David Sinclair· PhD
You give rapamycin to a yeast cell or a fly or a worm, they also live longer. So you can tap in with these drugs, into this universal longevity program, one of which is mTOR.
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The evidence is convergent. Multiple independent sources reach the same conclusion, the underlying mechanism is well-characterized, and even the field's most cautious voices treat it as worth doing.
You give rapamycin to a yeast cell or a fly or a worm, they also live longer. So you can tap in with these drugs, into this universal longevity program, one of which is mTOR.
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The "high risk" framing here is the right call. I've had three patients ask about rapa this month and none of them grasped the immunosuppression tradeoff until I walked them through it.
The PEARL trial framing in the dossier is the clearest writeup I've seen for a non-specialist. Worth linking from the AMA pages too.
I'm on 6mg/week, year two. Tracking IL-6, fasting glucose, lipids. Happy to share the spreadsheet if Whalespan wants longitudinal user data.
The dosing variance across the advocate camp is staggering. 3mg, 5mg, 8mg, biweekly, weekly… brief is right that "monitor or specialist only" is the responsible read.
I've been a big fan of rapamycin and tour in that entire pathway for several years now it's become almost an obsession if one can have an obsession that's not half a lot and I think what attracted me to your work a couple of years ago probably David Sabatini pointed me in your direction so maybe three years ago it was actually after the magic paper came out in which was around 2014 yeah right so 2014 really interesting look at the human data
rapamycin to me is the most interesting molecule out there because it is I think the only molecule that has demonstrated a longevity benefit across all four models of eukaryotic cells so that's a really big deal that can't be ignored
what about rapamycin what do we know about the use of rapamycin which has been studied so liberally across again everything from yeast flies worms mammals uniformly extends life potent inhibitor of mTOR which would signal a toff eg
the the logic at the time was what I mean it was a you know 10 years earlier the drug had been approved by the FDA for solid organ transplants and yeah so it was a known immune suppressant what was the logical step that took it too but we also think it could boost longevity people had just begun to make invertebrates that is worms and flies with the genetic modulation of the tour pathway tour is the target of rapy and the enzyme that rapy inhibits and you know they were long lived and in fact when you studied some of the yeast stuff that Matt cabine was was in on this early on with Brian Kennedy many of the things that seem to influence yeast lifespan were also related to the tour pathway
the logic at the time was what I mean it was a you know 10 years earlier the drug had been approved by the FDA for solid organ transplants so it was a known immune suppressant what was the logical step that took it to but we also think it could boost long longevity people had just begun to make invertebrates that is worms and flies with the genetic modulation of the tour pathway tour is the target of rapamycin the enzyme that rapamycin inhibits and you know they were long lived
was also replicated in other model systems meaning it wasn't just replicated again in mammals people went back and asked the question how does this drug rapamycin which inhibits mtor um how does it work in yeast in fruit flies in worms which by the way constitute about a billion years of evolution and it turns out that it always seems to work
was also replicated in other model systems meaning it wasn't just replicated again in mammals people went back and asked the question how does this drug rapamycin which inhibits mtor um how does it work in yeast in fruit flies in worms which by the way constitute about a billion years of evolution and it turns out that it always seems to work
there are only two interventions that have extended life across all four models of organisms from yeast, worms, flies and uh uh uh mammals, rodents and that is caloric restriction and rapamy and they have something in common which is they both result in the down reggulation of mTor.
And what has been shown in yeast, and worms, and flies, and mice is that if you dampen...you can't get rid of TOR activity, you need it for life. But if you dampen TOR activity either genetically or with the drug rapamycin, which is known to target one arm of the TOR pathway, you can extend lifespan.
Rapamycin extends median and maximum lifespan in mice across multiple lab strains and dosing protocols.
Rapamycin will extend human lifespan by 5+ years at standard weekly dosing.
Weekly rapamycin dosing in healthy adults shows favorable safety and immune markers in early observational data.
Chronic low-dose rapamycin imposes an immune trade-off that outweighs the longevity hypothesis for most healthy adults.
mTORC1 inhibition is the mechanistic backbone for rapamycin's healthspan effects in mammals.
The PEARL trial showed an acceptable 48-week safety profile in healthy adults on weekly rapamycin.