Rapamycin: longevity benefits, surge in popularity, unanswered questions, and more

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#13

Nothing new but Matt has mentioned:

  1. seeing “survival benefit” in his dog group (to answer the Q if there would be a negative lifespan).
  2. currently weekly dose is 0.15 mg/kg for his dogs
  3. So if the person is 60 kg then he would be on a 9mg weekly dose (someone double check).
  4. Overall, he is “under-dosing”.
  5. Matt: there is “structural rejuvenation of the ovaries” in the reproductive study with rapamycin (data presented privately thus far).
  6. After watching it, the conclusion is nobody knows. So I think I will go with how my body feels and be guided by regular blood tests of biomarkers but not serum levels.
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#14

Texas weather and with all the extreme “rucking” is my guess, but yeah he does not look great it also could be the lighting.
I always thought Attia had been over-training himself for too long (starting from his teenage years).

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#15

I’m in discussion with the author of this rapamycin rejuvenating ovaries paper (its in process) who is in Korea. The paper reviewers asked for more experiments to be performed, so its been delayed. I’ll ping him again in a few months…

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#16

Can you send over a good contact person who I could interview when the study is completed :pray:

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#17

The discussion of rapamycin’s effect on the brain was interesting. I almost spit out my coffee when David casually mentioned synthesizing an antibody to mtor. I have watched too many sci fi movies. That seems like a great way to wipe out all life on earth.

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#19

@DeStrider
Attempt to summarize:

I think everyone, especially anyone new to longevity, should listen to this talk. Rare opportunity to hear two of the true experts in Rapamycin. Only a few people on this forum that might not benefit from this talk.

Obvious this is my interpretation of what they said. Others may interpret differently.

Rapamycin best substance currently available for longevity and health span. “Airtight case” for mtor relationship to longevity.
Rapa works via inhibition of mTORC. Active mTORC is anabolic. Inhibition of mTORC is catabolic.

Side effect profile, especially for intermittent dosing of Rapa not well defined.
Data on Rapa dosing is remarkably inadequate. Best amount, timing, age to start all unknown. Dr K has requested funding for this and NIH rejected.
Rapa, in mouse model, clearly works even when started later in life.

Rapa positive effects generally attributed to blocking mTORC1 activity.

Rapa binds to FKBP and then binds to mTOR.
mTOR bound to RPTOR is mTORC1
MTOR bound to RICTOR is mTORC2
mTORC complexes interacts with hundreds of other proteins
Rapa binds to mTORC1 and inhibits mTORC1 function, although likely not completely.
Rapa does not inhibit mTORC2, but rather interferes with the synthesis of mTORC2.
Important because once mTORC2 is formed, Rapa doesn’t affect it. Apparently you only need 10-15% of mTORC2 function to keep things running.

The exact mechanism by which Rapa extends lifespan is not known. Primarily because of mTORC1 inhibition but mTORC2 could be involved and process very complex.
Dr K not convinced that all benefits are due to mTORC1, and that all side effects are due to mTORC2 inhibition.

MTORC is a nutrient sensor. Activated by nutrients.
Amino acids, especially Leucine and Arginine stimulate mTORC1. Strong bond between Leucine and mTORC1.
Since Rapa is catabolic, unclear why it does not cause sarcopenia. Maybe by also stopping inflammation.

mTORC1 and mTORC2 in all cells in large amounts.
Distribution of Rapa into different tissues not well known.
May take higher dose or longer exposure to get Rapa into CNS.
Crossing blood brain barrier may not be required to have positive impact on brain. Others signaling may occur.

Everolimus remarkably similar molecule to Rapa.

Rapamycin is an immune modulator, not an immunosuppressant and with intermittent dosing is an immune rejuvenator.

Rapamycin impacts all 12 hallmarks of aging, changes the epigenome, causes autophagy, and reduces inflammation.
Autophagy likely Rapa most important mechanism, although anti inflammatory effects may be just as important.
No great biomarkers for autophagy.

High degree of similar genetic impact on longevity across different species. Dr K. Feels this indicates that testing on worms and mice is useful.

They did discuss Dr K’s questionnaire study of Rapa users, the dog study, and fertility, but those have been discussed elsewhere.

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#20

Thanks for the synopsis.

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#21

True to that my friend. Thanks for clarifying.

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#22

Changes I am considering based on this talk.

