#21

This is well put. My path to where I am now was:

(1) follow the protocol that almost everyone uses and doesn’t have terrible consequences (goal #1: don’t hurt myself) … 6mg/week
(2) get as much benefit as possible. Increase the dosage until side effects show up (goal #2: don’t waste time on lower dosing than possible: BBB penetration, “I don’t feel anything”)…6mg/week plus fatty meal plus gfj
(3) I want some growth cycles in the mix, right? How to peak the rapa without having it stick around? (Goal #3: high peak, short half-life, periods with no rapa)…4mg/2wks with gfj

I also take an extra week off every 5th week to really focus on growth and zero rapa time.

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#22

Our thoughts are pretty much aligned on timing and dosages. With a 2 week dosing protocol, Rapamycin is still in your system about 50% of the time. I am also considering weekly dosing and cycling where time on = time off. With the knowledge we have at this point, I do not see a reason not to try different protocols as long as dosages are kept reasonable.

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#23

Here is my thinking: Rapamycin primarily inhibits mTORC1, which we are trying to modulate.
After taking a dose of rapamycin and then exercising in the next one or two days you will start to negate the effects of rapamycin on mTORC1.

I cannot find any evidence that rapamycin inhibits mTORC2 to any extent when taking rapamycin at the levels we are taking it for life extension. The practical evidence that it does suppress mTORC2 in some members of this forum is the fact that some users experience mouth sores etc. I have been taking rapamycin mostly weekly for the past 2 ½ years and have not experienced this or any negative effect on my immune system. I have caught no bugs even though I am exposed to a diverse population daily.

Other than the reports of mouth sores, a little acne, etc., I do not find many regular users reporting increased illnesses.

“Although mTORC2 is not acutely inhibited by
rapamycin, subsequent studies have shown that mTORC2 is inhibited
in cell culture as well as in vivo in mice when exposed to high concentrations of rapamycin for a prolonged period of time,”

“Though rapamycin does not directly interact with mTORC2, attaching with mTOR in a complex form with FKBP12, it can indirectly affect mTORC2”

Targeting the biology of aging with mTOR inhibitors | Nature Aging.

Recent advances and limitations of mTOR inhibitors in the treatment of cancer | Cancer Cell International | Full Text.

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#24

How many weeks after my full dose would you recommend I check? Or is even one week fine?
I took 1mg, then 3mg, and this week I took 6mg.

I see I should check the day before the next dose is due. Do you happen to know if that test should be fasted?

#25

What you wanna bet that the once a week dosing started as a couple guys after a couple drinks doing a little math on a napkin and saying “how about a week between doses?”

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#26

@约瑟夫_拉维尔 It’s amazing how we’ve followed the same dose trajectory. I am alternating between taking 4 mg + GFJ + fatty meal one week and then a ‘rest’ week of 1 mg + GFJ + fatty meal the next. The question is, does that extra 3 mg equivalent dose do much on the ‘rest’ week or should I just skip it altogether.

The great thing about dosing with Rapamycin is that even if you’re really wrong, you probably won’t cause any permanent damage (Remember that guy who took 500 mg equivalent at one time???). You simply have a less optimal result.

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#27

@DeStrider it’s a good question. For my own program I feel it is important to get to zero rapa in the blood regularly. This can be done with longer periods or holidays. The key, as always, is to measure biomarkers and assess progress. I have a blood test scheduled next week to catch up on my measurements that I had let slide a bit.

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#28

I believe there has been some discussion that significant increases in lipids or triglycerides may be caused by mTORC2 inhibition. In Joan Mannick’s studies at 5mg Everolimus per week levels only increased about 3% on average. Maybe it is possible to titrate dosages or timing based on these markers?

#29

Forgive a question that probably shows how much about this topic I don’t understand!! (Still learning!)

I get that rapa or fasting helps with MTOR

I get that the argument, right or wrong, is that too much meat activates too much MTOR (avoiding an internet fight here :slight_smile:

This would lead me to believe that low protein diets are better for MTOR

But, if that is the case, why would rapa cause lipids to go up? To me it would then track that a low protein diet would do the same, and I don’t think anyone says that.

What am I not understanding?

If I’m WAAAAYY off and this will require a ton of time to explain it, then you really don’t need to!!!

#30

I don’t have a definitive answer on the Rap vs Low protein part but I would be asking this.

Is the “effect” on inhibiting MTOR achieved through the same pathways?

Understanding why a particular compound or dietary intervention has similar results is part of the answer. The pathways for similar results are quite often very different.

My guess is that these 2 “interventions” are operating on different pathways and not directly comparable in how they achieve the result or conversely a “side effect”.

So I would start by looking at how Rapa influences MTOR and how protein restriction influences MTOR.

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#31

I think the main question is how long do we want to inhibit mTORC1.
We don’t know how much it affects mTORC2 except it is dose-dependent.
“mTORC2 is not acutely inhibited by rapamycin”
After taking rapamycin in doses of 4mg with GFJ for 2 1/2 years my body must have become accustomed to it because I don’t really feel much of anything after I take it.
The question is how long do we want mTORC1 to be suppressed?
We can modulate this by the timing of our exercise after taking rapamycin.
Resistance exercise initiates mechanistic target of rapamycin (mTOR) translocation and protein complex co-localisation in human skeletal muscle | Scientific Reports.

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#32

I am not sure why Rapamycin can increase lipids. I have seen a few theories and mTORC2 activation is one of them. I have listed a few possibilities. The first two are possibly good and the other two maybe not so good.

  • mTORC1 inhibition
    This occurs during fasting, stimulates lipolysis and the release of free fatty acids into the circulation.

  • Hyperlipidemia
    Chronic rapamycin treatment can cause hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue.

  • Hypercholesterolemia
    mTOR inhibitors can cause hypercholesterolemia in patients with tuberous sclerosis complex (TSC).

Rapamycin up-regulates triglycerides in hepatocytes by down-regulating Prox1 - in a mouse study.

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#33

Regarding #2, the big question to me is WHAT side effects show up. The mouth ulcers are s/w random and I believe are not necessarily dose dependent. Of course of WBC/RBC drop that would be a concern but rarely at these doses (and not a side effect really). So how do you assess for side effects, that is the million dollar question if it will help reach the ideal individual dose, ie side effects =too high a dose. Joan Mannick has suggested that monitoring lipids and glucose may be one way and that is what I am doing with pts and myself. But unfortunately, no way to know if that is really an accurate measure of ideal dosing.

4 Likes
#34

Yes, the amount of Rapamycin you take matters. If you take too little, it might not work well. If you take too much, it could cause problems. Finding the right amount is important for getting the best results without causing harm.

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#35

@elena
So how do you do this?

#36

I’m just following the dosage given by my healthcare consultant.

1 Like
#37

I’m curious how your health consultant came up with your dose. Just the standard 6 mg that everyone uses? Weight based? Etc

#38

In the vast landscape of uncertainty, does the quest for the elusive “correct dose” of Rapamycin hold the key, or does it merely obscure the broader significance?

#39

It is clear that up to a point more is better and then after that point more is worse. Rapamycin is, however, only one of a number of tools to fix the expression of the genome. However, it is best to ensure that the dose and frequency of dose works not necessarily optimally, but at least positively.

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#40

Rapamycin is a U shaped curve. We’re all hunting for the trough of the U. Luckily the curve is quite flat in that too low or high of a dose won’t kill you or cause any terrible problems. Somewhere between 3-20 mg a week or biweekly is probably it.

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