<p><a href="https://peterattiamd.com/davidsabatini-mattkaeberlein/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=230925-pod-davidsabatinimattkaeberlein&utm_content=230925-pod-davidsabatinimattkaeberlein-podfeed"> View the Show Notes Page for This Episode</a></p> <p><a href="https://peterattiamd.com/subscribe/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=230925-pod-davidsabatinimattkaeberlein&utm_content=230925-pod-davidsabatinimattkaeberlein-podfeed"> Become a Member to Receive Exclusive Content</a></p> <p><a href="https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=230925-pod-davidsabatinimattkaeberlein&utm_content=230925-pod-davidsabatinimattkaeberlein-podfeed"> Sign Up to Receive Peter's Weekly Newsletter</a></p> <p>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.</p> <p><strong>We discuss:</strong></p> <ul type="disc"> <li>David and Matt's expertise in mTOR and rapamycin [3:00];</li> <li>The discovery of rapamycin and its first use in humans as an immunosuppressant [13:15];</li> <li>The emergence of rapamycin as a molecule with the potential to prolong lifespan [19:30];</li> <li>The groundbreaking rapamycin study on mouse lifespan extension and the open questions about the timing and frequency of dosing [26:00];</li> <li>Explaining mTOR and the biology behind rapamycin's effects [35:30];</li> <li>Differences in how rapamycin inhibits mTOR complex 1 (MTORC1) versus mTOR complex 2 (MTORC2) [45:15];</li> <li>Reconciling the biochemical mechanism of rapamycin with its longevity benefit [49:15];</li> <li>Important discoveries about the interplay of amino acids (leucine in particular) and mTOR [54:15];</li> <li>Reconciling rapamycin-mediated mTOR inhibition with mTOR's significance in building and maintaining muscle [1:01:30];</li> <li>Unanswered questions around the tissue specificity of rapamycin [1:08:30];</li> <li>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];</li> <li>Rapamycin may act as an immune modulator in addition to immunosuppressive effects [1:21:30];</li> <li>Might rapamycin induce changes in T cell methylation patterns, potentially reversing biological aging? [1:34:15];</li> <li>Rapamycin side effects and impacts on mental health: fascinating results of Matt's survey on off-label rapamycin use [1:42:00];</li> <li>The impact of taking rapamycin in people who contracted COVID-19: more insights from Matt's survey [1:51:15];</li> <li>What David would like to study with mTOR inhibitors [1:54:45];</li> <li>Joan Mannick's studies of RTB101 and other ATP-competitive inhibitors of mTOR [2:00:30];</li> <li>The impact of mTOR inhibition on autophagy and inflammation and a discussion of biomarkers [2:10:00];</li> <li>The Dog Aging Project: what we've learned and what's to come from testing rapamycin in companion dogs [2:17:30];</li> <li>Preliminary results of primate studies with rapamycin [2:24:45];</li> <li>Dosing of rapamycin [2:27:45];</li> <li>The effect of rapamycin on fertility [2:36:45];</li> <li>The outlook for future research of rapamycin and the development of rapalogs [2:39:00]; and</li> <li>More.</li> </ul> <p>Connect With Peter on <a href="https://twitter.com/PeterAttiaMD">Twitter</a>, <a href="https://www.instagram.com/peterattiamd/">Instagram</a>, <a href="https://www.facebook.com/peterattiamd/">Facebook</a> and <a href="https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg">YouTube</a></p>
Actionable Insights
1. Avoid Compounded Rapamycin
Avoid using compounded rapamycin formulations due to uncertain purity and concentration; instead, opt for FDA-approved generic Sirolimus or brand-name Rapamune for guaranteed quality.
2. Ensure Enteric-Coated Rapamycin
To ensure bioavailability, rapamycin must be in an enteric-coated capsule, as it is unstable at gastric pH, and compounded versions without this coating may have no bioavailability.
3. Prevent Rapamycin Mouth Sores
To prevent rapamycin-induced mouth sores, consider using an FK506 mouthwash, which could occupy the FKBP protein in the mouth and prevent rapamycin from acting there.
