#31

That sounds much better, does the worm studies by Ora Biomedical have the same definition?

1 Like
#32

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.

4 Likes
#33

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
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
#34

Good points. I just wonder:

  1. Is the lab totally pathogen-free? I assume researchers can bring in germs and viruses (also potentially in food and water).
  2. I assume marmosets are not vaccinated as we are. Lactoferrin also reduces the risk of respiratory infection by 50% (source). And we have antibiotics.
2 Likes
#35

I have a few questions - maybe somebody knows the answer:

    1. Do we have any concrete data yet? (15% is like 10 → 11.5 years or is it 15% of remaining lifespan?)
    1. Do we have data based on gender? (male vs female)
    1. Did it use Rapamycin or some Rapalog like Everolimus?
3 Likes
#36

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

5 Likes
#37

Such excellent news. Only doubt remaining is whether our much lower and pulsed dose will work.

3 Likes
#38

How solid is this - is that published/good team?

#39

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
#40

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.

7 Likes
#41

As always, rapamycin is a candidate to be the new drug of the century. What is the FDA still waiting for? New rapalogs need to be developed urgently

4 Likes
#42

Maybe the dose is daily b/c their lifespan average is about 1/7 th of ours. 1 week of our life approximates 1 day of theirs…However, this still doesn’t explain the extremely high dose.

4 Likes
#43

10mg/day?
I take about 12mg once every two weeks. I feel poorly for 12 hours (I can sleep through most of that). Then I feel sore for 2 days from my lifting workout 24 hours before Rapa due to slower recovery. 4 days after my Rapa dose I’m back to normal and can start lifting again (rode the bike for 4 days after Rapa). I wouldn’t live my life like that all the time to get 15 more years.

This is why my rule is nothing just for longevity. I get an immediate benefit plus a longevity potential, or nothing.

7 Likes
#46

Can you talk me through how a CYP3A4 inducer reduces HL? Which one do you use?

1 Like
#47

It’s a meta-analysis by researchers from the UK, Pakistan, Australia, and Malaysia, in the journal of the European Society for Clinical Nutrition and Metabolism (with a good impact factor of 6), published by Elsevier: https://www.sciencedirect.com/science/article/abs/pii/S2405457721003077

So, it’s not Nature, but it’s descent. (And certainly better than the vast majority of papers (and tweets…) people base their health decisions on…) However it’s a meta-analysis, so the risk is always “Garbage in, garbage out”. I don’t have access to the whole text. We should look at the six trials included to see if they are of good quality.

(The paper was good enough to convince Bryan Johnson and his doctor to try/use lactoferrin.)

1 Like
#49

Thanks. The trials look good (but small-ish). Most in infants indeed but 3 in adults:

1 Like
#50

I’m starting to think so, another meta-analysis of small trials not consisent with larger trial?

We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233).

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32221-9/fulltext

No 43% reduction here.

#51

This trial was not included in the meta-analysis. Although the result is negative, it’s a very specific population: “very preterm infants born before 32 weeks’ gestation in 37 UK hospitals and younger than 72 h”!!! I don’t think it can be generalized to adults.

#52

I think it wasn’t included since it didn’t fit their criteria for URTI.

Sure, but most of the trials in that meta-analysis were in infants, too.

Two of the adult trials failed, one succeded.

The nearly 50% reduction was pretty unbelievable to start with, IMO.

1 Like
#53

No, 2 succeeded, one failed and the one that failed was in critically ill adults: Breaking: 15% Healthy Lifespan improvement via Rapamycin seen in Marmosets - #49 by adssx