When to do a 3-day fast when taking rapamycin

I’m interested to hear comments on the following: When someone is taking rapamycin once weekly every Sunday at dinnertime (6 PM). What would be the best 3 days to do a 3-day fast…A) Monday-Wednesday when sirolimus blood levels are highest or B) Friday-Sunday when sirolimus bloods levels have significantly declined…???

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I believe, based on this new data (see below) that you want to do the fasting when the risk of mTORC2 inhibition is at its highest; which I believe is around the time of peak blood/sirolimus levels and during some period afterward.

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@DrRoss Fasting has been on my mind lately as I’ve been wondering how to improve (lower) my insulin resistance. I used to do 3-day fasts every quarter, and was thinking of adding a weekly 24 hour fast. The question is how to time it vis a vis my weekly rapa dose? My thinking is that the weekly rapa doses create a high growth vs retrenchment cycle. I try to time my weightlifting and protein consumption to be heaviest in the growth end of the cycle, which is furthest from rapa dose. I think the fast is most compatible with the retrenchment part of the cycle, and so I am fasting today (Sunday) which started with my rapa dose this AM. I lifted Friday and will restart lifting on Monday night. What do you think?

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I agree, I take Rapa in the morning and don’t eat that day. The only thing that bothers me about it is the glass of Grapefruit juice that I drink with it. That can’t help. It messes up my whole system. How far do I have to run to burn up the sugar in that?

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I think you burned the 100 kcals just worrying about it.

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Back when I combined extended fasts and low-dose rapamycin (2-3mg), I’d start them simultaneously. My idea was that rapamycin would help with autophagy while my glycogen stores are still being used up. So that all 3 days of my 3-day fast would be beneficial for me for autophagy and not just the final day.

I’m not sure how long it takes to reach peak blood levels. What is a rough estimate?
I wonder if this means that I should already be fasting when I take rapamycin if I do such a protocol again.

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It’s a good question. I’ve thought about that as well but don’t know how I’d get my high fat food to help with rapa absorption.

RapAdmin…thanks for sharing this recent study. That is the first study I’m aware of that sheds some light on when is best timing of a 2 or 3–day fast when taking rapamycin once weekly.

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The issue I’m still not at all sure about is the possible timing of mTORC2 inhibition…when it does happen. I’ve not come across any papers on this, other than that people say that mTORC2 is inhibited after higher dosing and longer-term dosing of rapamycin.

I’ve also not done much effort at researching the topic, so if anyone has, please post anything you’ve learned…

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I think fasting would be best done right before taking rapamycin so the days immediately prior to taking rapamycin is what I would do. My reason for thinking so is that I think taking rapamycin during fasting is largely a waste because the fasting will inhibit mTORC1 by a lot and the rapamycin on top of the fasting is unlikely to make much of a difference in the already low mTORC1. Since lowering mTORC1 is the main point of taking rapamycin this means that rapamycin may be a waste when taken during fasting. An exception to this could be in some very old people that might be slightly resistant to the mTORC1 inhibition in response to fasting in which case the rapamycin might give some extra inhibition. That’s just my speculation though based on the potential age-related resistance to anabolic and catabolic stimuli often seen in old people.

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But conversely, if part of the reason to take Rapa is to inhibit mTORC1, why simultaneously do things that work against that end (high caloric/ protein intake and/or resistance training which raise mTORC1) ?

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It’s an interesting question. Should we take a bigger dose or more frequent dose to turn down mTOR more, or is fasting on top of rapa the same thing? Is turning down mTOR even more beneficial or neutral or detrimental? Is it a peak dose or an AUC that matters more? Perhaps the answers here depend on goals and current health status. I wish I knew.

This is my thinking as well. But what if we want to turn down mTOR in the immune system but not the muscles? (Just an example ). Perhaps the things we add to rapa can modulate the effect on different parts of the body and brain.

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You can’t avoid it. Even if you’re on a low calorie low protein diet, you will still activate mTORC1 a lot more on days you eat than on days you fast and it makes sense to take it on those days rather than on days where your mTORC1 would be very low anyways.

That’s where resistance exercise comes into the picture. Whenever you do resistance exercise you will temporarily activate mTORC1 in skeletal muscles but not elsewhere. Combine that with regular fasting or rapamycin and you will tend to inhibit mTORC1 less in skeletal muscles than the rest of the body.

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Good comments…thanks for your input.

I heard somewhere that the 16/8 time of fasting is a waste because the glycogen storage of humans, in contrast to mice, is to big. Do you guys know how long of a fast, is necessary to achieve a meaningful amount of autophagy.

Metabolism, and amount burnt Kcal. must also affect the time needed?

The notion of 16/8 being a waste because of glycogen storage is based on the fact that once the liver glycogen becomes empty the body will be forced to break down amino acids to provide glucose for the brain which will stimulate autophagy because the body will need to break down tissues to provide those amino acids. In reality this is very much of a simplification. Things are not that black and white with autophagy being either on and off. Autophagy is always sort of on just to differing degrees, and while autophagy will increase even more once your liver glycogen empties, it will still be activated during fasting before that happens, just most likely to a smaller degree. Therefore I think it’s not correct to say that 16/8 is a waste if autophagy activation is your goal. It will most certainly increase autophagy but the increase will not be as intense as with a longer fast. How much of a difference there is compared to longer fasts is hard to say. Btw I think exercising and having very low body fat can also help activate it more strongly and quickly.

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Yeah, that sounds like a reasonable explanation. Though I still am reasonably ripped and active for my age, I feel a big difference from when I was in my twenties… If I skipped a meal after exercise I could literally feel how my body was cannibalizing on it self. I always got very cranky, and that I couldn’t behave civilized before having a proper meal.

Can’t say that I miss that feeling, but think it was very healthy to have that experience quite often.

Will definitely try some longer fasting when I get hold of my rapa. 16/8 isn’t that hard if I just eat plenty in the eating window… will try longer fasting and ad a long run in the fast.

There are many reasons to do short eating windows. Autophagy is probably not the main one. Forcing your body to burn fat for fuel is important for metabolic flexibility and insulin sensitivity. Low intensity exercise is another way to train the body to use fat. I’m not an expert but this is what experts tell me.

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