#1

This trial was discussed by the principal investigator, Dr. Adam Konopka at the University of Wisconsin, in a presentation to the Transhumanist Party webcast starting around 32:33 here:

This will be by a substantial margin the best human trial of a rapalog for aging in people without overt disease yet launched.

The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve physiological and molecular hallmarks of aging in humans. [86] Participants who are 55-80 years old and insulin resistant or prediabetic will be randomized to treatment and can expect to be on study for up to approximately 38 weeks. Participants aged 18-35 will not receive the intervention and can expect to be on study for up to approximately 8 weeks.

The two dose regimens are the same as in the original Joan Mannick trial, which is where everyone got the once-weekly regimen from, with two different placebos to match against the alternative doses. The primary outcome will be insulin and glucose response to an OGTT (using labeled glucose in the dual-tracer method) but they’re going to do a lot of testing of subjects over the course of the trial.

Using a double-blinded, randomized, placebo-controlled clinical trial, the investigators will perform a battery of gold-standard and innovative techniques to test the hypothesis that daily low dose or weekly everolimus treatment will improve 4 inter-related domains of physiological aging: metabolic, cardiac, cognitive, and physical function. The investigators will also assess the incidence of adverse events and changes from baseline blood chemistry, blood cell counts, lipids, glucose, and insulin.

To comprehensively examine the molecular target specificity and the impact on mechanisms of aging by everolimus, the team will evaluate mTORC1 and mTORC2 signaling, assess mitochondrial bioenergetics, and perform a multi-omics approach (epigenomics, transcriptomics, proteomics, lipidomics, and metabolomics) in blood and/or muscle biopsy samples.

|Actual Study Start Date : |March 24, 2023|
|Estimated Study Completion Date : |December 31, 2026|

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#2

This is amazing news

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#3

The dosing is disappointingly low (which I believe may minimize the results they see). Everolimus is roughly equivalent to 2/3 of a dose of rapamycin, so its like taking rapamycin at 3mg or so for 24 weeks. I’m sure they did this to minimize risk as seen by their IRB, but I’m not sure they will see much in the way of results at that dosing level for 24 weeks. I hope I’m wrong.

Drug: Everolimus 0.5 MG once per day
Drug: Everolimus 5 MG once per week

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#4

Remember that these are 2 of the 3 doses successfully used in the original Mannick trial, with 5 mg once weekly as the best of the crop.

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#5

Very exciting in general. Look forward to seeing what they find around this:

Also wonder how they will be doing that and whether perhaps non trial participants could do such testing somehow?

#6

There was a thread on this{testing mTORC1]

If you did not see, review link below;

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#7

Thank you @Joseph. Did you ever ending up finding a way/place to measure mTORC1 (and 2)?

#8

I have posted before cost is around $4,000 to do each test.

All standard off the shelf equipment.

All out of pocket payment.

Not willing to spend $8k for two test.

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#9

Wow, yeah, not me either.

Seems like a business opportunity for someone to run with as more and more people around the world are taking up rapa…

#10

Yes - for the immune response and for side effect profile. Given the “higher is better” results of rapamycin dosing in mice longevity studies, I have to suspect that the optimal dosing for rapamycin for longevity is higher than the optimal dose may be for immune response in the short term. But as with so many things, we really lack clarity on this from a research perspective.

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#11
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#12

Rapamycin shortens lifespan in mice with diabetes:
https://academic.oup.com/biomedgerontology/article/71/7/850/2605132?login=false

I don’t think it will work - they got participants that are the worst candidates for Rapamycin

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#13

“The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve physiological and molecular hallmarks of aging in humans. [86] Participants who are 55-80 years old and insulin resistant or prediabetic will be randomized to treatment and can expect to be on study for up to approximately 38 weeks. Participants aged 18-35 will not receive the intervention and can expect to be on study for up to approximately 8 weeks.”

The dosing, timespan, and participants make this appear to be a weak trial. Hopefully, it won’t produce negative results for this participant group, but that may depend on the tests being given.

