Peter Attia MD272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more
At a glance
WHAT IT’S REALLY ABOUT
Sabatini and Kaeberlein Dissect Rapamycin's Longevity Promise and Unanswered Questions
- Rapamycin was discovered in an Easter Island soil bacterium and developed slowly as a transplant immunosuppressant, a history the guests say shaped its reputation as a dangerous drug and delayed testing for other uses.
- Sabatini explains that rapamycin acts as a molecular glue via FKBP to partially block mTORC1, and over time can also disrupt formation of mTORC2, while both guests stress that mTOR behaves like a dial rather than an on/off switch.
- The 2009 mouse Interventions Testing Program study and Joan Mannick's human everolimus trial are presented as milestones showing lifespan extension from middle-age treatment and immune rejuvenation with low intermittent doses.
- Many basic questions remain open, including the best dose, timing and tissue targets, whether rapamycin is best in class among mTOR inhibitors, and how it affects muscle, brain, fertility and mood, with ongoing dog, marmoset and small human trials trying to fill the gaps.
- Kaeberlein's survey of off-label users found mouth sores as the main side effect, and the guests describe the field as limited by funding structures that do not favor inexpensive, off-patent drug research.
IDEAS WORTH REMEMBERING
5 ideasRapamycin's history shaped its image more than its biology did.
Because it was developed for organ transplant patients taking several toxic drugs together, it was labeled a dangerous immunosuppressant, though the guests say low-dose use in healthy older people looks different.
Starting rapamycin in middle age can still extend lifespan in mice.
Kaeberlein notes the 2009 study began treatment at about 20 months by accident, and its success shifted thinking toward treating middle-aged animals and people.
mTOR inhibition is not a simple on/off effect.
Both guests describe mTORC1 and mTORC2 as knobs, with dose and duration changing outcomes, so the model that MTORC1 inhibition gives benefits and MTORC2 inhibition gives side effects remains unproven.
Rapamycin may act as an immune modulator rather than a pure suppressant.
A mouse vaccine study and Mannick's human trial showed improved vaccine responses after six weeks of transient dosing, and Kaeberlein suspects reduced sterile inflammation may explain much of the benefit.
Dosing and timing are largely unresolved.
Mice in the ITP got continuous doses that convert to roughly 0.1 mg/kg daily in humans, while off-label users mostly take about 6 mg weekly, and Kaeberlein worries his dog trial's weekly dose may be too low.
WORDS WORTH SAVING
5 quotesI would say, without question, it is the most robust and reproducible drug, at least from preclinical studies, that we know about today for impacting not only longevity, but to the extent that we can measure various metrics of healthspan, um, in complex animals.
— Matt Kaeberlein
You can't prevent the aging of an old house or much less rejuvenate an old house by having a plumber, having an electrician, right? You need a general contractor that brings in all those people because an old house has everything wrong with it.
— David Sabatini
They're kind of like... You can think of them as knobs, right?
— Matt Kaeberlein
We should, as a research enterprise, develop an appetite for higher risk, higher reward projects.
— Matt Kaeberlein
Tell me a biological system that does not age.
— David Sabatini
High quality AI-generated summary created from speaker-labeled transcript.
