Guest
#146
Concerning data on mTOR activity I would be skeptical: as of my knowledge, in humans these were entirely generated out of blood cells, i.e. the type of cells by far most exposed to any intake of rapa. A notable paper would be:
https://ascopubs.org/doi/10.1200/JCO.2007.14.1127
which informed the Mannick papers
Whereas the mTOR activity in the ITP was measured in visceral fat pads of mice, i.e. tissue not directly exposed to circulating rapa, but eventually affected as high dose rapa is penetrating every tissue:
[I’m a new member and can’t post a second link]
quote:
“To test effects of rapamycin on mTORC1 targets, we measured phosphorylation of ribosomal protein S6 (Ser240/244), a substrate of S6 kinase 1, in visceral adipose tissue. Adipose tissue was surgically dissected from mice that had been fed rapamycin diet for 420 days”
Also note it appears, that the marmosets are only receiving rapa Mo-Fr and not Sa/Su:
[I’m a new member and can’t post a third link]
quote:
“Animals were dosed Monday-Friday with dose received between 08:00 and 10:00. Animals were not dosed on Saturday or Sunday.”
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Neo
#147
Can you reply to this with a source on the above?
Guest
#148
of course, dear Neo, it’s:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415526/
“Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets.”
which is the pilot phase of the marmoset trial discussed in this thread
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A good question to ask then would be home much mTOR inhibition is occurring in human adipose tissue at dosages humans are taking. I think this would inform us as to whether or not our dosing is accurate.
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Guest
#150
It may be of interest, that in a previous pilot trial, lower circulating blood levels of rapa in marmosets resulted in marekedly less mTOR inhibition:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400395/
This trial also collected data of liver tissue and adipose tissue of marmosets. Only individuals with a high circulating levels of rapa got mTor suppression in liver/fat tissue. Those monkey with blood through levels of 1.93–2.43ng/mL did not achieve notable mTor effects outside of blood cells.
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That’s all good, but I think it would be more valuable to find out what happens in human adipose tissue regarding mTOR inhibition for someone taking Rapamycin. Then we could correlate blood levels with tissue levels.
If tissue levels of mTOR inhibition aren’t high enough, then dosage levels are probably too low.
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Guest
#152
Sure, I agree - someone needs to test that in humans.
I was more reasoning about previous posts claiming significant mTor inihibition even at lower doses/blood levels in humans (as in the Mannick papers). As outlined these are based on blood cells, while the mice studies used adipose tissue. And the pilot trials in marmosets demonstrated, that lower through levels of rapa in blood inhibit mTor in blood cells - but they do not achieve mTor inhibition in liver and adipose tissue.
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This kind of confirms my belief that the recommended 6mg/week dose is pointless. Anything below 20-30mg as a single dose won’t sufficiently spread through tissue and it is an open question whether taking such a high dose weekly or biweekly has the same longevity effect as taking it five times a week.
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Guest
#154
Well; the recommendations were never based on clinical outcomes or reliable markers of clinical outcomes. Peter Attia for example explicitly states that he got no real idea if it’s doing anything impactful and is going by the strategy of minimizing side effects.
It’s just a strong possibility, that dosing to minimize side effects equals dosing to minimize actual effects.
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I tend to think that the path towards optimizing the benefits of rapamycin in terms of lifespan and healthspan is through rigorous testing and carefully increasing doses to higher levels. Exactly what “higher levels” means, is still an open question. Perhaps its time to reopen discussions around this topic: Ideas on Protocols for Testing Higher Rapamycin Doses
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Put me in for the unpopular “lower is better” camp for rapamycin dosing. After taking between 3 and 5 mg every week for about 1.5 years. I stopped, mainly due to consecutive increases (over 6 months) in apoB numbers and fasting blood glucose, which couldn’t be explained by changes in diet or exercise regimen (those 2 stayed the same). So it looks like my “intermittent” dosing had become somewhat chronic over time.
