What Questions about Rapamycin do you have for Researchers?

I plan to interview some rapamycin and NIA ITP researchers over the coming months. Please post any questions you have about rapamycin that you think the researchers might be able to answer and I’ll try to get responses. (obviously don’t ask for personal medical recommendations because they can’t give that).

Some Questions I have include:

  • What rapamycin research might we expect to get results on in the coming year, 2 years? - in mice, dogs, monkeys, etc.? What studies by what labs going on right now show the most potential to move our under standing of rapamycin in longevity applications forward the most over the coming years?

(Note: I do know that the rapamycin / acarbose combined NIA ITP mouse study results are completed and in final review - so results will hopefully be published soon. I’m very hopeful of the results of this combined approach…)

  • From the researcher’s standpoint, what would a well-done human clinical study for testing higher doses of rapamycin look like - given the studies that have already been done with everolimus? Would it basically be the same as this study for everolimus, or different? Why?

  • What would be the key issues and risks that a clinical study testing higher doses of rapamycin need to plan for, and what blood tests would they see as most important in a study like this?

In the Dog Aging Study:

  • What is the dose being used in TRIAD in terms of mg/kg?
  • Why is a special formulation of enteric-coated rapamycin being used in the Dog Aging trial?
  • How, specifically, are side effects monitored in the dogs in TRIAD - is it by way of unprompted check-ins with the Dog owners, or are there checklists of possible symptoms that owners report on regularly (e.g. monthly, quarterly, etc.)?
  • What is the timeline for any results being available from TRIAD - are we talking 2023, 2024, 2025? Will preliminary results be made available to the public?

Please add your own questions below…

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Per the recent Attia podcast with Matt Kaeberlein, they’re using 0.15mg/kg once weekly in the Dog Aging Project study. It’s a decrease in dose and frequency from the previous safety/toxicity study because he wanted to help minimize potential risk of side effects while at the same time maximizing adherence to the dosing regimen by making it just once/week.

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Very interested in learning about the known or expected interactions between rapamycin and other anti-aging agents. For example, Dr Green is reported to avoid senolytics during the first week after his rapamycin dose. Or, e.g. do we risk too much autophagy when we combine rapa therapy with spermidine? And besides the risk of over inducing, might we be hindering the beneficial effects of rapa by, e.g, consuming DIM, as Davin8r pointed out,

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Questions:
#! What is average time from ingestion of rapamycin to peak plasma levels?
#2 What is the rate of decline in plasma levels of rapamycin following ingestion of a dose and reaching peak plasma levels?
#3 Are the generic sirolimus manufacturers using the same nanocrystal technology that Pfizer uses in Rapamune?

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Do dogs have sirolimus induced inflammation similar to human? What’s the proposed mechanism behind it? And what’s the intuition to avoid/reduce it

What is the most obstacle in longevity progress (ex: Investment way, cultural norm, lack of people, law…), and how to improve it?

What do you think the most urgent thing needed in longevity research field now?

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Is anyone adjusting their dosing of rapamycin because of covid? It appears that rapamycin is contra-indicated for the new pfizer anti-covid drug. Should we be concerned by that? (Maybe the covid issue could be elevated to a category to discuss?)

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There seems to be a significant difference between the weekly & bi-weekly strategies. The 1st has a lower dose but keeps a consistent level each week & doesn’t wash out to the extent of the bi-weekly. The bi-weekly has a much larger dose initially but is offset by a much lower average in week 2, w/ a more significant washout at the end. Which strategy seems the best bet given our current understanding?

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Can rapamycin (at high enough doses) increase blood glucose spikes by inhibiting mTORC2? (I just had one lb of strawberries spike my glucose to 175 [and still counting…]) which, like, usually doesn’t happen [though i last had rapamycin almost a week ago). Maybe it’s the 2000mg of metformin I took…

Would rapamycin synergize well with SGLT inhibitors b/c of this? (b/c SGLT inhibitors bring down glucose spikes)

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Omg, I’d love if you could ask any of these questions:

(i) How do rapamycin and dietary protein (or lack thereof) interact with respect to
(a) prevention of sarcopenia
(b) protein synthesis ?
If rapamycin intake doesn’t affect protein synthesis, this means that mTOR is not necessary for protein synthesis? If not, what is the mechanism by which protein synthesis continues to takes place?

(ii) How exactly do fasting and rapamycin differ with respect to mTOR inhibition?
Does fasting /lack of protein inhibit mTOR more or does rapamycin? Any knowledge about tissue specificity for this (for e.g. effects on the brain)?

(iii) It’s known that there are immune benefits of rapamycin w.r.t vaccines and generated antibodies that can be observed a week or so after the dosage. BUT does taking rapamycin cause any immediate issues w.r.t immunity against viruses?

(iv) What is the impact of rapamycin on the effect of senolytics? For the best benefit, would one want to take these together or apart from each other?

(v) It is said that rapamycin reduces the body weight set point. By what mechanism does this happen?

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Are there any answers that go beyond intelligent guesses to the once per week vs once every two weeks at double the dose question?

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Which is the best test to take before beginning the rapamycin/metformin protocol? Do epigenetic clocks measure the effects of rapamycin/metformin?

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Regarding the bioclocks… this may be the best info anyone has - see the info from Prof. Morgan Levine:

(vi) In the fasting literature, an extended fast and the subsequent refeeding can be considered to be different processes which when done right can be beneficial for longevity. Is there a similar analogue to “being on rapamycin” and the subsequent “ramping off of rapamycin”? Studies that show improved immune function immediately after having been on rapamycin suggests something similar could be at play. What implication does this way of thinking have for an optimal rapamycin dosing/schedule?

(vii) How do you optimize for rapamycin dosing during the pandemic? Rapamycin ON when the numbers around you are low, and Rapamycin OFF when you are in the middle of a wave?

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is there a protocol out there that mixes rapa and metformin?

There is no “formal” protocol for mixing rapamycin and metformin as far as I’m aware.

I believe that many people mix the typical rapamycin anti-aging pulsed dosing protocol, and mix it with the TAME trail metformin dosing (the dosing protocol used in the large Metformin Anti-aging Trail that Nir Barzelai has spearheaded. Here is what I believe the TAME trial is using for metformin dosing (note - I don’t think the study has started yet, so things may change):

In the TAME study itself, the dose is listed as 850mg of Metformin 2 x per day, one morning, one night, this would equal 1700mg of Metformin in total per day.

TAME Design

  • Double Blind Randomized Placebo Controlled Trial
  • Dose: 850 mg 2x per day
  • 18 Month Recruitment
  • Range of Follow-up Times: 37-54 months (median 45 months)

Source PDF: Targeting Aging with Metformin: Design and Rationale, OAIC Annual Meeting April 19, 2016

there are different ways in theory to do this.

  1. take metformin the first 72 hours after rapa, to “double up” the effect, and deal with any hyperglycemia side effects from the rapa
  2. take metformin every day independent of rapa dosing
  3. take metformin the 2nd half of the week (if doing weekly dosing) to cover the interval when rapa is at its lowest

any thoughts on the pros/cons of these approaches?

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Hi, when are you planning to send in these questions? Looking forward to your interview :slight_smile:

New results are due out from the NIA ITP program studies very soon… The acarbose and rapa study, etc.

I am in contact with the researchers and hope to interview them next month. But more generally i am just trying to get questions that i can pose as appropriate for different researchers i speak to going forward.

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Oh wow, I look forward to the new results. I feel like in some ways those results may also generalize to any (sglt2 or keto) + rapa

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Yes, it does seem that would probably be true given the key functions of both those drugs. I will discuss this with the researchers.

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