Higher dose of Rapa, despite side effects to ensure impact on all tissues including CNS.
Lengthen dosing interval to allow resynthesis of mTORC2.
Fast after Rapa dose to avoid competing stimulation of mTORC1
Stop anabolic supplements around Rapa dose.
Reconsider need for senolytics as Rapa may do that.

Gonna look at process as:
Take Rapa to catabolize and then let body rebuild better.

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#23

Thanks KarlT,

this was an excellent summary. Very useful and important. BTW, anecdotally I had switched to 10mg+GFJ+EVOO and I felt amazing, so in a way I was ahead of this podcast. I doubt you’ll encounter any side effect of very high dose, since I had none when I switched from 5mgs to 10mg (at 5mg i almost always had either small infections or mouth sores). An infection on my left forearm that had lingered for about 4-5 weeks cleared literally the next day i did the 10mg dose, in its own no other remedy. But that is clearly one of your summary point above where the intermittent dosing is an immune rejuvinator.

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#24

@KarlT That was informative. Thank you. :slight_smile:

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#25

I listened to the podcast on Rapamycin with Dr. Attia, Sabatini and Kaeberlein. It’s interesting and concerning that David Sabatini is reluctant to take Rapamycin. He decided to wait until 2026 when the Dog Progect is completed.
It’s also clear that nothing is certain about many aspects of longevity and Rapamycin yet.

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#26

so are you thinking of every 10 days or two weeks instead of weekly?
On a somewhat related topic, Dr. Blagosklonny recently tweeted that “he is winning” so that is very encouraging.

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#27

Not sure. Maybe every 2 weeks or even monthly? The only thing I’m sure of is that nobody know the right answer. I’m thinking brief periods of catabolism/autophagy followed by longer periods of repair.

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#28

I also was thinking along the lines of changing to a very high dose once a month and watch what happens and adjust accordingly based on how I feel.

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#29

Guys I saw many more takeaways to the interview. For anyone gulping at the 3 hour length, I recommend you watch it at 1.5-2x speed on YouTube that way you’ll gain at least 1-1.5 hours of life expectancy regardless of your rapamycin regimen :slight_smile:

  1. put more stock in life extension studies performed on organisms far removed from us in the evolutionary family tree: apparently the genetic mechanisms of lifespan extension are highly conserved across most species — I used to take results in rats or C. Elegans with a huge grain of salt. From now on I’ll just sprinkle a tiny bit.

  2. the rapa probably isn’t getting to the central nervous system due to its extremely high lipophilia. In all likelihood, to get it across the blood brain barrier you need high continuous doses, every 8 hours for a few times, not letting the trough level get too low for a while. It almost needs to be pushed through. For older folks though who have an impaired blood brain barrier getting it up there might be naturally easier. Some food for thought there on how to schedule dosages.

  3. more details on how mTORC2 gets inhibited. The thinking being that even mice who were fed rapa DAILY in the studies were technically on an intermittent pulsed dose because they only ate every so often. It wasn’t in their blood stream / intracellular fluid constantly. And it takes mTOR connecting to RAPTOR just once for mTORC2 to form. Once it’s formed rapa can’t inhibit it. It only directly inhibits mTORC1 (but also binds to mTOR so if it catches ALL free mTOR then there won’t be any possibility for mTORC2 to get formed, but this sounds like an extreme and unlikely scenario). My takeaway here is that even daily doses are probably fine, so long as there’s some washout periods intermittently to make sure all the rapa is eventually cleared.

  4. they mention a study whose details they can’t recall on the spot but say they wish they could, re: mTOR hypomorphic alleles, to get to the tissue specific effects of mTOR inhibition. I found the study in question and it’s fascinating (https://www.sciencedirect.com/science/article/pii/S2211124713003926) These mice have genetic mutations that make them express less mTOR, about 25% of the mTOR of wild type phenotype controls. And… they have a much higher life expectancy and max lifespan than control. This would be almost the equivalent to getting rapamycin in their blood stream continually since they were embryos, basically no intermittent dosage even compared to daily feeding. It is SUPER interesting though because mTORC2 is proportionally lowered vs mTORC1 here, they’re both at ~25% normal values because their precursor mTOR is itself lowered by that much. And here we have a MUCH higher percentage of the lower mTOR mice DIE prematurely of infections compared to the controls. So that’s a fat tail distribution of life expectancy with many dying younger due to infections and yet many others dying of extreme old age. I’m not sure if they removed those early deaths from the averages of life expectancy so not sure if the tradeoff was worth it to the mice, statistically speaking. Maybe you can sort out the weeds of the data in the study and let me know. On the flip side of more frequent and severe infections, the lower mTOR mice significantly fewer tumors. Basically at some point if you have constant inhibition of mTOR and consequently of mTOR2, you’re likely much more immunologically vulnerable: immunomodulation slides into immuno suppression. Also super interesting that not ALL tissues get rejuvenated or aged slower with suppressed mTOR. Most did — in these mice — but bone degeneration happened FASTER and so did cataracts. I’m very keen on getting the story straight Re: bones as rapamycin seems to help fight osteoarthritis and osteoporosis based on my limited research but there may be a dose depended U shaped response or something trickier going on. I’ve noticed that the modality I’ve researched ad nauseam, PEMF, which has solid evidence as far as I’m concerned for promoting osteoblast activity, increases mTOR expression in the bones.

