Peter Attia MD272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more
CHAPTERS
- 0:00 – 12:01
Meet the Guests: David Sabatini and Matt Kaeberlein on mTOR and Rapamycin
Peter Attia introduces a three-way discussion and asks each guest to describe his expertise. David Sabatini describes his career-long work on rapamycin and mTOR as a nutrient-sensing hub, and Matt Kaeberlein describes his path from yeast genetics to a dog clinical trial.
- •Sabatini purified mTOR while studying how rapamycin works
- •mTOR links nutrient availability to anabolic versus catabolic states, and he describes mTORC1 and mTORC2
- •Kaeberlein found mTOR by accident in an unbiased yeast longevity screen
- •He calls rapamycin the most robust and reproducible preclinical longevity drug
- •The two describe their work as complementary, from bench to bedside
- 12:01 – 19:06
Discovery of Rapamycin on Easter Island and Its Slow Clinical Path
Sabatini recounts how rapamycin was isolated from a soil sample from Rapa Nui and how it was developed over decades as an immunosuppressant. Kaeberlein and Attia discuss how the transplant-era use gave it a reputation for side effects.
- •Rapamycin came from Streptomyces hygroscopicus in an Easter Island soil sample
- •It was tested for antifungal and immunological activity before being pursued as an immunosuppressant
- •FDA approval came in 1999, decades after the early chemistry
- •Kaeberlein argues the transplant-based dosing context gave it a lasting reputation as a dangerous drug
- •Attia describes giving it to transplant patients alongside other toxic immunosuppressants
- 19:06 – 28:04
The 2009 ITP Study and Conservation of Aging Biology
The group discusses how the 2009 Interventions Testing Program study connected yeast findings to mammals and how rapamycin is unusual in working across species. Kaeberlein stresses that the genetics of longevity are conserved, and Attia contrasts geroprotection with disease-specific interventions.
- •Rapamycin spans organisms from yeast to mice
- •Kaeberlein notes genetic inhibition of mTOR also extends lifespan in model organisms
- •Longevity genes show statistically significant conservation between yeast and worms
- •Attia contrasts geroprotection with disease-specific strategies such as lowering ApoB
- 28:04 – 36:27
Starting Rapamycin in Middle Age and Open Questions on Timing, Dose, and Funding
Kaeberlein explains that the ITP study showed lifespan extension even when treatment began in middle age, by happy accident. The speakers note that optimal start time, dose, and schedule remain unknown and are hard to get funded.
- •The 2009 study started treatment at about 20 months because of a formulation problem
- •This made middle-age treatment a realistic translational goal
- •No full dose-response or optimal starting time has been established in mice
- •ITP mice are dosed continuously through chow, unlike intermittent human regimens
- •Kaeberlein says NIH study sections have rejected his grants on dose, interval, and other mTOR inhibitors
- 36:27 – 47:45
How mTOR Works: Complexes, Lysosomes, and Rapamycin's Mechanism
Sabatini explains how rapamycin uses FKBP as a molecular glue to partially block mTORC1. He describes the discovery of mTOR complexes, raptor and rictor, and the lysosome as mTOR's site of action. He also discusses how mTOR is distributed across cells and tissues.
- •Rapamycin hijacks FKBP and binds mTOR as a molecular glue
- •It acts as an allosteric inhibitor, partially blocking substrate access like a boulder at a cave entrance
- •mTOR needed binding partners to show activity, leading to mTORC1 (raptor) and mTORC2 (rictor)
- •mTOR is found in nearly every cell, including some in red blood cells and platelets
- •Regulation happens mostly upstream rather than through mTOR levels
- 47:45 – 56:41
Why Chronic Rapamycin Inhibits mTORC2 and Whether That Matters
Sabatini describes the discovery that prolonged rapamycin exposure prevents mTORC2 assembly. Kaeberlein and Sabatini discuss whether longevity benefits come purely from mTORC1 inhibition and whether mTORC2 inhibition causes the side effects.
