Thorin
#138
You are redefining clinical significance (in my opinion) to be “medically significant in your opinion.”
Antibody titers may be extremely important but they don’t have “a real genuine, palpable, noticeable effect on daily life” whereas, say, pain and shortness of breath upon exertion does. So in the common parlance antibody titers are not clinically significant (although they may be medically important!).
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Karel1
#139
The following question came up reading other posts in this topic:
- are peak levels most important to reach our goal of longevity
– do they need to be above a given value to reach and bind to the target (mTOR1)
– do they need to be below a given value to avoid important adverse effects
– will anything above certain values/doses just go down the drain
- are through levels most important (absent the drug holidays)
– do they need to be above a given value to create the effect
– do they need to be below a given value to avoid important adverse effects
or is it the AUC (area under the curve) that is most important.
concentrations either free rapamycin or total (including protein bound fraction)
high peaks can be avoided by spreading intake over multiple doses, and still getting similar or higher through levels depending on the dosing interval…
I would be inclined to go with @RapAdmin and avoid drug interactions as much as possible especially GFJ.
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It’s possible that Acarbose and 17a estradiol help a bit with mTORC2 but I doubt they will help much. I’ve seen many anecdotes of people having signs of mTORC2 inhibition (like elevated lipids and higher blood glucose) despite the fact that they are taking acarbose also.
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This does seem like something we all want to test and see the response on our own bodies. It would be interesting to test (blood sugars and lipids) on a given dose of weekly rapamycin (after you’ve been taking that level/dose for a few weeks), then retest with dosing levels of acarbose - 50mg/meal, 100mg/meal, 200mg/meal, etc. I wonder if there is a good dose reponse relationship with acarbose and mTORC2 activation. The human dose equivalent of acarbose used in the ITP trials is considerably higher than the 100mg per meal that I think is the typical recommended dose of Acarbose for blood glucose control.
Fasting also helps with mTORC2 activation, so perhaps different levels of fasting is another variable we should consider and test.
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Neo
#142
Thanks @Olafurpall
Do you have a sense of the dosing sizes of the rapa vs acarbose in those contexts?
My other question is, how strong is the relationship between mTORC2 being the driver of those two issues?
For instance, this thread here suggests that rapa might increase glucose in ways that are independent from mTORC2 via less + damage to beta cells. My CGM data while on Rapamycin - #34 by Neo
These threads are reasonable starting points to investigate the mTORC2 inhibition side effect theories (see also the links to pubs within the twitter posts):
and related:
mTORC2 takes the longevity stAGE
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25294787/
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Neo
#144
Thx for share of that last paper - found this very interesting:
We have determined that mTORC2 is required for the normal lifespan of male, but not female, mice [6].
Chronic treatment with rapamycin, which inhibits both mTORC1 and mTORC2, is more beneficial to females than males, which may be due to the negative influence of mTORC2 inhibition on male lifespan.
Sex-based side effects may be seen during the clinical use of mTOR kinase inhibitors for cancer treatment.
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IMO: The way to easily increase mTORC2 is to upregulate mTORC1 the following day after taking rapamycin by exercising and eating proteins. Amino acids are a positive regulator of mTORC1 activation. This is what I do to modulate mTORC1.
When amino acids are low or become limiting, mTORC1 activity declines.
“Since rapamycin allosterically inhibits mTORC1 but not mTORC2, most of the studies on mTOR pertain to mTORC1.”
“mTORC2 activation is enhanced by withdrawal of amino acids (e.g., glutamine) and by glucose starvation in the presence of serum”
‘Inhibiting mTOR by rapamycin also increases the expression of growth factor receptors such as IGF1R, thus further enhancing PI3K/mTORC2 signaling (124). Elevated mTORC2 signaling feeds back to dampen insulin signals via mTORC2-mediated regulation of IRS-1 turnover, thereby subsequently downregulating mTORC2 (125).’
“An allosteric effect is when a change to one part of a molecule or enzyme (such as effector binding) structurally changes another part of the molecule or enzyme (such as the active site of an enzyme).”
The bottom line is; that we need to find out how much inhibiting mTORC1 affects mTORC2. We are assuming that slow wound healing, mouth sores, etc. after taking rapamycin represents a significant suppression of mTORC2. The anecdotal fact that I never catch anything belies this.
Regulation and metabolic functions of mTORC1 and mTORC2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424549/
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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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