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Peter Attia MD#09 – David Sabatini, M.D., Ph.D.: rapamycin and the discovery of mTOR
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At a glance
WHAT IT’S REALLY ABOUT
David Sabatini Recounts Discovering mTOR and Why Rapamycin Might Extend Life
- Sabatini describes how, as an MD-PhD student in Solomon Snyder's lab, he chose to study rapamycin (originally just a control compound) and purified and cloned mTOR from rat brains, publishing in Cell in 1994.
- He explains how years of failure to find mTOR's partner proteins ended when a postdoc found that the detergent CHAPS preserved the complexes, leading to mTORC1 and mTORC2 around 2002.
- Sabatini argues that mTORC1 may affect longevity because it acts like a general contractor for the cell, though he stresses the mechanism is unknown and that both too little and too much mTOR activity are harmful.
- His lab has identified sensors that link amino acids such as leucine, arginine, and methionine (via SAM) to mTORC1, and he sees upstream regulators as a route to a better drug than rapamycin.
- The two discuss intermittent rapamycin dosing, comparisons with fasting and methionine restriction, mTOR in the brain, and the experiments Sabatini would most like to run.
IDEAS WORTH REMEMBERING
5 ideasFreedom to choose a project shaped Sabatini's science.
Solomon Snyder simply told him "we work on the brain" and left the rest open, which Sabatini now sees as the most important thing anyone did for him and tries to foster in his own students.
Luck and technical details drove key breakthroughs.
He recovered the full-length 9,000-base-pair cDNA only after letting slow-growing phage plaques grow longer, and the complexes were found only after a postdoc switched to the detergent CHAPS.
mTOR may extend life because it is a single control point for many processes.
Sabatini says aging likely requires changing about 100 things, and mTOR is the one "button" that does that, though he states up front that the answer is not known.
Complete mTORC1 inhibition is not tolerable.
mTORC1 is probably required for the growth of any normal cell, and deleting raptor in tissues like gut epithelium is quite bad; rapamycin also only partly inhibits mTORC1 substrates and can eventually inhibit mTORC2, which may disturb glucose homeostasis.
Balance matters: both too little and too much mTOR activity are harmful.
Deleting raptor or deleting the tuberous sclerosis complex repressors can both cause muscular dystrophy in muscle, which is why Sabatini says intermittent dosing makes sense.
WORDS WORTH SAVING
5 quotesto some extent, mTOR is like the general contractor for the cell. I don't know of any other pathway that does as many things, right? mTOR basically has a finger in every major process in the cell.
— David Sabatini
to impact the state of a cell, to rejuvenate it, to slow the aging process, you can't do one thing. You can't do two things. You can't do three things. You can't do 10 things. You probably have to do 100 things, and the only way you can do all of those things with one button ... is to go after mTOR
— David Sabatini
I realize now in retrospect what he did is he actually was giving me complete freedom to do what I wanted to do, and that was, as I said, probably the most important thing anyone's ever done for me.
— David Sabatini
It's clear that both mTOR, you need just right amounts, right? You can't have too little, it's toxic. You have too much, it's toxic. The same thing with autophagy.
— David Sabatini
I always tell my students that my paper, which was the discovery of mTOR, which at the time, to be fair, we did not realize how important mTOR would be, my paper basically is like figure 1AB of their papers, right?
— David Sabatini
High quality AI-generated summary created from speaker-labeled transcript.
