#272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more | David Sabatini, M.D., Ph.D. and Matt Kaeberlein, Ph.D.
Sep 25, 2023
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Peter Attia welcomes David Sabatini and Matt Kaeberlein, experts on rapamycin and mTOR. They discuss the discovery of rapamycin, its potential benefits on lifespan, and the biology behind its effects. They also touch on the dosing of rapamycin in humans and reservations about prescribing it as a longevity drug. Topics include emergence of rapamycin as a geroprotective molecule, groundbreaking mouse study on lifespan extension, and the biochemistry of rapamycin and the mTOR protein complex.
Rapamycin binds to FKBP and forms a complex with mTOR, a central regulator of biological processes.
Rapamycin inhibits mTORC1 and partially inhibits mTORC2, impacting lifespan and health span.
mTOR is closely linked to nutrient sensing and amino acids play a crucial role in activating mTOR.
There are knowledge gaps regarding the specific mechanisms and optimal dosing of rapamycin for longevity.
Rapamycin has shown rejuvenating effects on the immune system and potential benefits for mental health.
Various dosages and delivery schedules are being investigated for rapamycin usage.
Deep dives
The Discovery of Rapamycin and the Role of mTOR
The podcast episode discusses the discovery of Rapamycin and the role of mTOR in longevity research. Rapamycin, a unique drug, binds to a protein called FKBP and then brings it in close proximity to mTOR, forming an important complex. mTOR, which stands for mechanistic target of rapamycin, is a protein that plays a central role in nutrient sensing and regulates various cellular processes. The episode explores how mTOR works and its connection to the availability of nutrients in the environment. The mTOR protein exists in different complexes, such as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which have distinct functions. Rapamycin inhibits mTORC1 and, over time, partially inhibits mTORC2. The effects of rapamycin on lifespan and health span are still being studied, and there is ongoing research to understand the mechanisms behind its benefits.
The Significance of Middle-Age Treatment and Dosage
The first study to show that rapamycin can extend lifespan in mice was conducted by the Interventions Testing Program (ITP) in 2009. This study was particularly significant because it demonstrated that treatment with rapamycin starting in middle age, the equivalent of a 60-65-year-old human, could increase lifespan. The dosage and timing of rapamycin treatment have been subjects of interest and exploration in subsequent studies. While the effects of rapamycin on different mTOR complexes and their implications are still being studied, it is believed that rapamycin turns down mTOR complex 1 (mTORC1) activity more significantly, while mTOR complex 2 (mTORC2) activity is partially inhibited. Further research is needed to fully understand the mechanisms by which rapamycin impacts aging biology.
The Importance of Nutrient Sensing and the Role of Amino Acids
Research has shown that mTOR is closely linked to nutrient sensing, particularly the availability of amino acids. When amino acids are present, mTOR is activated and plays a key role in promoting cell growth and anabolic processes. Conversely, the absence of amino acids signals mTOR to inhibit anabolic processes and promote catabolism, such as autophagy. Branch chain amino acids, including leucine, have been found to play a crucial role in activating mTOR. Experiments have revealed that the presence or absence of amino acids influences the localization of mTOR in cells, indicating a dynamic response to nutrient availability. The interaction between mTOR and amino acids is an important area of research for understanding the pathways involved in longevity and healthspan.
Complexities and Knowledge Gaps in mTOR Research
While significant progress has been made in understanding the role of mTOR in aging and longevity, there are still many complexities and knowledge gaps. The mTOR signaling pathway is highly intricate, with various proteins and processes involved. The specific mechanisms by which rapamycin and mTOR inhibition impact lifespan are not yet fully understood. There are ongoing debates and research regarding the relative contributions of mTOR complex 1 (mTORC1) inhibition and mTOR complex 2 (mTORC2) inhibition to the benefits and potential side effects of rapamycin. Additionally, questions remain about the optimal dosing and timing of rapamycin treatment. Further studies are needed to explore these complexities and gain a more complete understanding of the role of mTOR in aging and potential interventions for promoting healthy aging.
Impact on immune system and vaccination response
Rapamycin has shown the ability to rejuvenate the immune system in aged mice and humans. In a study with older adults, rapamycin treatment improved the response to flu vaccination, similar to the rejuvenation observed in mice. This suggests that rapamycin can enhance the immune response in older individuals. The study also highlighted the potential effectiveness of lower doses of rapamycin in healthy older adults with minimal side effects, contrary to the common perception of rapamycin as an immune suppressant.
Depression and anxiety effects
There is some evidence that rapamycin may have positive effects on depression and anxiety. Survey data from rapamycin users indicated lower rates of depression and anxiety compared to non-users. This suggests that rapamycin could have potential benefits for mental health beyond its immunomodulatory effects. Further research is needed to explore the mechanisms underlying this relationship and to validate these findings.
Mouth sores as a side effect
Rapamycin users reported a higher incidence of mouth sores, a commonly known side effect. This aligns with previous observations in transplant patients using rapamycin as an immunosuppressant. How exactly rapamycin causes mouth sores remains unclear, but it is likely related to its impact on hyperproliferative cells in the epithelia, such as those in the mouth.
COVID-19 infection and severity
The survey did not find a significant difference in the frequency of positive COVID-19 cases between rapamycin users and non-users. However, there may be some potential benefits of continuous rapamycin usage in reducing the severity of COVID-19 symptoms or preventing long COVID. Further research is needed to fully understand the impact of rapamycin on COVID-19 outcomes.
Rapamycin use may lower the severity of COVID-19 and decrease the likelihood of long COVID
Statistically significant data suggests that continuous use of rapamycin throughout the period of COVID-19 infection and resolution of symptoms may be associated with a lower likelihood of severe outcomes and long COVID. The drug's potential benefit lies in its ability to inhibit the hyperinflammatory response associated with severe COVID infections. This link between rapamycin and reduced severity of infection highlights the drug's potential for treating various viral infections, not limited to COVID-19.
Different dosages and delivery schedules are used with rapamycin
Various dosages and delivery schedules are being investigated for rapamycin usage. The most popular dosage is 6 milligrams once a week, while others have experimented with higher doses up to 20 milligrams once a week. Once-weekly dosing is preferred due to ease of administration, as shown in studies where once-weekly doses have demonstrated similar efficacy with lower potential side effects compared to daily doses. However, concerns exist that the current dosages being used may be too low for optimal results.
The potential impact of rapamycin on reproductive health
Rapamycin studies have demonstrated potential effects on reproductive health in mice. It has been shown to delay or reverse ovarian atrophy and restore fertility to sterile female mice. However, in male mice, rapamycin seems to impair spermatogenesis and potentially induce sterility. Further research is needed to understand the mechanisms behind these observations and the potential impact of rapamycin on human fertility. Clinical trials are currently underway, studying the effects of rapamycin on premature ovarian failure in women.
The need for further exploration and funding
While rapamycin shows promise as an anti-aging intervention, more research is needed to understand its full potential and optimal dosing strategies. Current studies, including the Dog Aging Project and the Marmoset study, are contributing valuable data, but larger trials with increased funding are necessary to achieve conclusive results. It is essential to overcome challenges in securing funding for clinical studies, as rapamycin offers a unique opportunity to explore the biology of aging and potential interventions.
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