- •Rapamycin-FKBP binds naked mTOR and prevents assembly of mTORC2 over time
- •Catalytic inhibitors block both complexes, whereas rapamycin only partially does
- •Kaeberlein is not convinced that benefits map to mTORC1 and side effects to mTORC2
- •mTORC1 and mTORC2 act like knobs rather than switches
- •Low-dose dosing may let some mTORC2 escape inhibition
- 56:41 – 1:04:44
Leucine, Sestrin, and Amino Acid Sensing by mTOR
Sabatini recounts how mTOR was found to localize to lysosomes in response to amino acids and how his lab found sestrin as the leucine sensor. He describes the crystal structure of leucine bound in sestrin.
- •Removing amino acids moves mTOR off the lysosome, and adding them moves it back within minutes
- •About 20 proteins are involved in signaling to the lysosomal docking site
- •Leucine and arginine were early amino acid regulators identified by Joe Avruch
- •Sestrin is the leucine sensor, and its structure shows a pocket made to fit leucine
- •Leucine enters the pocket easily, but getting it out may require an active step
- 1:04:44 – 1:12:12
Rapamycin, Muscle Mass, and Sarcopenia
Attia asks how blocking mTOR can extend lifespan when mTOR activation is needed to build muscle. Kaeberlein explains that rodent data show preserved muscle mass at lifespan-extending doses, offers possible explanations, and cautions against extrapolating from mice to humans.
- •The prediction that rapamycin would worsen sarcopenia was not borne out in rodents
- •Too high a dose would probably accelerate muscle loss
- •No human or rodent data exist on rapamycin and resistance training at longevity doses
- •Kaeberlein speculates reduced chronic inflammation may help preserve muscle
- •Mice are not particularly prone to sarcopenia, so extrapolation is risky
- 1:12:12 – 1:27:10
Tissue Specificity and Brain Penetration of Rapamycin
The speakers discuss which tissues rapamycin reaches, including disputed evidence on blood-brain barrier penetration at different doses. Attia shares anecdotal C2N amyloid observations, and Kaeberlein proposes that peripheral effects, such as liver signaling and immune modulation, could benefit the brain.
- •High, frequent dosing inhibits mTORC1 in all tissues, but the brain takes a few doses
- •Effects at the low doses used in lifespan studies are unknown
- •Tissue-specific genetic mTOR studies for lifespan have not been done systematically
- •Attia's anecdotal C2N amyloid improvements in two patients on weekly rapamycin
- •Kaeberlein notes liver-specific S6 kinase knockout partly rescued a mouse brain disease model
- 1:27:10 – 1:40:41
Rapalogs and Joan Mannick's Everolimus Immune Study
The group explains that rapalogs such as everolimus are simple derivatives of rapamycin with similar biochemistry. Attia and Kaeberlein walk through the Mannick study and the earlier mouse flu-vaccine experiment, which suggested rapamycin-like drugs can modulate and rejuvenate aged immune function without major side effects.
- •Rapalogs bind FKBP12 and differ mainly in bioavailability, clearance, and distribution
- •The mouse study showed six weeks of rapamycin restored vaccine protection in old mice
- •The human trial tested everolimus at 5 mg weekly, 20 mg weekly, and 1 mg daily versus placebo
- •Antibody responses improved at 5 mg weekly and 1 mg daily
- •Side effects at 5 mg weekly were similar to placebo, supporting the immune modulator framing
- 1:40:41 – 1:49:01
Epigenetics and Mechanisms Behind Immune Rejuvenation
Attia asks whether rapamycin rewrites T cell methylation patterns. Kaeberlein and Sabatini are skeptical of epigenetic clocks and of a direct signaling link, and Kaeberlein suggests that reduced chronic inflammation could explain immune rejuvenation without an epigenetic mechanism.
- •Both guests expect epigenetic changes but doubt they reflect reversal of biological aging
- •Sabatini's lab found no specific methylation signal beyond cell cycle delay effects
- •Epigenetic state may reflect a different cell state rather than the cause of it
- •Kaeberlein proposes transient dosing may reset immune function by reducing sterile inflammation
- •Persistent effects after stopping treatment are seen in several tissues in mice
- 1:49:01 – 2:03:25
Survey of Off-Label Rapamycin Users: Side Effects, Mood, and COVID
Kaeberlein summarizes the survey of rapamycin users versus non-users, in which mouth sores were the only significantly increased side effect. The discussion covers possible causes and ideas for mouth sores, rapamycin with ketamine, and the COVID findings from users who took rapamycin throughout.
