I’ve mentioned on several occasions my concerns regarding high doses of rapamycin and secondary excessive autophagy leading to possible cancer promotion. Here’s an article giving the same caution regarding dosing. They point out that rapamycin induced autophagic stress can directly lead to amyloid plaque formation in the brain. Once again, dosing is everything, and we must be very cautious.
Can you elaborate more on this? I can’t access the article you linked.
See the discussion portion of this study:
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While both tested doses of Rapatar (25 and 5 mg/kg) were equally effective in reducing proliferation in the prostate, evaluation of the overall extent of UG disease demonstrated that the low dose of Rapatar (5 mg/kg, Rapa-5) was most effective in suppressing tumor progression.
but still this converted to 70 kg human (and in addition probably rapatar has higher bioavailability than generic sirolimus or even rapamune):
low dose would be 25 mg / daily
high dose would be 140 mg / daily
I don’t love using the conversion factors. Not sure that they always apply. Humans seem to get responses, both good and bad, at very low doses. We appear to be Much more sensitive than mice.
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Sure, but in human cancer patients if I remember correctly the average dose was still 90 mg/week… but you are saying that that dose might / could promote cancer? I know that this concerns arose with Blagoskony’s metastatic lung cancer… I did not follow his experiments with high doses he did to prove rapamycin is not toxic and how many he did…
What would a low dose be in your opinion in human and what hight dose might be? I know this is highly speculative, but since you use rapamycin and you did some digging into this subject what are your thoughts?
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So let’s assume that prevention is very different from cure. Aspirin has been associated with prevention of colon cancer but certainly not with curing it.
Putting mice aside, MB’s case made me wonder if it were possible for rapa to prevent cancer and also promote it, the difference being dose related. Is there a plausible mechanism to explain it?
In researching this I found that autophagy could be the key determinant, with some amount being beneficial but in excess could be cancer promoting. The study I posted proposed a mechanism for this . In low doses rapa gives some inhibition of S6k leading to inhibition of AKT and this would be cancer preventative. In large doses, AKT is not inhibited, and this would be cancer promoting.
All of these mechanisms were linked to some degree of autophagy.
So now that we have a plausible mechanism, we need to know if low rapa doses cause physiological tissue responses in humans. The Mannick study clearly said yes at about 4 mg/ week. The phase 1 prostate cancer study also showed a response at the extremely low dose of 0.5 to 1.0 mg per week, and responses were fairly long lived even after discontinuing the drug. This doesn’t prove that low doses prevent cancer, only that it’s possible via enhanced immunity.
We also know from case reports that people get effects like acne, fatigue, tachycardia, and insomnia from very low doses. So low doses in humans actually have effects.
To get longevity we must delay age related diseases like CVD, cancer, and dementia in particular and do absolutely nothing to hasten their appearance or aggressiveness. Safety in mice should not be exaggerated in importance.
I think many of us felt that since longevity in mice seemed to follow a dose response curve, that the same may be true for us. We got very cavalier in dosing a rather potent drug. I’ve been on 5 mg for 6 years and will probably back down to 3 mg per week for about 12 weeks followed by a 3 month break. But again, it’s really just a guess, but Everyone’s just guessing. There are No experts with the limited amount of human data presently available.
For now I’m emphasizing safety.
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Yes, I took some time to read the study and trying to understand mechanisms. Yes, it is pretty frustrating since there is so little human data. I understand the caution and safety first, but do you think your protocol of 5mg/week which is pretty standard and conservative needs to be even reduced to this extent? And what is the gain in 12 week break? What risk are you hypothetically trying to migrate with this schedule? IMO and I am playing with this idea since seeing Pankaj Kapahi interview with 1mg/daily for two weeks and two weeks off. Seems more reasonable with similar quantities of rapamycin… but my reasoning was not cancer but more suppression of inflammation factors.
I’m also interested in the alternative dosing schedule. Why do you think it is superior for inflammation?
There’s really nothing standard about 5 mg’s. I remember my first meeting with Alan Green about 6 years ago and he told me in a very compelling fashion what his dramatic response was like to the drug and I asked him how he chose the dose. His answer was very frank and he said that he basically just guessed. I was one of his first patients and he was the first doctor to actually prescribe rapa so I believe that’s how 5 mg per week got started. Nothing particularly scientific about it.
My ultimate goal with rapamycin is to delay age related diseases while mitigating side effects as much as possible . That generally means the lowest efficacious dose, so if there’s evidence from actual human trials, as scant as that may be, that 1-4 mg per week affects the immune system in a positive manner , then that’s what I’ll take.
I don’t want to be in a position where I need to risk medication side effects to treat rapa side effects.
I also see very consistently that rapa has a long memory and that its effects last for quite a while after stopping the drug.
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Sure. What I meant it is the most widely used in people who take it for longevity. Maybe Alan Green was guessing, but Matt Kaeberlein is using in more or less same dose in his Dog Aging Project and this dose was probably not just a lucky guess as they completed a preliminary study ahead that was using if I remember correctly different doses and schedules. It is used off label for some dermatological diseases and we have some studies and data from this studies too. So we are not really clueless. We just don’t know if it will matter for healthspan and longevity in humans. This is where we are like blind leading the blind. That I agree.
But in 6 months I am taking rapamycin I have observed several things that are alone worth taking it no matter the longevity. But yes, my goal was not primarily preventing cancer, I was more let’s try it and see if there will be some difference. If my important markers like glucose, insulin, cholesterol etc. will start moving in the wrong direction I will certainly reconsider.
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Well I was reading several studies for skin diseases where different inflammation factors are involved and they show a good response from chronic schedules and relatively low doses, which makes me think that low level suppression of mTOR is better in this regard and as @rivasp12 pointed out rapamycin effects have certain memory and effects last some time after ceasing the drug itself. I am currently playing this two weeks on two weeks off schedule in my head since it is relatively low dose (and some studies show this might be better for longevity and quality of life = less unwanted side effects) and gives you also a period when your body is totally clear of rapamycin. The second rationale is that schedule must be simple to stick to, so a week is a good measurement. Another schedule that I was playing was week on week off, but week off potentially does not give enough time to completely clear rapamycin from you body.
But the rest will be trying and seeing…
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Please report back on your findings. I am very interested. Thanks.
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Sure, I will. I wont’t be changing anything until mid September when I have medical check up and if everything goes well I will test new schedule for next few months to see if there is any difference in biomarkers and also my personal observations.
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This is exactly why I’m planning to take it, as an alternative to a prescription immune suppressant, and on a similar schedule; starting with a low dose, gradually increasing and maybe pulsing depending on side effects. I start next month and will post results.
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