After a 6-month break, I re-started back with 2mg, and got a very strong immune response, akin to taking a flu/COVID shot: low-grade fever, nausea, fatigue, gastrointestinal distress. These symptoms lasted a full 10 days. To me, this indicates that my dosage is enough.
I plan to take 1-2mg every 2 weeks in the future, just to make sure my dosage is truly intermittent. I believe that at least in my case that more is not necessarily better, and I might get 80% of the benefits on 25% of the “adequate” dosage, akin to how statins work. I’ve also always believed that some side effects like canker sores, elevated blood sugar, etc are signs my dosage is too high.
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I’m in your camp bud. I took 6 mg for 1 year and a 1/2. And had excellent biological markers.
I started increasing my dosage up to…
30 mg, and 7 months later it was a shit show from my biological markers stand point.
I’m back on at 4 to 8 mg. Going on 1 1/2 years. And all my bological markers look great again.
My next biological markers results should be back within the week – GlycanAge and TruMe.
I cringe every time I see somebody on this site… pushing for higher and higher. Blogsklonny did that, but he also has major cancer. Matt Kaeberlein, who knows all the research, also wasn’t sold on higher is better. He doses at 8mg weekly. Just say’in.
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Same here:
-
2-3 mg + GFJ - excellent immune response to usual events like colds/flu (+substantial reduction in autoimmune conditions); blood glucose in the normal range.
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4-5 mg + GFJ - huge volatility of blood glucose and fasting glucose in the prediabetic range, plus one case of tooth root inflammation with subsequent surgical root tip resection (might be just a coincidence, but I never had something like this before).
Unfortunately, I am not able to test blood levels of rapa in Germany. 
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Neo
#159
Wow, that is frustrating- why is that? Clearly they must be testing in and many thousands or organ transplant recipients around the country?
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Sneak peak
… got my GlycanAge results on body inflammation. My 66 year-old body is measuring at 44 years old, meaning a 22 years difference, which is about the life extension years… rate you’re supposed to get from constant rapamycin use in life extension.
Very positive about my 8 to 12 mg weekly dose coming from 4 mg zydus with fresh 5 ounces Red GFJ at dosing.
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Awesome results @Agetron
I’m right there with you with the 4 mg + GFJ weekly! Let’s live longer and set a great example for everyone else.
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Bicep
#163
That’s the dose I use every 2 weeks. Maybe I shouldn’t watch my lipids and blood sugar so closely, but I’m sticking with this for a while.
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I’m not sure what you’re asking here. If you’re wondering what doses of rapamycin are needed to inhibit mTOR2 and how much acarbose is needed to partially prevent that, that’s going to be very individual. In case of rapamycin it depends just as much on the frequency than the dose.
I would say it’s very strong. As far as rapamycin increasing glucose in ways that are independent of mTORC2 such as by damaging beta cells, I strongly doubt that’s what we are seeing in people that take rapamycin weekly and notice increased blood glucose. The reason why is because most of these people are healthy with healthy beta cells and their blood glucose improves again in a matter of weeks after stopping the rapamycin. If it were caused by damage to beta cells I doubt it would recover nearly that fast if at all. Another reason why I think this is the case is because organ transplant patients will get a lot more mTORC2 inhibition than the people taking weekly doses for longevity, yet they don’t seem to be getting type II diabetes left and right due to beta cell destruction. That said, it’s good to keep in mind that high doses might have negative effects on the beta cells.
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Apparently not: the lifespan cohort was started at age 7, and 15% is median:
https://spotify.localizer.co/uploads/default/original/3X/0/d/0d28cb6151909debfc25b88e36fe5750846d1757.jpeg
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That would be the case if it only increased median. They don’t have data on maximum yet; obviously animals that outlive all the controls because of rapa would still contribute to increased median LS, but would not be animals that would otherwise have died prematurely.
Different researchers calculate it differently: traditionally it’s the average LS of the longest-lived 10% of the group, or it’s the first death of the longest-lived 10%. More recently a more complicated, less intuitve, but more robust test (Wang-Allison II) has been used.
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