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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 barrier and its potential impacts on brain health and neurodegeneration [1:13:45];
• Rapamycin may act as an immune modulator in addition to immunosuppressive effects [1:21:30];
• Might rapamycin induce changes in T cell methylation patterns, potentially reversing biological aging? [1:34:15];
• Rapamycin side effects and impacts on mental health: fascinating results of Matt’s survey on off-label rapamycin use [1:42:00];
• The impact of taking rapamycin in people who contracted COVID-19: more insights from Matt’s survey [1:51:15];
• What David would like to study with mTOR inhibitors [1:54:45];
• Joan Mannick’s studies of RTB101 and other ATP-competitive inhibitors of mTOR [2:00:30];
• The impact of mTOR inhibition on autophagy and inflammation and a discussion of biomarkers [2:10:00];
• The Dog Aging Project: what we’ve learned and what’s to come from testing rapamycin in companion dogs [2:17:30];
• Preliminary results of primate studies with rapamycin [2:24:45];
• Dosing of rapamycin [2:27:45];
• The effect of rapamycin on fertility [2:36:45];
• The outlook for future research of rapamycin and the development of rapalogs [2:39:00]; and
• More.

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