Do You Have Questions About the Marmoset (monkey) Rapamycin Studies?

I’m hoping to talk next week with Adam Salmon who has been running the Marmoset / Rapamycin trials for many years. If you have any questions about his research, post them and I’ll try to get answers.

His published papers on this topic are below:

DNA methylation age analysis of rapamycin in common marmosets

Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets.

Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate

Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus)

Mouse Studies:

Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging

Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice

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Any compelling questions people have on these studies and their implications for humans? Please post.

Are they going to do a lifespan trial on marmosets? Who funds these things?

Slightly unrelated, the only animals we have here on the farm (besides dogs and cats) would be goats. I wonder if the Rapa would make it through the rumen. I think it’s ph neutral and sits in there for about 3 days.

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I’ve been reviewing all the papers in preparation to talking with Adam later this week. These papers are really interesting because they may provide the best longterm studies for people to go by until real human clinical trials are done… which may or may not ever happen.

The results are extremely encouraging. I didn’t realize it before - but they are dosing these monkeys at 1mg/kg of rapamycin - which would equate to us taking like 50mg or 60mg per day… so the doses are aggressive…(of course, these monkeys are housed in pathogen-free cage environments, do don’t try this at home folks).

See more below. If you have thoughts on additional questions, please add to them below:

9 month Rapamycin / Marmoset Study:

Questions about the August 2018 Paper on Rapamycin in Marmosets

23 middle aged marmosets, 9 month study on rapamycin.

A total of six males and six females received
rapamycin for this period while five males and five females were
included in the control cohort; one control female died prior to this
time point and was not included in further data analysis.

How often did you do Blood Tests on the animals during the 9 month period?

While at the end the hematological markers were only minimally changed, do we know if it was that way during the entire study duration, or were there earlier blood measure disregulation that moderated over time?

Do we have a sense for how much the immune systems in these monkeys has been supressed at this dosing? Do we understand the dose/response relationship of rapamycin on the marmoset immune system? Are you measuring TRegs in these marmoset studies?

What biomarkers / epigenetic / “omics” based pre and post testing are you doing on the marmosets as part of the larger study. Did you do any on this study - and did you have any results you can share?

1mg/kg dosing for nine months. What level did your group estimate the 1mg/kg dosing in marmosets to equate to in terms of the ppm dosing in mice?

You reported on the trough blood/sirolimus levels. Did you also measure the Peak (or AUC) for the rapamycin levels in the blood during the study?

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 of5 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

we found that rapamycin concentrations in male marmosets were significantly higher than those in females (Figure 2). Rapamycin concentrations in the blood averaged 8.4 ± 1.7 ng/ml for male marmosets and 4.4 ± 0.6 ng/ml for female marmosets.

we found no significant
effect of sex among these changes and a significant effect of
rapamycin on only two outcomes: change in red blood cell (RBC)
count and change in basophil count (Table 2). In both cases, rapamycin
resulted in significantly higher values for these outcomes compared to
samples from control animals. We also found no significant interaction
effects between sex and rapamycin treatment. Importantly, rapamycin
had no effect on total white blood cell (WBC) count or on any particular
leukocytes other than basophils. In general, this would suggest
rapamycin is not driving a general decline in immune cell count at this
point in treatment.

Rapamycin also had no significant effect on changes in fasting
blood glucose, cholesterol, or triglycerides compared
C-reactive protein levels were also unaffected by sex
or rapamycin treatment suggesting limited effects on general
inflammation among these animals

In this study, we report at least two important findings from a novel
cohort of marmosets enrolled in a study to test the effect of rapamycin
treatment on longevity in this species. First, we report that among
middle-aged animals in our unique specific-pathogen free marmoset
vivarium that there are few hematological differences between male
and female animals prior to treatment. Second, the effects of chronic
(9 month) treatment with rapamycin has relatively minor effects on
hematological markers and, importantly, no marked clinical manifestations
of significant potential side effects noted for this drug, namely
thrombocytopenia, leucopenia, and anaemia (Hong & Kahan, 2000;
Kreis et al., 2000). our results suggest little effect of rapamycin on these
clinical laboratory markers through at least 9 months of treatment.

Overall, this suggests that it is largely safe and, potentially, that
detrimental effects on hematological markers previously noted for
rapamycin may be limited at this particular dose, time-frame and
species.

In a previous study we also mentioned no significant effect of
rapamycin on some hematological markers in marmosets (Tardif et al.,
2015) and a similar lack of effect was noted on clinical hematological
parameters in dogs treated with rapamycin, albeit at a much lower dose

Rapamycin has been associated with
hyperlipidemia, but again generally in health-compromised populations
(Morrisett et al., 2002). Here, and before (Ross et al., 2015), we
report limited effects on lipid panels in marmosets treated with
rapamycin.

Paper: Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate

You mentioned that “Finally, autophagy was increased in skeletal muscle and adipose, but not liver, from rapamycin-treated marmosets."

Do we have an idea how much autophagy was increased via the rapamycin at that dosing, and do we have an idea of the dose/response relationship for autophagy triggered by rapamycin in marmosets?

You mentioned:

We previously reported that chronic treatment of marmosets
with eudragit-encapsulated rapamycin inhibited
mTORC1 in peripheral blood mononuclear cells, liver
and adipose (23). In tissues collected from those same
animals, we show here a similar reduction in skeletal
muscle mTORC1 signaling

Do you know if mTORC2 was also inhibited in these monkeys? Given what we see in mice, daily 1mg/kg of rapamycin in marmosets would be expected to inhibit mTORC2 don’t you think?

Do you have any knowledge as to whether there is different levels of tissue specificity of different mTOR inhibitors / rapalogs, like everolimus compared to rapamycin?

Do you have any idea about how well rapamycin penetrates the blood/brain barrier in marmosets?

Larger Rapamycin / Marmoset Study:

How many marmosets total, controls?

When did the study start? When will it complete?

Will any interim results be available or are they available?

Are you familiar with any other longevity-oriented rapamycin animal trials going on or starting soon?

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Agree, that’s a crazy high dose. It’s hard to imagine taking 50-60 mg of rapamycin once per week let alone once per day. Like you, I’d be interested in the rationale of such a high daily dose, and wonder if he’s looked at the once weekly dosing and at lower levels like most people are doing.

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The good news is that we now know ultra-high doses won’t kill you.

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Well, the dose is high, but the trough is about right. They didn’t mention what the peak blood level was? Apparently these animals have a much steeper curve than humans, so not 60 hour half life.

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The marmoset may be the closest relation to humans I’ve seen in testing, but how relatable are the results with such frequent and massive dosing?

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Have you considered suggesting an ITP program for marmosets? There is a possibility that the Hevolution foundation may be willing to provide funding for it.

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Did this convo happen? If so, where can we find it?

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Finally published here: Adam Salmon's Marmoset Longevity Study

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