Rapamycin Update - Summary of Recent Matt Kaeberlein, Dr. Green, Blagosklonny Conference Call (June, 2022)

@EnrQay did an excellent job of summarizing the latest online video conference call (with some commentary by EnrQay) that the U. Washington Rapamycin Survey Study did the other weekend. Key participants were professor Matt Kaeberlein, Dr. Alan Green, and professor Mikhail Blagosklonny.

To make it easier to access and more visible to new visitors, I’ve created this single thread and copied it out of the Rapamycin Dosing thread that it was originally posted in.

My Summary of Discussion 0:00 - 0:30
Discussion of what is an optimal dosing:
Dr. Green: varies by person, stage in life, and reaction to the dosing; he currently does 12mg on each of 2 days in a row, with about a 12 day interval between. He generally recommends a starting weekly dose of 6mg for men and 4mg for women.

Dr. Blagosklonny: conservation of blood rapamycin can vary 10-fold, so the dose shouldn’t be the same for everyone. He considers the 6mg men/4mg women does safe. Animal studies have almost never shown that a higher dose does worse for extending lifespan than a lower dose. So he recommends the highest tolerable dose. More tissues, such as the brain, will have mTOR inhibition at a higher dose. Animal models show that peak levels are important.

Dr. Green judges the results of his dosing for patients by looking at their HOMA-IR (insulin resistance) score since high insulin causes high mTOR.

Do they recommend measuring blood rapamycin?
Dr. Green: yes, high and low levels might be of interest
Dr. B: we don’t know what levels should be for anti-aging. His main guidance would be adjust if there are or are not side effects.
MK: think about different types of side effects, since some take a long time to develop. He would not push higher dosing if someone is already on a high dose (based on community consensus) but has no side effects.
Dr. Green: #1 side effect to be concerned about is bacterial infection

0:30 - 1:00
Are you concerned about hyperlipidemia?
Dr. Green: there is an idea that such lipids are not going into the tissue. And then there is the idea that rapamycin is dramatically decreasing inflammation. But he still like LDL to be 120 or less and HDL in a nice range. He recommends Crestor, which doesn’t cross the blood-brain barrier. Animals studies show very high cholesterol levels at the same time they were clearing cholesterol plaque.
Dr. B: In humans, rapamycin prevents atherosclerosis. Increases in blood glucose happens uncommonly in humans, related to a decrease in insulin due to rapamycin. That way you can be insulin sensitive, but glucose intolerant, much like after fasting.
Dr. Green: He sees a decrease in insulin level in his patients, and wants them to increase insulin sensitivity.

Metformin + Rapamycin
Dr. Green: uses metformin with people who are insulin resistant, but not the insulin-sensitive patients
Dr. B: research on metformin used to be more positive, but now there is complete confusion about the mechanism of metformin. There are like 1000 mechanisms. He agrees about adding metformin for the insulin-resistant. Only one study showed extended lifespan with met+rapa, so there is no real data.
MK: metformin is a dirty drug with many targets, while rapamycin is very clean, with only one target. That makes it hard to know the consequence of taking metformin
Fasting + Rapamycin
Dr. Green: he doesn’t like fasting, but does intermittent fasting. Fasting in mice studies are mostly showing a reduction in AGEs compared to their usual high-AGE diets.
Dr. B: combo is very good for weight loss and possibly longevity. He would add exercise to this combo since fasting can cause muscle loss. Rapa helps maintain healthy muscle.
Dr. Green: In studies, the #1 way to reverse sarcopenia in the elderly is caloric restriction. Reducing mTOR helps maintain healthy muscles.
Dr. B: rapa rejuvenates satellite cells in muscles, increasing muscle strength in aging.

Protein restriction + Rapamycin
Dr. Green: high protein increases mTOR, so he likes a moderate protein diet
Dr. B: depends on age and goal. The only negative of protein is mTOR activation, but all food does that and there is nothing special about protein.
MK: human data shows that for the young, low protein reduces mortality, but in old age, HP reduces mortality. Other studies show HP is not detrimental at younger ages.
Dr. Green: with high supplements of high glycine and cysteine, glutathione levels might be maintained
MK: his intuition is that moderate to high protein detrimental effects, if any, would be offset by rapa, as would most lifestyle interventions that might otherwise raise mTOR.
Dr. Green: lifestyle can override rapamycin, such as in lifestyles that cause insulin resistance, which causes high levels of mTOR
Dr. B: in 2005 and 2007, human studies showed that despite (high?) protein, subjects given rapa did not become insulin resistant

Here is my summary from 1:00 - 1:34 of the 2nd AMA. It is not verbatim, just my understood summary. Does anyone have in problems with some of the things they are saying in the AMA? Mostly it is good info, but I think there are some problems.

