What are people’s thoughts about the daily dosing versus the weekly spike? If most are taking once a week, would be nice to see a study that replicates that cadence.
6 Likes
So a 15% increase in median lifespan. That’s what we want. Of course there will probably be an associated increase in max lifespan as well.
When those Rapamycin-taking marmosets eventually do die. I hope that that data takes a looong time to gather. 
8 Likes
gris
#24
Nice, I stand corrected. That’s pretty impressive given the late start.
6 Likes
All that has been discussed and the research gathered in this thread: What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?
Virtually all of us take the rapamycin once every week or once every two weeks. Some, like Bryan Johnson, have a lower dose one week, then a higher dose the second week. Weekly dosing is largely based off the Mannick study that is mentioned in the previous thread, but which @Agetron also mentioned here: New to Rapamycin? Start Here - #42 by Agetron
But this new information in this thread showing how marmosets are getting a significant healthy lifespan effect in a positive direction is something that also has to be considered. The marmoset study is not directly translatable to human application because these marmosets live in laboratory / pathogen-free environments so risks for infections is very low. Humans live in a very different environment, generally.
The issue with daily dosing of rapamycin, especially as you increase dosing levels, is that frequent, higher dose rapamycin dosing results in mTORC2 inhibition. And mTORC 2 inhibition is generally hypothesized to be a bad thing for human health; see this thread: Evidence that mTORC2 inhibition is detrimental, by Dudley Lamming
So I think we have a lot of work to do with regards to what is the optimal dosing regimen for rapamycin in humans. If you are in a lower risk environment (for infectious diseases), then perhaps a higher dose rapamycin on a more frequent basis my not be that risky. But if you have young children, or work in a higher potential risk environment (e.g. school, hospital, etc.) then perhaps a lower dose is in order.
This is a whole new conversation that we need to dive deeply into, and which will require much more research. But at least we have some guidance on what direct to test now…
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AnUser
#26
That’s basically helping people who would previously die before the normal life expectancy, is that correct?
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It is saying that when looking at the populate they treated with rapamycin, those mamosets lived 15% longer on average than the control group which didn’t take rapamycin.
If this translated to humans, then humans taking rapa would live on average 15% longer.
2 Likes
AnUser
#28
What’s maximum lifespan then, just how long any individual lived?
People can choose their own definition of “max lifespan”, but Richard Miller has suggested it doesn’t matter so much and is largely driven by sample size (the larger the sample, the greater the likelihood of some outlier with higher lifespan). But for practical purposes Richard Miller has suggested (and used in the ITP I believe) the “Max Lifespan” be defined as the lifespan of the last remaining 10% of the cohort.
I’m not sure how Martin (above) or Adam Salmon, have defined “max lifespan” in this situation.
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Maximum lifespan is usually the age at which 10% of the cohort is left, I believe. Median is when it’s 50%. Please correct me if I’m wrong on this.
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AnUser
#31
That sounds much better, does the worm studies by Ora Biomedical have the same definition?
1 Like
I appreciate that the research was conducted in more clinical laboratory conditions, but I still fail to understand why they opted for such a high dose. If the aim was to use this study to gain a better understanding of the potential to improve lifespan in humans, would it not be more sensible to use much lower dosing? The equivalent of about 13-14mg daily (for an 80kg man) is entirely different than any of us here will be using. This also means that the resulting 15% increase in healthy lifespan could be only a fraction with our dosing. We saw for instance the same with the ITP testing of Astaxanthin. It’s very encouraging on the one hand, but frustrating at the same time as we have to second guess if our dosing makes any difference.
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I forget the exact rationale for the 1mg/kg dose level. We’ll have to ask Adam Salmon.
But - I suspect they looked at the mouse data, and then implemented a dose that seemed reasonable given the mouse positive results. The 1mg/kg seems to be right in two of the ranges that the NIA ITP had studied (in terms of mg/kg) and had positive results. The 1mg/kg in human terms seems to equate to somewhere between 14ppm and 42ppm that the NIA ITP tested with good longevity results.
You can see the human mg/kg dosing equivalence in these mouse studies below (I imagine the were trying to dose at this level and see what if any the adverse effects were for primates).
I think it remains to be seen whether we can translate this dosing (in some manner) to humans. 10mg/day is definitely high - but perhaps there is a pulsed dosing approach that minimizes side effects and maximizes benefits. its still early in testing this type of thing in humans and working to moderate risks or downsides.
Sirolimus
Dose |
Mouse
mg/kg/day
Dose |
Mouse:
Blood/Sirolimus
Level |
Human
mg/kg/day
Dose |
Dose for 60kg Human |
Daily Dose adjusted for longer half-life (/4) |
| 4.7ppm |
∼2.24 |
3 to 4 ng/mL |
0.182 mg/kg |
10.92 mg |
2.73 mg |
| 14ppm |
~6.67 |
9-16 ng/mL |
0.542 mg/kg |
32.54 mg |
8.135 mg |
| 42ppm |
~20 |
23-80 ng/mL |
1.626 mg/kg |
97.56 mg |
24.39 mg |
| 126ppm |
~60 |
|
4.878 mg/kg |
292.68 mg |
73.17 mg |
| 378ppm |
~180 |
45 to 1800 ng/mL |
14.634 mg/kg |
878.04 mg |
218 mg |
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Sirolimus
Dose |
mg/kg/day
Dose |
Blood/Sirolimus
Level |
Male Median LS Increase |
Female Median LS Increase |
|
| 4.7ppm |
∼2.24 |
3 to 4 ng/mL |
3% |
16% |
|
| 14ppm |
~6.67 |
9-16 ng/mL |
13% |
21% |
|
| 42ppm |
~20 |
23-80 ng/mL |
23% |
26% |
|
5 Likes
adssx
#34
Good points. I just wonder:
- Is the lab totally pathogen-free? I assume researchers can bring in germs and viruses (also potentially in food and water).
- I assume marmosets are not vaccinated as we are. Lactoferrin also reduces the risk of respiratory infection by 50% (source). And we have antibiotics.
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I have a few questions - maybe somebody knows the answer:
-
- Do we have any concrete data yet? (15% is like 10 → 11.5 years or is it 15% of remaining lifespan?)
-
- Do we have data based on gender? (male vs female)
-
- Did it use Rapamycin or some Rapalog like Everolimus?
3 Likes
I forget where I read or heard it, but I recall the half life of rapamycin in marmosets being a lot shorter than humans.
This post doesn’t give the half life exactly, but indicates a fairly low trough level after 24 hours after a 1 mg/kg dose:
In our previous pilot study, we
showed that the delivery of a dose similar to this produced trough
concentrations (24 hr since last treatment) of rapamycin of ∼5 ng/ml
(Tardif et al., 2015). This previous report also details the pharmacokinetics
Here, with approximately double the number of
animals, the average trough concentration of rapamycin for all animals
24 hr after dosing was 6.4 ± 1.0 ng/ml
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Such excellent news. Only doubt remaining is whether our much lower and pulsed dose will work.
3 Likes
Neo
#38
How solid is this - is that published/good team?
The only information we have is what is posted above. It was from a presentation that Adam Salmon did at the conference, so we are only hearing second hand info.
The group of marmosets are the same ones that they reported this study on (looking at OA), so you can get some details from it: https://www.biorxiv.org/content/10.1101/2024.05.14.594256v1
They used oral rapamycin ( I think it is E-rapa).
2 Likes
Are humans the only species that see a deterioration in lipid profiles? I think I recall there was for rats in one study too. It’s something that would be great if we got to the bottom of.
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