Rapamycin Dosing Day - Dos and Don'ts

#21

That’s a great question. My guess is that it’s fairly consistent if you consume enough grapefruit juice. If you consume just barely enough grapefruit juice to increase the bioavailability then the bioavailability could vary quite a bit because maybe you drank x amount of grapefruit juice one week, then next week you drink again x amount, but maybe the juice you drank the second week is from a different batch of grapefruits, or is of different age or source. There are many variables that can influence how much of the compounds that improve bioavailability are in x amount of juice. Therefore, if you want more consistent effects it’s wise to drink a bit more than the minimum you would need.

This is the case because there is a threshold effect whereby x amount of grapefruit juice of a particular batch will lead to almost maximal increase in bioavailability. Consuming more than that will not increase the bioavailability significantly more. Lets say that for one batch of grapefruit juice the amount that leads to maximal inhibition for you is 200 ml. It would be good idea to consume 300 ml each time, instead. That would make sure you’re likely to still get close to full inhibition even if the juice you buy next time contains 50% less of the compounds that improve bioavailability.

One more important thing. Regarding the predictability. If you drink a high dose of grapefruit juice every time you take rapamycin the amount you absorb might actually be less variable and more easily comparable to that of other people. One of the main reason people get different levels of rapamycin after ingestion is that they have different amounts of the CYP enzymes in their digestive tract. But two people drinking a lot of grapefruit juice will both have much lower levels and therefore will likely have more similar bioavailability. So I think drinking grapefruit juice with rapamycin will tend to reduce the variability between individuals in absorption.

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#22

Consuming more than that will not increase the bioavailability significantly more

This is fascinating and very informative, thanks for the lesson! I had incorrectly assumed if, for example, 20 ounces of GF turned 1mg of rapa into an effective dose of 5mg, that 40 ounces would turn it into 10mg, and so on… that it would keep multiplying vs hitting a ceiling.

So, once I have to have 300ml of gf juice to make sure I get a fairly consistent dose from week to week, I guess at that point I might as well just have the 8 pills instead (because my rx from CVS is really cheap).

THX again!

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#23

That makes sense. The average person that drinks grapefruit juice is not doing it purposely to increase the absorption of a specific drug while simultaneously being careful to not consume other things that are metabolized by the CYP3A4 enzymes. The average person is ingesting it habitually and is not likely to be aware of or be careful about things ingested around the grapefruit intake. I bet many people eating grapefruit are taking some drugs whose absorption is increased with the intake, while not realizing they may be getting a much higher dose of that drug than they are intending. To use grapefruit more safely you really have to look into how it effects things and which things it effects.

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#24

Don’t take it with Taurine.

I tend to be fasting and halt my Taurine supplementation the day before and during the day of taking Rapamycin.

Another don’t is - don’t take it too frequently (allow sufficient time for previous dose to wash out). Most people go with 1x weekly dosing. I go with a higher dose, but 1x fortnight frequency.

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#25

What does taurine do with rapamycin? I have taurine with my breakfast daily, so I should stop it the day before and the day of dosing rapamycin?

#26

Taurine is an MTOR activator and could possibly blunt the effects of both Rapamycin and Taurine, canceling each other out.

Yes, it’s also probably a good idea to get all of the Rapamycin out of your system by waiting a week or two for it to clear before your next dose. My dosing schedule is a hybrid. 2 weeks on and one week off of 4 mg + GFJ + EVOO. However, I may just do it every 2 weeks due to side effects. I’m constantly trying new routines. The problem is that my body is adapting and the side effects keep changing - the good and bad both.

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#27

I was under the impression rapamycin was so effective at suppressing mTOR that other things wouldn’t be able to touch it. I will try to remember to avoid taurine the day before and day of rapamycin dosing.

I just started last week so I’m unsure if I want to do weekly or fortnightly dosage. I am going to be taking it on an exercise rest day however, does this sound like a good idea?

I wonder if I could do a naringin supplement with rapamycin to increase potency? I’m looking at a study, it isn’t as effective as GFJ, but it still has an effect and is easier to keep on hand than grapefruit.

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#28

You are probably correct. So don’t waste your taurine. I think there was one study that showed taurine reduced the effectiveness of Rapamycin a bit.

Rapamycin can affect taurine:
Rapamycin may also affect taurine transport and release, although the specific mechanisms and effects are still being investigated, according to the American Physiological Society Journal.

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#29

Yes, that’s my approach too. Not because the evidence of interference is ironclad, but out of an abundance of caution. So, I don’t take taurine on the day of the rapamycin dose and the day after. Probably jumping at shadows, but I’d rather be too conservative than not enough - rapamycin is too important an intervention for me to risk effectiveness. YMMV.

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#30

Hi @Beth I have no knowledge at all in this area, other than I think there’s a lot of individual variability in drug absorption. What Olafurpall said seems perfectly logical to me that if you “saturate” CYP enzymes with GFJ, you’ll hit some sort of ceiling of Rapa absorption.