Grapefruit juice and Bioavailability of Rapamycin
Dr. Green: discourages GFJ because you want to have a high level initially and have the body metabolizes it to a low level. GFJ will maintain it at high levels. He is concerned about possible increased side effects.
Dr. B: discourages it because other drugs and supplements will also be affected by GFJ. People are doing it to save money.

Compounded Rapamycin
Dr. Green: He prefers Pfizer Rapamune and a producer in India. He is concerned about compounding pharmacies’s products, but likes the powder for topical rapamycin. Studies show the topical decreases senescent cells and SASP.
Dr. B: if you have a powder, people want to make rapamycin (pills) themselves, but he doesn’t want to teach people this. His goal is to change doctor’s attitudes toward rapamycin, and not to encourage people to take it on their own.
MK: topical study was at Chris Sell’s lab at Drexel: Bioavailability of powder was low because of stomach pH. One study of compounded capsules from a pharmacy showed about 4-fold lower bioavailability.

Acarbose, NMN, Berberine
Dr. Green: Berberine is much like metformin. Acarbose: a diabetes drug that is good for those with pre-diabetes; it is an age-extension effect, but it is not a new pathway.
Dr. B: senolytics are unproven as a life extension drug that kills senescent cells. A study showed it extended life span, but not how they did it: killing cells or inhibiting mTOR? Data support is minimal.
MK: most literature on senolytics have to do with their ability to clear cells that are expressing p16, p21, and SA-β-gal and turn off SASP. Whether this is due to reduced mTOR or activated immune cells is unclear. Rapa is more effective, probably both as a senomorphic (turning off SASP) and a senolytic.
Dr. Green: rapamycin in skin has been shown to decrease the production of senescent cells and decrease their inflammation

Followup survey:
MK: maybe another in the next 12 months, and it would be great to do followups annually, but no promises

How do we know mTOR inhibition is not deleterious?
Dr. B: how can something that extends lifespan be harmful?
Dr. Green: wait 20 years, and see how we are doing with rapamycin. If it reduces age-related disease and increases lifespan, how bad can these speculated deleterious effects be? We see some lifestyles around the world that reduce mTOR having a good lifespan effect.
MK: most everyone will benefit from rapamycin, but it is not 100%

AMA #2: 1:34 - end
Autism

MK: mTOR activation is associated with autism. Some mutations that lead to mTOR hyperactivation are associated with autism. There is good reason to think rapamycin will help with some forms of autism.

What theory of aging do you use to underpin your research?

Dr. Green: Earlier beings like reptiles had minimal senescence. Later animals, such as mammals, had senescence that would lead to aging for the improvement of genetic variation. Animals that die earlier are better able to adapt to a changing world. Senescence supercharged evolution.

MK: Alan (Green) is very much in the camp of programmed aging being evolutionarily beneficial.

Dr. B: hyperfunction theory: the same processes and pathways that drive development growth also drive aging, becoming hyperfunctional.

Dr. Green: these are not conflicting theories

Dr. B: SASP is a typical hyperfunction. Cell hyperfunction eventually leads to organ damage.

Dr. Green: Dr. B’s 2006 paper gives an example of bees: with the same genetic code, different bees can increase their lifespan 10-fold, such as the queen. If animals want to live longer, they can find a way to do it.

Is there a good way to monitor inflammation with blood tests?

Dr. Green: hard to monitor non-bacterial inflammation

MK: Not now, but he is cautiously optimistic in a few years we will have useful blood tests of inflammatory markers associated with aging. Anecdotally, many people taking rapamycin have reduced aches and pains.

Neutrophil reduction is a known effect of sirolimus. Is there is threshold of concern?

Dr. Green: below the normal range is a contraindication (of the sirolimus dose)

Does rapamycin reduce hearing loss and slow graying of hair?

Dr. Green: better at preventing hearing loss at an early stage

Any views on gene therapy, e.g. follistatin and telomerase?

Dr. B: telomerase knockout mice have a greatly reduced lifespan. In humans, there are some genetic diseases with a fault in telomeres, and these people die from bone marrow failure, but this is not typical aging. Telomere length does not limit lifespan. After a long life, say 200 or 300 years, it might be life-limiting.

MK: gene therapy as a life-extending strategy: concerns that it is too early and irreversible.

Dr. Green: would like to target epigenetic changes by genetic therapy

Do older mice show improvements when taking rapamycin?

MK: yes: delay in functional decline, and actually improving immune function, cognition, and in many tissues

Dr. Green: periodontal diseases respond to mTOR inhibition and to the removal of senescent cells, like it is the same thing

MK: rapamycin effects are more impressive than those of senolytics (fisetin, D+Q); clearly there is an overlap between the two approaches

Dr. Green: cardiac studies also show the role of senescent cells in promoting coronary disease. Senolytics and rapamycin do the same thing.

