@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.
