272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more

KEYPOINTS

• 01

  mTOR connects nutrient availability to whether the body builds up or breaks down.

  Sabatini purified mTOR as a student in Solomon Snyder's lab. He describes it as the protein that links nutrients to anabolic versus catabolic states, which is why it touches nearly everything. Rapamycin was found in an Easter Island (Rapa Nui) soil sample collected around 1966–67, and Suren Sehgal championed it. FDA approval for transplant patients didn't come until 1999. Both guests think that transplant history, where the drug was given daily alongside prednisone and other harsh immunosuppressants, gave it an undeserved reputation as a dangerous drug.

• 02

  Rapamycin is the most reproducible longevity drug across species.

  Kaeberlein found mTOR by accident in an unbiased yeast lifespan screen. Rapamycin, and genetic inhibition of mTOR, extend lifespan in yeast, worms, flies and mice, and appear to improve nearly every healthspan measure tested. His 2007 work with Brian Kennedy and Daniel Promislow showed that genes controlling longevity are often shared between yeast and worms. That's why simple organisms can tell us about aging in mammals.

• 03

  How rapamycin works: it's a 'molecular glue,' and it inhibits only part of mTOR's activity.

  Rapamycin binds FKBP12 and attaches it to mTOR complex 1 near its active site, like a boulder partly blocking a cave entrance. Some substrates get through and others don't. With prolonged exposure, it also prevents mTOR complex 2 from forming, by binding mTOR before Rictor can join it. Sabatini's postdoc showed this around 2004–2005, and Sabatini didn't believe it at first. Cells need only about 10–15% of complex 2 to keep AKT working. Catalytic (ATP-competitive) inhibitors block both complexes fully. Sabatini says they're highly toxic and can kill a mouse within hours.

• 04

  Leucine is sensed by sestrin, at the lysosome.

  Tim Peterson's experiments showed mTOR moves onto lysosomes within minutes of adding amino acids, docking on a 'pier' made of about 20 proteins. Earlier work by Joe Avruch had pointed to leucine and arginine as the key signals. Sabatini's lab identified sestrin as the leucine sensor, and its crystal structure shows a small pocket with a lid that fits only leucine. That explains why better-than-leucine mimics have been so hard to make.

• 05

  The muscle paradox.

  mTOR activation builds muscle, so rapamycin was expected to cause sarcopenia. Instead, rodents treated throughout adulthood kept more muscle into old age, perhaps through reduced inflammation. Kaeberlein notes there's no human data on whether lifespan-type doses blunt resistance-training gains. He also warns that mice are poor models of sarcopenia, so mouse protein-restriction findings may not carry over to people.

• 06

  Starting rapamycin in middle age still works.

  The 2009 ITP study started treatment at 20 months, about the equivalent of a 60-year-old human, only because the drug couldn't be formulated sooner. Kaeberlein calls it one of the most important studies in the field and says a grant proposing that design would never have been funded. Full dose-response and timing studies have never been done, and his grants for them have been rejected.

• 07

  Mannick's everolimus trial changed how the drug is viewed.

  In mice, six weeks of rapamycin before vaccination raised flu protection in old animals from about 30% to 100%. In Joan Mannick and Lloyd Klickstein's trial (about 80 per arm), older adults took everolimus for six weeks before a flu shot. Doses of 5 mg weekly and 1 mg daily improved antibody responses, and the 5 mg weekly arm had side effects close to placebo. The guests now call rapamycin an immune modulator rather than an immunosuppressant. A later pivotal trial used RTB101, a non-specific PI3K/mTOR inhibitor, without everolimus. It was stopped early, so it says nothing about rapalogs.

• 08

  What people in the off-label survey reported.

  Kaeberlein's survey compared about 300 rapamycin users with nearly 200 health-conscious non-users. All data were self-reported. Mouth sores were the only side effect more common in users, at about 15%. Abdominal cramps, depression and anxiety were less common. Most users took 6 mg once weekly, with a smaller cluster at 3 mg and some up to 20 mg. People who took it continuously through COVID reported milder illness and less long COVID, though the numbers were small.

• 09

  Why it may work: autophagy, inflammation, or the 'general contractor' effect.

  Sabatini would pick autophagy, via TFEB and lysosome production. He adds that you can't fix an old house with just a plumber; mTOR matters because it touches everything. In worms, the benefit runs mostly through autophagy; in yeast, through protein translation. Kaeberlein increasingly credits reduced sterile inflammation for the organ-level benefits in mammals. Attia points out there's no good clinical biomarker of autophagy.