#272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more | David Sabatini, M.D., Ph.D. and Matt Kaeberlein, Ph.D.

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this episode of The Drive, Peter welcomes guests David Sabatini and Matt Kaeberlein, two world-leading experts on rapamycin and mTOR. David and Matt begin by telling the fascinating story of the discovery of rapamycin and its brief history as a pharmacological agent in humans. They then unravel the function of mTOR, a central regulator of numerous biological processes, and they discuss the pathways through which rapamycin exerts its potential benefits on lifespan. They touch upon initial studies that suggested rapamycin may have geroprotective effects and the ongoing research that continues to shed light on this unique molecule. Furthermore, they discuss the elusive details surrounding the frequency and dosing of rapamycin use in humans, and Peter emphasizes his reservations about indiscriminately prescribing rapamycin as a longevity drug for patients. We discuss: David and Matt's expertise in mTOR and rapamycin [3:00]; The discovery of rapamycin and its first use in humans as an immunosuppressant [13:15]; The emergence of rapamycin as a molecule with the potential to prolong lifespan [19:30]; The groundbreaking rapamycin study on mouse lifespan extension and the open questions about the timing and frequency of dosing [26:00]; Explaining mTOR and the biology behind rapamycin's effects [35:30]; Differences in how rapamycin inhibits mTOR complex 1 (MTORC1) versus mTOR complex 2 (MTORC2) [45:15]; Reconciling the biochemical mechanism of rapamycin with its longevity benefit [49:15]; Important discoveries about the interplay of amino acids (leucine in particular) and mTOR [54:15]; Reconciling rapamycin-mediated mTOR inhibition with mTOR's significance in building and maintaining muscle [1:01:30]; Unanswered questions around the tissue specificity of rapamycin [1:08:30]; What we know about rapamycin's ability to cross the blood-brain ba