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#31

Does inhibiting CYP3A4 lead to negative effects outside of drug metabolism though?

#32

While taurine activates mTOR, it’s probably a relatively weak activator compared to other amino acids, specially comopared to BCAAs. In any case, if someone is concerned aboutt a small increase in mTOR from taurine he should be even more concerned about mTOR activation from ingesting protein, which will likely have a much stronger effect on mTOR than taurine. So I would think taurine is a non-issue here unless the person is fasting.

It appears to very strongly but not completely blunt mTOR activation in response to things that acivate mTOR (like exercise or protein ingestion). Here is one study showing that: Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis - PubMed
My personal approach is not to try to avoid the things I eat or the supplements I take that activate mTOR on the day (and few days after) when I take rapamycin. My approach is a bit opposite. I think, if I am taking supplements that might activate mTOR a bit, then the best time to take them is precisely arond the time I take rapamycin, because that’s when it’s mTOR activating abilities will be least likely to cause significant harm. Some people here take a different approach by trying to avoid everything that activates mTOR and even fasting on days they take rapamycin, to try to maximize their chances of strongly inhibiting mTOR.

That’s a great question. I doubt it has other negative effects but I can’t say I’m fully certain of that. I’m not aware of CYP3A4 having any important roles aside from metabolism of drugs and other ingested compounds.

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#33

I never thought of that. Anyway I’m just starting. I’ll try some different things out and see what works.

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#34

For Matcha Tea enthusiasts:

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#35

If I am working out on the day I take rapa, I take it a few hours after my workout, not before. I try to avoid a hard workout for about 48 hours following.

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#36

Surely the site of mTOR activation is what we care about, right?

Doing a lifting session is going to temporarily stimulate mTOR in skeletal muscle as a means of recovery and adaptation. That’s how you undergo hypertrophy. I can’t think of any way in which that is detrimental to your health or longevity. More skeletal muscle means more strength, more glycogen stores, usually better metabolic health, less intramuscular fat and insulin resistance - all very very good things.

However, persistent/chronic mTOR activity in organs and tissues (immune cells, stem cells, endothelial cells, liver, adipose etc) suppresses autophagy and seems to be negative. That’s what we’re trying to avoid. We know that mTORC1 activity increases with age in all of those places, and it’s also driven by things like over-eating. But that’s more of a “baseline” or “chronic” mTORC1 activation, not the short-term, localised activation we see after exercise.

Basically what we’re wanting to know is: does exercising around Rapamycin blunt some of the Rapamycin benefits? Or, does exercising help us avoid some of the potential negatives of Rapamycin?

I did ask ChatGPT Pro (the $200/month version) and it gave a very complicated answer (with study references that I did briefly fact check and were correct) that basically with aging, we do see increased baseline mTOR activity in a subset of myocytes, and also satellite cells. In particularly, the neuromuscular junction (NMJ) (where your motor neurones tell the muscle to contract) seem particularly high in mTORC1 activity with age. And that is actually correlated with sarcopenia. That isn’t what I expected. Apparently animal studies show that Rapa is helping to preserve NMJ function and slow down muscle atrophy, rather than building size.

So IMO, coupling exercise around Rapamycin is a good thing because you have Rapa suppressing the “bad” mTOR activation around the body (immune, fat, liver etc), and the exercise still provides other benefits. Apparently you can’t “override” Rapamycin, so an older person where who is unlikely to make gains in muscle mass will get the maximum benefits in slowing atrophy while also still having plenty of other training stimulus; the glycogen depletion, the strain through tendons and joints, the mitochondrial stress, the cardiovascular benefits etc.

So personally I don’t see much logic in avoiding or reducing training about Rapamycin. IMO it should be the opposite. Any thoughts?

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#37

This is complicated and I think the answer is, maybe a little bit. Exercise might slightly blunt the benefits of rapamycin and could also help avoid some of the negatives of rapamycin. Importantly this is likely just the case in muscles and tendons that exercise will stimulate to grow and get stronger. Everywhere else you wouldn’t really expect exercise to interfere. It’s not going to influence mTOR activation in the various other organs of the body as an example.

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#38

Yeah, I think maybe a little bit too. End of the day, you can’t expect maximal anabolism while taking an anti-anabolic drug. Hopefully some study results should be announced soon which might address this. Brad Stanfield was supposedly announcing results in September of his trial of old people exercising after Rapa.

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#39

I hope the study will report on which days they take rapamycin and which they exercise. That could be important part of the reuslts.

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#40

I think we may be slightly overthinking this. The half life is so long anyway. I just think having it with fats to improve absorption is really the main thing we need to do. Otherwise, I have it every Sunday with my usual breakfast pills and don’t do anything differently. Maybe I’m missing out on added efficacy but I’m not that convinced.