#272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more | David Sabatini, M.D., Ph.D. and Matt Kaeberlein, Ph.D.
Peter Attia, David Sabatini, and Matt Kaeberlein, world-leading experts on rapamycin and mTOR, discuss the molecule's discovery, its role as a central regulator of nutrient sensing, and its potential to prolong lifespan. They explore human and animal studies, the complexities of dosing, and side effects, emphasizing reservations about indiscriminate use.
Deep Dive Analysis
23 Topic Outline
David and Matt's Expertise in mTOR and Rapamycin
Discovery of Rapamycin and Its Early Use as an Immunosuppressant
Rapamycin Emerges as a Potential Lifespan-Prolonging Molecule
The Groundbreaking 2009 Mouse Lifespan Extension Study
Understanding mTOR and Rapamycin's Biological Effects
Rapamycin's Differential Inhibition of mTORC1 and mTORC2
Reconciling Rapamycin's Mechanism with Longevity Benefits
Amino Acid Sensing by mTOR, Especially Leucine
Rapamycin, mTOR Inhibition, and Muscle Mass Preservation
Unanswered Questions on Rapamycin's Tissue Specificity
Rapamycin, Blood-Brain Barrier, and Brain Health
Rapamycin as an Immune Modulator, Not Just an Immunosuppressant
Rapamycin's Potential Impact on T Cell Epigenetics and Aging
Rapamycin Side Effects and Mental Health: Insights from a User Survey
Rapamycin Use and COVID-19 Outcomes from a User Survey
Future Directions for mTOR Inhibitor Research
Discussion of ATP-Competitive mTOR Inhibitors like RTB-101
mTOR Inhibition, Autophagy, Inflammation, and Biomarkers
The Dog Aging Project: Rapamycin in Companion Animals
Preliminary Results from Primate Studies with Rapamycin
Dosing Considerations for Rapamycin in Humans and Animals
The Effect of Rapamycin on Fertility
Outlook for Future Rapamycin Research and Rapalogs
9 Key Concepts
mTOR (mammalian Target of Rapamycin)
A protein that links nutrient availability to cellular states of anabolism (growth) or catabolism (breakdown). It acts as a master regulator of many physiological processes, sensing nutrients like amino acids to control cell growth, metabolism, and autophagy.
Rapamycin
A unique drug that, unlike most, binds to a protein called FKBP inside the cell, forming a complex that then binds to and partially inhibits mTOR. It was originally discovered as an antifungal and immunosuppressant, but later found to have geroprotective effects across the animal kingdom.
mTORC1 (mTOR Complex 1)
One of two protein complexes involving mTOR, defined by its binding to the protein Raptor. It is primarily responsible for sensing nutrients and regulating processes like protein synthesis and autophagy. Rapamycin primarily inhibits mTORC1.
mTORC2 (mTOR Complex 2)
The second protein complex involving mTOR, defined by its binding to the protein Rictor. While rapamycin does not directly bind to and inhibit pre-formed mTORC2, prolonged exposure can prevent its formation by binding to 'naked' mTOR, thus indirectly inhibiting mTORC2 over time.
Allosteric Inhibitor
A type of inhibitor, like rapamycin, that binds to a site on an enzyme (mTOR) other than the active site, causing a conformational change that affects the enzyme's activity. Rapamycin partially inhibits mTORC1 by sterically blocking certain substrates from accessing the active site.
Catalytic (ATP-Competitive) Inhibitor
A type of inhibitor that directly competes with ATP for binding to the active site of an enzyme (mTOR). These inhibitors are generally much more potent and less specific than allosteric inhibitors, often obliterating both mTORC1 and mTORC2 activity.
Lysosome
A cellular organelle that functions as the cell's recycling center, breaking down cellular components into basic nutrients. mTORC1 is localized to the surface of lysosomes, acting at this interface to sense and respond to nutrient availability.
Sestrin
A protein identified as the receptor for the amino acid leucine. Sestrin binds leucine, and this interaction is critical for communicating leucine availability to the mTORC1 pathway, thereby influencing anabolic processes.
Immune Modulator
A substance that can alter the function of the immune system. Rapamycin, initially known as an immunosuppressant, is now also considered an immune modulator because studies show it can rejuvenate the aged immune system, improving its ability to respond to vaccines and fight infections.
11 Questions Answered
mTOR (mammalian Target of Rapamycin) is a protein that serves as a central regulator, linking the availability of nutrients in our environment to whether the body is in an anabolic (growth) or catabolic (breakdown) state. It controls numerous biological processes based on nutrient sensing.
Rapamycin is unique because it first binds to a small protein called FKBP inside the cell. This rapamycin-FKBP complex then binds to mTOR, acting as a 'molecular glue' to inhibit its activity, primarily mTORC1, by sterically blocking certain substrates from reaching its active site.
Yes, a groundbreaking 2009 study showed that rapamycin treatment in mice, even when started in middle age (biologically equivalent to a 60-65 year old human), could significantly extend lifespan, which was a surprising and important discovery at the time.
Contrary to initial predictions, rapamycin treatment at longevity-promoting doses in rodents has been shown to preserve muscle mass into old age, rather than accelerate sarcopenia. The exact mechanisms are unclear but may involve anti-inflammatory effects.
