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Peter welcomes guests David Sabatini & Matt Kaeberlein, two world-leading experts on rapamycin & mTOR. David & Matt begin by telling the fascinating story of the discovery of rapamycin & its brief history as a pharmacological agent in humans. They then unravel the function of mTOR, a central regulator of numerous biological processes, & 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 & the ongoing research that continues to shed light on this unique molecule. Furthermore, they discuss the elusive details surrounding the frequency & dosing of rapamycin use in humans, & Peter emphasizes his reservations about indiscriminately prescribing rapamycin as a longevity drug for patients.

We discuss:
0:00:00-Intro
0:01:00-David & Matt’s expertise in mTOR & rapamycin
0:12:00-The discovery of rapamycin & first use in humans as an immunosuppressant
0:19:05-Emergence of rapamycin as a molecule with the potential to prolong lifespan
0:25:53-Groundbreaking rapamycin study on mouse lifespan extension & the open questions about the timing & frequency of dosing
0:36:26-Explaining mTOR & the biology behind rapamycin’s effects
0:47:13-Differences in how rapamycin inhibits mTOR complex 1 (MTORC1) versus mTOR complex 2 (MTORC2)
0:51:20-Reconciling the biochemical mechanism of rapamycin with its longevity benefit
0:56:42-Important discoveries about the interplay of amino acids (leucine in particular) & mTOR
1:04:43-Reconciling rapamycin-mediated mTOR inhibition with mTOR's significance in building & maintaining muscle
1:12:00-Unanswered questions around the tissue specificity of rapamycin
1:18:09-Rapamycin’s ability to cross the blood-brain barrier & its potential impacts on brain health & neurodegeneration
1:26:40-Rapamycin may act as an immune modulator in addition to immunosuppressive effects
1:40:41-Might rapamycin induce changes in T cell methylation patterns, potentially reversing biological aging?
1:49:00-Rapamycin side effects & impacts on mental health: fascinating results of Matt’s survey on off-label rapamycin use
1:59:32-Impact of taking rapamycin in people who contracted COVID-19: more insights from Matt’s survey
2:05:20-What David would like to study with mTOR inhibitors
2:09:50-Joan Mannick’s studies of RTB101 & other ATP-competitive inhibitors of mTOR
2:20:10-Impact of mTOR inhibition on autophagy & inflammation & a discussion of biomarkers
2:28:24-The Dog Aging Project: what we’ve learned from testing rapamycin in dogs
2:36:20-Preliminary results of primate studies with rapamycin
2:39:31-Dosing of rapamycin
2:49:33-Effect of rapamycin on fertility
2:55:30-Outlook for future research of rapamycin & the development of rapalogs

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About:

The Peter Attia Drive is a deep-dive podcast focusing on maximizing longevity, & all that goes into that from physical to cognitive to emotional health. With over 70 million episodes downloaded, it features topics including exercise, nutritional biochemistry, cardiovascular disease, Alzheimer’s disease, cancer, mental health, & more.

Peter Attia is the founder of Early Medical, a medical practice that applies the principles of Medicine 3.0 to patients with the goal of lengthening their lifespan & simultaneously improving their healthspan.

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