4. Common Off-Label Rapamycin Dose
Among off-label rapamycin users, the majority take six milligrams once a week, a practice popularized partly by early clinical studies and prescribing patterns.
5. Low-Dose Everolimus Tolerated
A study in healthy older people showed that five milligrams of Everolimus once a week had a side effect profile essentially no different than placebo, suggesting it is well-tolerated at lower doses.
6. Continuous Rapamycin & COVID
Continuous rapamycin use throughout a COVID-19 infection may be associated with lower severity of infection and a reduced likelihood of reporting long COVID symptoms, potentially due to its anti-inflammatory effects.
7. Combine Rapamycin with Ketamine
Combining rapamycin with ketamine may enhance ketamine’s effects, potentially allowing for lower doses and reduced frequency of ketamine use in patients with severe depression or chronic pain.
8. Rapamycin for Mood
Rapamycin use may be associated with lower self-reported depression and anxiety, suggesting potential beneficial effects on neurocognitive and behavioral aspects.
9. Rapamycin Preserves Muscle Mass
In rodents, rapamycin treatment throughout adulthood has been observed to preserve muscle mass into old age, contrary to initial predictions that it would accelerate sarcopenia.
10. Rapamycin & Male Fertility
Rapamycin negatively impacts spermatogenesis and male fertility, likely due to its effect on rapidly proliferating cells.
11. Intermittent RAPA for Male Fertility
While rapamycin can impair male fertility during use, there is some evidence in mice that sperm quality may be preserved after cessation of treatment, suggesting intermittent use could be a consideration.
12. Avoid mTOR Inhibition in Youth
Do not necessarily inhibit mTOR in young organisms that are in a state of anabolism and growth, as it would be suboptimal for their development.
13. Assess Rapamycin’s Added Benefit
If you already maintain a healthy diet and exercise regimen, question whether rapamycin will provide significant additional benefits, as it may mimic some aspects of a healthy lifestyle.
14. View mTOR as a Knob
Understand that mTOR complexes function like ‘knobs’ that can be turned up or down, rather than ‘on-off switches,’ meaning rapamycin modulates activity rather than completely shutting it down.
15. Distinguish RAPA & Diet Effects
Recognize that rapamycin and dietary restriction, while overlapping, have distinct effects; rapamycin can impact mTOR systemically in ways diet cannot, but diet also has other effects rapamycin doesn’t.
16. Caution: Mouse Sarcopenia Data
Be cautious when extrapolating sarcopenia findings from mouse studies to humans, as common inbred mouse strains are not as prone to age-related sarcopenia as humans.
17. Peripheral Effects for Brain
Consider that rapamycin’s effects on the peripheral immune system, such as reducing inflammation, might indirectly benefit brain health without requiring high levels of CNS penetration.
18. Weekly Rapamycin & CNS
If taking classic rapamycin weekly, it is probable that you are not achieving significant central nervous system (CNS) penetration, based on data from aggressive dosing in mice.
19. Explore Extreme mTOR Inhibition
Consider exploring very short, intermittent use of potent mTOR modulators, such as catalytic inhibitors, to achieve a level of systemic impact that cannot be replicated through dietary interventions alone.
20. Mouse-Equivalent Human Dose
The rapamycin dose that extended lifespan in mice in the ITP study, when converted to a human equivalent, is approximately 0.1 milligrams per kilogram per day.
21. Dog Aging Project Dose
The Dog Aging Project is currently using a dosing protocol of 0.15 milligrams per kilogram of rapamycin once a week for its large clinical trial, based on outcomes from shorter pilot trials.
22. Monitor Ovarian Function Trial
A double-blind, placebo-controlled, randomized clinical trial is ongoing at Columbia University, studying rapamycin’s effects on women with premature ovarian failure, and its results should be monitored for insights into ovarian function.
Some studies suggest that metformin might impair the positive response to both resistance and cardiovascular exercise, though the data is not yet definitive.
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