison - will post in the next few days:

rapaOrEverolimus2

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Good summary of side effects of everolimus:
https://chemocare.com/chemotherapy/drug-info/everolimus.aspx

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Interesting - but misleading. Those are the side effects seen seen in the high daily doses seen in applications for cancer therapy, etc. - not the side effects seen in the weekly dosing (or once every two weeks) that is typically used in anti-aging applications.

Here are the side effects seen with Everolimus (RAD001, Novartis Afinitor) in the famous Mannick 2014 clinical trial (with elderly but healthy people, dosed weekly) where it was shown to improve aging immune systems in people.

Interestingly, they reported only 1 serious adverse event in the study:

Only one severe adverse event was assessed as related to RAD001: mouth ulcers in a subject treated with 20 mg weekly RAD001.

EverolimusSE2

Here is the packet insert for Everolimus / Afinitor (for cancer, etc. applications with daily dosing) with all the detailed product information that people might want to review, (note, all side effect info different from seen in weekly, anti-aging dosing protocols):

28 hrs half-life is attracting.
Sirolimus takes approximately 13 days to clear its concentration under 3%, while Everolimus only takes about 6 days, that’s a big difference

Do you know anyone in aging field using Everolimus instead of Sirolimus?

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I’ve not heard of anyone in aging field using everolimus yet. I brought up the issue a year ago when the drug was starting to become available as a generic in India inexpensively and you can see the discussion below. Blagosklonny was interested. I think it may make sense to at least alternate with everolimus, if not go exclusively everolimus.

Also - it will be a lot easier to import higher quantities of everolimus because it comes in 5mg and 10mg tablets. In the USA - if you import 360 tablets (a reasonable number to get in for personal use, and usually not a Customs/border problem), with rapamycin / sirolimus you only get 360 mg total, whereas with everolimus @ 10mg, you get 3600mg of the drug. Even thought everolimus needs to be dosed at a slightly higher level for dose equivalency, its still easier to import in higher quantities.

The only caveat is that I’ve not seen any 3rd party lab analysis on everolimus product the different Indian manufacturers of everolimus and therefore have no idea about the quality, purity and contaminants.

EverolimusBlag1

Though, one doctor focused on aging, has said this:

everolimusAgeDoc1

blagEvero2

More of the twitter thread here:

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Just noticed this important bit of information on everolimus in the new clinical study announced by Dr. Bradley Stanfield this week:

Selection of orally bioavailable Rapamycin Analogue

Pure Rapamycin has poor bioavailability, which lead to the development of the rapalogs: Sirolimus and Everolimus. Everolimus is a second generation Sirolimus derivative specifically developed to have improved pharmacokinetic properties including, but not limited to, facilitated oral formulation, higher oral bioavailability and better metabolic stability in comparison to sirolimus. As these regions of the Sirolimus and Everolimus molecules are structurally similar, it was hypothesized that both molecules have the same effects on the mTOR pathway, however this is not the case. Like Sirolimus, Everolimus inhibits mTORC1, but at the clinically relevant concentrations tested, Everolimus was much more effective at inhibiting mTORC2 [27].

It is important to note that the lifespan-enhancing effects of mTOR inhibitors have been linked to mTORC1 inhibition, whereas inhibition mTORC2 might even be detrimental, because mTORC2 controls insulin-mediated suppression of hepatic gluconeogenesis [28]. Therefore for this proposed trial, Sirolimus is the preferred rapamycin analogue as it does not inhibit mTORC2 to the same extent as Everolimus.

Relevant research papers:

and

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Useful information that Everolimus affects the mTOR pathway differently than sirolimus and has a higher potency in terms of interacting with mTOR complex 2

Does that means it’s better stick in sirolimus

Yes, probably not a bad idea to just stick with sirolimus for now. Its only one research study, and no full lifespan studies have been done with everolimus, but it seems that sirolimus is a slightly lower risk approach than everolimus. If I already had everolimus I would still take it, but I’m a little less enthusiastic about everolimus now that I’ve seen that data.

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