- •Mouth sores, reported by about 15%, were the only side effect more common in users
- •Depression, anxiety, and abdominal cramps were reported less often in users
- •Sabatini suggests mouth sores reflect effects on fast-proliferating epithelia
- •Rapamycin combined with ketamine is being used off-label, with anecdotal reports of benefit
- •Users who took rapamycin throughout infection reported lower severity and less long COVID, based on small numbers
- 2:03:25 – 2:20:12
Catalytic mTOR Inhibitors, RTB101, and Whether Rapamycin Is Best in Class
Sabatini explains why he has not taken rapamycin and what he would like to study with mTOR inhibitors. Attia and the guests then discuss catalytic inhibitors and the RTB101 trials, and Kaeberlein notes that rapamycin may not be the best drug in its class.
- •Sabatini wonders whether rapamycin adds benefit for someone with a healthy diet and exercise
- •He wants to study intermittent strong inhibition with catalytic inhibitors
- •Catalytic inhibitors are acutely toxic at high doses in mice, whereas rapamycin is not
- •The RTB101 pivotal trial stopped early and had no rapalog in it, so it does not show rapalogs fail
- •Nobody knows whether rapamycin is best in class or just the most studied
- 2:20:12 – 2:28:32
Downstream Pathways: Autophagy, Inflammation, and Biomarkers
Sabatini and Kaeberlein discuss which pathways downstream of mTOR may drive rapamycin's benefits. Sabatini ranks autophagy first but argues mTOR matters because it acts broadly, and Kaeberlein has shifted toward anti-inflammatory effects in mammals. Attia notes there is no good autophagy biomarker.
- •Sabatini offers the old-house/general-contractor analogy for mTOR's broad effects
- •Autophagy and TFEB are prominent direct mTOR targets
- •Kaeberlein notes autophagy dominates in C. elegans, while translation matters more in yeast
- •Kaeberlein increasingly emphasizes knocking down sterile inflammation in aged mammals
- •Attia says inflammation biomarkers are plentiful but autophagy biomarkers are lacking
- 2:28:32 – 2:39:31
The Dog Aging Project and Marmoset Studies
Kaeberlein describes the Dog Aging Project's randomized, placebo-controlled rapamycin trial in older pet dogs, including its design and dosing. The discussion also covers Adam Salmon's marmoset study and its limits.
- •The trial will enroll 580 dogs and is powered to detect a 9% change in total lifespan
- •Dogs must be at least seven years old, healthy, and 40 to 110 pounds
- •Dosing is 0.15 mg/kg once weekly, and Kaeberlein worries it may be too low
- •Preliminary marmoset data suggest possible survival benefits but are incomplete and captive-based
- •Both Attia and Sabatini say they are waiting for the dog study readout
- 2:39:31 – 2:49:33
Human Dosing in the Wild and Cautions on Compounded Rapamycin
Attia and Kaeberlein compare mouse, dog, and human doses and describe what survey respondents were taking, most commonly 6 mg once weekly. They also discuss cost and warn about compounded formulations that may lack bioavailability.
- •ITP mice received dosing equivalent to about 0.1 mg/kg per day in humans
- •Most survey users took rapamycin once weekly, with 6 mg the most common dose
- •Sources of the common 5-6 mg weekly dose include the Mannick study and early off-label prescribers
- •Attia says generic rapamycin costs about $5 per milligram
- •Compounded rapamycin not in an enteric capsule may have essentially no bioavailability
- 2:49:33 – 3:01:28
Rapamycin and Fertility, and the Outlook for Rapalogs
The speakers discuss rapamycin's effects on ovarian aging and male fertility in mice, and early human trials in reproductive aging. They close with the funding obstacles for studying an off-patent drug and Sabatini's view on rapalog development and other nutrient-sensing targets.
- •Transient rapamycin can delay or reverse ovarian atrophy in female mice, whereas male mice show impaired spermatogenesis
- •Sabatini attributes the difference to rapamycin's effect on rapidly proliferating cells
- •A Columbia trial in women with premature ovarian failure is ongoing
- •Kaeberlein is frustrated that small grants and slow funding delay answers
- •Sabatini sees renewed interest in rapamycin derivatives but little appetite for other pathway targets