  5. speaking of tricky tissue specific effects, there was a caution Re: sarcopenia because mice don’t develop sarcopenia like humans do. So just because rapa in mice doesn’t seem to accelerate sarcopenia in their old age it doesn’t mean we can take the corresponding result for granted in humans. On the one hand, we have @Agetron and others rocking their muscle building while on rapa. On the other hand, they ain’t that old so a note of caution there.

  6. the dosage we’re taking on this forum is probably on the low end of the likely effective (or optimal range) according to the experts here. Their biggest concern Re: ongoing dog study is that they’re dosing way too low (the equivalent of 6-8g / week for average sized humans if we scale linearly based on body mass). Even so they’re seeing some positive noise so far.

  7. the known rapalogs are BS molecules not in any way superior to rapamycin and purely fabricated for regulatory capture purposes, to reset the clock on the pharma patents.

  8. rapa seems to work best at slowing down the cell cycle and seems to benefit the most those cells that reproduce slowly. Different effects in fast reproducing cells. That might explain why it seems to help female reproduction but hamper male reproduction (at least while actively being administered).

  9. autophagy and lowered systemic inflammation seem to be the main pathways these two believe rapa is working its magic through. We have great biomarkers for inflammation but not for autophagy. Hint: other meds / modalities that lower sterile inflammation might lead to life extension benefits. I’m thinking of LDN off the top of my head.

  10. a bunch more but I forget. Do yourself a favor and watch the whole thing at 1.5x speed.

A few interesting observations re: Dramamine, apparently an mTORC1-specific inhibitor, made the more interesting based on points 2 and 4 above:

https://scholar.google.com/scholar?hl=en&as_sdt=0%2C20&q=Meclizine+inflammation+&btnG=#d=gs_qabs&t=1695786465330&u=%23p%3DMeBPYYVvAVwJ

https://scholar.google.com/scholar?hl=en&as_sdt=0%2C20&q=Meclizine+blood+brain+barrier&btnG=#d=gs_qabs&t=1695786822943&u=%23p%3DdImY7o0wxD0J

Last open loop, I promise, check out this list of novel (not rapalog) mTORC1 inhibitors:

https://scholar.google.com/scholar_lookup?title=Small+molecules+bind+human+mTOR+protein+and+inhibit+mTORC1+specifically&author=Allen,+S.A.&author=Tomilov,+A.&author=Cortopassi,+G.&publication_year=2018&journal=Biochem.+Pharmacol.&volume=155&pages=298–304&doi=10.1016/j.bcp.2018.07.013#d=gs_qabs&t=1695787176028&u=%23p%3DFt38rBU7n6AJ

Meclizine has friends! I’ll research them more this week.

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#30

@medaura Thanks for your summary! I need to sit down and watch the whole thing now. :slight_smile: Good stuff!

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#31

Thanks for the overview… and your comment Agetron is not that old… hahaha… 65 years young.

@Agetron and others rocking their muscle building while on rapa. On the other hand, they ain’t that old so a note of caution .

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Pic yesterday.

Driving on a long trip… plan to listen to this.

Also, Matt Kaeberlein mentions again AKG…alpha-ketoglutarate as potential longevity supplement… been talking it.

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#32

I’m taking AKG too. My stack is one well diversified portfolio. :slight_smile:

But you know what I mean, sarcopenia might not become a real issue for someone who’s in shape until he or she hits mid 70s or 80s. My dad is 72 and he seems to have experienced a decline this past few years that I didn’t see coming even 5 years ago.

You ain’t that old

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#33

Excellent summary, and lots of food for thought.

I’m about 2/3 through it. I never watch podcasts (no patience/focus for sitting and watching) - I’ve been listening in my car. At 1.25 speed like I do for all podcasts.

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