There is disagreement, but some data suggest that classical rapamycin may require higher or repeated dosing to effectively penetrate the brain. It's speculated that in older animals/humans, the blood-brain barrier may be less robust, potentially allowing better penetration.
While initially used as an immunosuppressant for organ transplants, rapamycin is increasingly viewed as an immune modulator. Studies in aged mice and humans have shown it can rejuvenate the immune system, improving vaccine response and potentially reducing infection risk, rather than broadly suppressing immunity.
A survey of off-label rapamycin users found that mouth sores were the only statistically significant side effect reported more frequently than in non-users, occurring in about 15% of users. Other severe side effects commonly associated with high-dose transplant regimens were not observed.
A survey of rapamycin users during the COVID-19 pandemic suggested that continuous rapamycin use throughout infection might be associated with lower severity of symptoms and a reduced likelihood of long COVID, possibly due to its anti-inflammatory effects.
The optimal dosing is currently unknown. Most off-label users take 6mg once a week, influenced by early human studies showing immune benefits at 5mg weekly. Research in dogs is testing 0.15 mg/kg once weekly, but there's concern this might be too low compared to daily mouse longevity doses.
In female mice, rapamycin can delay or even reverse ovarian atrophy and restore reproductive capacity. However, in male mice, it appears to impair spermatogenesis and potentially induce sterility while on the drug, likely due to its impact on rapidly proliferating cells.
While mTOR impacts many processes, autophagy (the self-eating and recycling of cellular components) is considered a major and prominently regulated pathway. However, mTOR's broad impact on numerous cellular functions, including inflammation and protein synthesis, likely contributes to its overall anti-aging benefits.
23 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.
23. Metformin & Exercise Response
Some studies suggest that metformin might impair the positive response to both resistance and cardiovascular exercise, though the data is not yet definitive.
9 Key Quotes
I would say without question, it is the most robust and reproducible drug, at least from preclinical studies that we know about today for impacting not only longevity, but to the extent that we can measure various metrics of health span in complex animals, rapamycin also seems to positively impact pretty much every aspect of health span that we measure.
Matt Kaeberlein
I think that last statement is a hundred percent true. I think we almost have no evidence to make that decision one way or another. But I think the reason, if mTORC2, its inhibition is toxic, which we have published papers arguing it is, the reason that I think it's actually quite tolerated is because, you know, in general, the amounts of rapamycin used in the longevity studies are relatively modest.
David Sabatini
I'm a little bit wary of extrapolating too far from the rodent studies to humans in the context of sarcopenia in particular. And in particular, I'm talking about mouse studies to humans. Mice are not, at least the commonly used inbred mouse strains are not particularly prone to sarcopenia with age.
Matt Kaeberlein
As far as I know, it's really the first where you actually rejuvenate some organ system in a human being, right? And so I think her study really was mind-blowing.
David Sabatini
If you're an old mouse, no rapamycin, you get a vaccine, only 30% of the mice actually were protected. So this is showing you the impact of just normal biological aging on the ability to respond to a vaccine... The cool thing in that study was if the mice got six weeks of rapamycin treatment before the vaccine, they were then 100% protected.
Matt Kaeberlein
A cell state, Rick Young always used to say, epigenetics is the setting of the state, not the thing that gave you that state at the beginning, right? And this is an important distinction.
David Sabatini
If I starve myself, what happens? My body synthesizes certain nutrients, breakdowns other things to release them... So what I'm much more curious about is, can I use rapamycin or other mTOR modulators... to take that system to a state that I cannot simply do with a dietary intervention whatsoever.
David Sabatini
I don't know that we're going to be successful trying to point to one thing and say, that's the most important thing. David's absolutely right, though, that in C. elegans, at least, it seems to be the case that most, if not all, of the benefits of inhibiting mTOR can be directly attributed to activation of autophagy.
Matt Kaeberlein
I would be shocked if we see a shortening of lifespan from rapamycin treatment. Just given everything that I know to this point in mice and the data we've gotten so far in dogs, it is possible. And I totally understand that reasoning would surprise the heck out of me if we see any lifespan shortening.
Matt Kaeberlein
3 Protocols
Mouse Immune Rejuvenation Study Protocol
Matt Kaeberlein (describing Pen Zheng's study)- Treat aged mice (24 months old) with rapamycin for 6 weeks.
- Administer a flu vaccine.
- Observe for 100% protection against subsequent lethal influenza infection.
Human Immune Rejuvenation Study Protocol
Matt Kaeberlein (describing Joan Mannick's study)- Enroll healthy older people (over 65).
- Administer Everolimus (a rapamycin derivative) at 5 milligrams once a week or 1 milligram daily for 6 weeks.
- Administer a flu vaccine.
- Measure antibody titers to assess vaccine response.
Dog Aging Project (TRIAD) Protocol
Matt Kaeberlein- Enroll dogs aged at least 7 years, weighing 40-110 pounds, without significant pre-existing age-related disease.
- Randomize dogs to receive either placebo or rapamycin at 0.15 milligrams per kilogram once a week.
- Administer treatment for a period of 3 years.
- Monitor multiple healthspan metrics (cardiac, neurological, activity, cognitive function) and lifespan as the primary endpoint.