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#14

I’m puzzled as to why people this trial seems like it won’t “work”. Are people worried about negative results? Negative results are still useful. Are people worried that there won’t be much difference between the medication and placebo? That seems unlikely, but still useful .

I’m just happy this study doesn’t involve mice for once. Don’t let the perfect be the enemy of the good here.

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#15

There are some problems with that study:

    1. Rapamycin in mice with diabetes SHORTENS lifespan - here they choose people with prediabetes. Rapamycin increased lifespan in 90% types of mice, but not here - they choose type of people that will respond the worst
    1. They measure blood chemistry, blood cell counts, lipids, glucose, and insulin - all of this is impaired in mice with Rapamycin - even though Rapamycin extends lifespan in normal mice, it still causes high glucose, high cholesterol, low blood counts - so they measure traditional “markers of health” - all of this probably will be worse (based on studies on mice)
  1. Rapamycin is for now the best drug in mice for lifespan extension - but this is study has very low probability of success - I don’t know why they didn’t add Acarbose or Metformin - it had better results in mice than Rapamycin alone - Acarbose removes high glucose from Rapamycin
    Also, just compare this 2 survival curves for male mice (14 ppm Rapamycin + 14 ppm Rapamycin + 1000 ppm Acarbose):

https://phenome.jax.org/itp/surv/Rapa/C2009
https://phenome.jax.org/itp/surv/RaAc/C2017

  1. Good thing is that they measure: epigenomics, transcriptomics, proteomics, lipidomics, and metabolomics - but the problem is that most clocks don’t show any difference in Rapamycin treated mice in blood - most epigenetic clocks showed that Rapamycin doesn’t slow down epigenetic clock in blood (it had some effect on liver and some other tissues but not blood)
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#16

All your evidence points to mice studies. Human studies might or might not replicate results found in mice. In either case, it will be a useful data point going forward.

We have a lot of mice knowledge. We need more human knowledge.

#17

Usually when you design clinical trials you design them in a way that maximizes the probability of “positive” results - i.e. the results you hope for. The concern i have is that the Institutional Review Board is likely extremely risk adverse and so has forced Adam to accept the shortest time period and lowest dosing protocol. Unfortunately that lowers the probability of success. And if it fails then more clinical trials are less likely.

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#18

Thanks for the explanation, that makes sense.

#19

Anyone who wants to learn more and is considering everolimus instead of rapamycin, see this thread here: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?

#20

I do share this concern: whether you look at blood levels or convert doses based on metabolic rate, the animal studies suggest that even standard clinical doses may not be enough, let alone these. I expect that they were (a) trying to replicate a positive previous result, and (b) being conservative with safety for the IRB and maybe the NIA, and (c) thinking of real-world translation: many people on this forum are willing to put up with a lot of side effects and non-trivial risks, but the average aging person likely won’t — especially since we’re never going to get a lifespan study and may never get one with hard outcomes.

I’ll spell it out: if the results are indistinguishable from placebo (=negative), then we won’t know if the dose was too low or if it just doesn’t work. We would really like to know the difference :wink:. And after a negative result, neither the NIA nor anyone else is likely to pony up the rather large amount of money it will already have taken to run this first trial just to give it another go at a higher dose.

That’s a very good point. On the other hand, the mouse model in the study you’re referencing is the db/db mouse, which develops quite severe diabetes and obesity and is extremely short-lived (" The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively."). It’s plausible that people who are only slightly insulin resistant might respond differently. I wish we had more rodent data on this question.

To play Devil’s advocate a bit, 72% of the US population is overweight or obese, and 48.8% of adults over the age of 65 are prediabetic, so it would be unrepresentative not to at least have a lot of prediabetic people in the trial.

There are safety signals they will need to monitor. In the original Mannick trial and other studies using these doses nothing too awful happened on basic CBC and clinical chemistry; provided that happens again in this larger study, having the bloodwork be broadly consistent with what’s seen in the mice will be evidence of translatability.

That would introduce serious confounding: scientifically, you’d really want to go step by step. Also, the acceptability of acarbose by Americans is low (GI issues), and the doses used in the ITP are really pretty astonishing and unlikely to be translated.

Would you please identify your source for this?

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