Tinnitus and Rapamycin

Dr. B: he would not be surprised if it would help

Dr. Green: prefers treatment before disease happens

Is rapamycin contraindicated for those who have recovered from active cancer?

Dr. B: it should not be for all. It is used for cancer therapy and prevents cancer.

Dr. Green: having recovered from cancer is a strong indication to take rapamycin. Rapamycin slows angiogenesis and cancer proliferation. It is a strong anti-cancer drug, more at the proliferation level than in the genesis of cancer.

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@EnrQay you mentioned you had some issues with some of the information conveyed in the conference call… can you expand on where you think there might be some issues or disagreements in terms of what was conveyed? Just want to understand better…

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Green said he used insulin resistance as his guide to adjusting the dose of patients. Although this is a useful data point, I think trough level of blood rapamycin, which he acknowledged as possibly useful, would be of equal value. Since the metabolism of rapamycin is so individualized, the whole dosing-period curve of blood sirolimus vs. time would be marginally even more useful, particularly for high doses.

Blagosklonny recommends the highest tolerable dose, based on tolerable side effects. I think this could lead to overdosing, as Kaeberlein implied when he talked about some side effects taking longer to develop; this might be especially be true for side effects caused by mTORC2 inhibition.

What about other standard measures of inflammation, such as CRP-hs and homocysteine?

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You think? All clinical work with rapamycin uses trough or pharmacokinetic levels in some way. He’s got hundreds of patients on rapamycin, and doing a blood test(s) to measure n=1 therapeutic signal is not part of the tracking protocol? So what’s the longevity biomarker target then?

He won’t come right out and say it, but my gut (data) is telling me, he KNOWS the longevity dose is much higher, but us mere humans cannot tolerate the tradeoffs with current administration. Side effects at standard oral administration protocol is precluding uncorking the FULL rapamycin therapeutic potential.

Important and easy measurable parameters in terms of improving health trending on rapamycin.

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I don’t think that he Knows higher doses are necessary, but he suspects it. He also knows that the blood levels on varying doses are highly individualized.
As far as side effects and getting to the highest tolerable dosing, I believe that he’s not overly concerned with some glucose/ lipid issues but by side effects he’s referring to symptomatic things like mouth sores ( though I can’t speak for him but I’ve read much of what he has to say).

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While they had many informative statements, I’ll quickly summarize other issues I had with some of what they said.

  • hyperlipidemia: bad or irrelevant? Green seemed to sit on the fence, while Blagosklonny was unclear about whether the cases of rapamycin-caused hyperlipidemia were an exception to his statement that rapamycin prevents atherosclerosis.
  • metformin: they all seemed down on its use except for the insulin-resistant patients, due to many of its mechanisms being unknown, but there are loads of studies showing benefits to many populations. Surely among these many beneficial mechanisms there are some other than insulin-sensitizing ones.
  • while fasting has the benefits they indicate, it is not just about dietary AGEs reduction and weight loss. There are many other benefits (stem cell activation, tissue regeneration, immune system pruning) that are likely different from effects of rapamycin
  • protein restriction: Blagosklonny says there is nothing special about protein and mTOR activation, but I believe it is well-established that particular amino acids more potently activate mTOR than carbs or, certainly, fat.
  • Green said that grapefruit juice will maintain high rapamycin levels, but we’ve had discussions in this forum that GFJ inhibits CYP3A4 only in the intestines, not the liver, giving higher absorption but not a longer half-life.
  • in general, they seemed to imply that since nothing was as good as rapamycin, why bother with them (metformin, acarbose, senolytics, gene therapy, NMN, etc.) except for certain individuals? If all I have is the rapamycin hammer, everything problem is an mTOR-nail.
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He certainly did not say he did that measurement, but only said it might be useful. Maybe he does order it.

Yes, agreed. They are trying to balance clinical and reputational risk with the patients desire for the optimal dosing and greatest benefits.

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Straw poll.

How many people on this site are patients of Dr Green and have had at least one Sirolimus blood test?

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While I really give kudos to Dr. Green for helping to start this whole rapamycin movement, I find him increasingly hard to follow and disagree with some of his opinions based on my readings of other experts.

Currently, I am more likely to follow the example of professor Mikhail Blagosklonny. He seems much more lucid to me at this point.

Dr. Green: discourages GFJ because you want to have a high level initially and have the body metabolize it to a low level. GFJ will maintain it at high levels. He is concerned about possible increased side effects.
(And then:)
Discussion of what is an optimal dosing:
Dr. Green: varies by person, stage in life, and reaction to the dosing; he currently does 12mg on each of 2 days in a row, with about a 12- interval between.

(Seems to me that 12mg, two days in a row would maintain a high-level longer than 12mg. with grapefruit juice for one day. We’ve had this discussion before about pulsed dosing with grapefruit juice. )

Dr. Green: He prefers Pfizer Rapamune and a producer in India.
(Seems a little disingenuous to me to name Pfizer and not name the India company.)

I understand his reluctance about grapefruit juice. Personally am not taking any essential medications and I just forego the meds for 48 hrs after a grape-fruit/rapamycin dose.

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My understanding is that the way grapefruit juice works on drugs including rapamycin is it increases initial absorption from the stomach and digestive system in the range of 3.5 fold. At that point clearing the drug from the blood stream occurs as it usually does with the same drug half lives. I get this from a posting right on this forum from pollux. I quote
"from Dr. Mark Thimineur post in age-reversal forum 2 years ago:
"to answer this with adequate explanation I’ll defer to study of grapefruit juice on drugs called “statins” which treat hypercholesterolemia. Like rapamycin the have low bioavailability (5%) vs 14% for rapa. The reason is both drugs have a first pass effect in which most drug succumbs to the enzymes in the lining of the duodenum. Grapefruit juice irreversibly inhibits the enzyme until more is made which takes 24 hrs to fully reverse. In the presence of grapefruit juice the statin drugs absorb dramatically more with huge increase in plasma concentration. The subsequent hepatic metabolism is unaffected with the same half life with or without grapefruit. But for the 5 half lives needed to clear the drug the levels are increased thereby increasing the area under the elimination curve (AUC) and, in the case of statins producing deadly toxicity. The same for rapamycin - the AUC is increased but not the elimination half life. If grapefruit juice is used there needs to be dose alteration. Ex: a 5mg dose will effectively become 12.5-17.5mg with juice. Notice it is a range because the increased bioavailability has been measured to be a range of 250-350% - so we are not all the same. "
Dr. Mark Thimineur is a practicing physician with considerable experience in the use of rapamycin for potential life extension. I believe he is a member of this forum too. I have also found the same information in several other places.

This indicates that Dr. Green stated objection related to drug clearance is meaningless. If he is objecting to dose consistency, I think using the same quantity of the same brand of juice each time will yield similar enough results each time. If he is objecting to dosage levels (which is not what he said), we are all seeking to find an optimal dose for ourselves. If it is possible to do it at a lower cost with 1/3 as much rapamycin, I don’t see why anyone would object to that.
As to concerns over grapefruit juice interactions with other drugs we are taking, that too, is overstated. You can determine the effect of GFJ on any drug you are taking in seconds with google. I, myself take atorvastatin. I decrease my dose by 2/3 for 2 days when I drink GFJ.

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It sure seems straight forward enough. It jacks up the initial blood levels via an intestinal effect but not the half life. Basically saves money.

Sorry, @desertshores , it’s my fault that I couldn’t make out what he said on my first listen. He did name it. At 1:06:19, the best I could interpret was “Dr. Betty’s Pharmacy in India.”

You make good arguments for grapefruit juice for those who want to use it.

I would argue further that since we don’t know the proper dose, having variable absorption might even be desirable, as over time you will cover a band of dosages, and there is a better chance one might be optimal, or perhaps some dosages are optimal for some benefits, other dosages for other benefits. Just check you trough levels initially and then occasionally for safety.

Sorry! My bad!
Thank you for the translation. I honestly couldn’t make out half of what Dr. Green Said. I really should be more careful. Dr. Green is truly one of the pioneers.

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It is “Dr. Reddy’s” Pharmacy not “Dr. Bettys”. Just FYI.!

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The company is a pharmaceutical company in India called Dr. Reddy’s Labs

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FWIW this is the brand I have been using (2mg tablets), supplied by the Local ACME Pharmacy. Since I started {February, 20 2022)

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@EnrQay Thank you for this excellent summary. A few thoughts to add to other comments.

Dosing and levels - trough probably the most valuable at this point and time since it can be reliable and consistent where peak are too hard to guess with too many variables contributing. Signs of mTOR2 activation is too high is a blunt tool, but has value. GFJ seems to muddy the water of already a tough subject, but I get the reasoning of why many chose it.

Who is the best expert? Being an expert has many components, but does not mean your right all the time, it just means you’re a better at guessing. All of these guys are pioneers and are doing work that is invaluable. I love the intellectual banter on this site that allows everyone to learn and be exposed to many thoughts and points of view.

Thanks again for all the value you bring to the site:)

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As a ‘patient’ of Dr Green since 10/21, I don’t get the feeling there’s any ongoing program.