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Peter Attia MDPeter Attia MD

#118 – Lloyd Klickstein, M.D., Ph.D.: Rapamycin, mTOR inhibition, and the biology of aging

Original release date: 7/6/20 Lloyd Klickstein is the Chief Science Officer at resTORbio, a biopharmaceutical company that develops medications to target the biology of aging. In this episode, Lloyd discusses his company’s clinical application of rapamycin and its derivatives. He also elucidates details of his 2014 paper—a paper that greatly influenced Peter’s perspective of rapamycin in the context of longevity. Peter and Lloyd go on to discuss the dose-dependent effect of rapamycin on immune function and compare rapamycin, fasting, and caloric restriction. We discuss: 00:00:00 - Intro 00:06:15 - His background and decision to leave academia for translational medicine 00:10:30 - Translational medicine—bridging the gap between basic science and clinical medicine 00:18:00 - What prompted Lloyd to focus on mTOR inhibition? 00:21:30 - Defining mTOR, TORC1, and TORC2, and the consequences of inhibiting them with rapamycin 00:42:15 - Dose-dependent impact of rapamycin on immune function, mTOR inhibition, and toxicity 00:53:00 - Lloyd’s 2014 experiment—mTOR inhibition improves immune function in the elderly 01:13:00 - Insights into autophagy, antigen presentation, and the pleiotropic benefits of a rapalog, and how it compares to fasting 01:18:45 - Lloyd’s 2018 experiment—TORC1 inhibition enhances immune function and reduces infections in the elderly 01:29:00 - Creation of resTORbio, subsequent studies, and takeaways about dosing, TORC2 inhibition, and tissue selectivity 01:40:00 - Comparing the longevity effect of rapamycin, fasting, and caloric restriction 01:47:00 - Excitement around RTB101—resTORbio’s mTOR inhibiting molecule 01:56:15 - Identifying rapalogs selective for TORC1 02:00:00 - Treating depression with ketamine, an activator of mTOR 02:03:30 - Epigenetic clocks, rapalogs, and metformin Show notes page: https://peterattiamd.com/lloydklickstein/ About: The Peter Attia Drive is a weekly, ultra-deep-dive podcast focusing on maximizing health, longevity, critical thinking…and a few other things. With over 30 million episodes downloaded, it features topics including fasting, ketosis, Alzheimer’s disease, cancer, mental health, and much more. Peter is a physician focusing on the applied science of longevity. His practice deals extensively with nutritional interventions, exercise physiology, sleep physiology, emotional and mental health, and pharmacology to increase lifespan (delay the onset of chronic disease), while simultaneously improving healthspan (quality of life). Learn more: https://peterattiamd.com/ Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on: Facebook: http://bit.ly/PeterAttiaMDFB Twitter: http://bit.ly/PeterAttiaMDTW Instagram: http://bit.ly/PeterAttiaMDIG Subscribe to The Drive: Apple Podcast: http://bit.ly/TheDriveApplePodcasts Overcast: http://bit.ly/TheDriveOvercast Spotify: http://bit.ly/TheDriveSpotify Google Play: http://bit.ly/TheDriveGooglePlay

Peter AttiahostLloyd Klicksteinguest
Jul 9, 20202h 14mWatch on YouTube ↗

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At a glance

WHAT IT’S REALLY ABOUT

Lloyd Klickstein on Low-Dose Rapalogs, mTOR Inhibition and Aging Immunity

  1. Klickstein explains that mTOR is the master integrator of nutrient and growth signals, existing as TORC1 (protein and lipid synthesis) and TORC2 (cytoskeleton), with rapamycin acting on TORC1 first and on TORC2 only after prolonged exposure.
  2. He describes the 2014 study in people over 65, where low or intermittent doses of everolimus (RAD001) improved flu vaccine response and reduced infections, while the highest weekly dose did not.
  3. A follow-up 2018 study found that the catalytic inhibitor BEZ235 (now RTB101) cut respiratory tract infections, likely through upregulated interferon-stimulated antiviral genes, and led to the creation of resTORbio and a phase III program.
  4. The conversation covers open questions: aging rats lose the fasting-induced mTOR suppression seen in young ones, rapalogs don't appear to reset epigenetic clocks, and newer work suggests selectivity may depend on which FKBP binds the drug.
  5. Attia opens by disclosing that Klickstein works for resTORbio, and notes the interview was recorded in September 2019, before the phase III trial missed its primary endpoint.

IDEAS WORTH REMEMBERING

5 ideas

Dose and schedule determine whether mTOR inhibition suppresses or enhances immunity.

In the 2014 study the low daily dose and the 5 mg weekly dose improved flu vaccine response, while the 20 mg weekly dose, which fully inhibited TORC1 continuously, did not.

TORC1 inhibition appears beneficial while TORC2 inhibition appears harmful.

Klickstein says conditional TORC1 knockouts in adult mice extend lifespan and healthspan, whereas TORC2 inhibition accelerates death; in humans, TORC2 effects show as hyperglycemia and hypertriglyceridemia after a week to a month of a rapalog.

Rapamycin's toxicity is driven by trough levels, so drug-free time matters.

Klickstein and Attia contrast it with drugs like Cialis, noting that rapamycin and gentamicin are monitored by trough rather than peak, which supports intermittent dosing.

Reduced infections may come from innate antiviral activity, not better vaccine responses.

RTB101 reduced respiratory tract infections without improving vaccine response, and samples showed upregulated interferon-stimulated antiviral genes, suggesting a different mechanism from adaptive immunity.

The company's approach targets age-related disease rather than longevity directly.

Klickstein says the aim is to treat serious aging-associated conditions, with longevity as a hoped-for side effect, using the immune system's 'age' as a measurable proxy.

WORDS WORTH SAVING

5 quotes

In a nutshell, mTOR is the master integrator of external availability of nutrients and growth factors, and then is the master regulator of the outputs of that integration, deciding whether cells are gonna make proteins, make lipids, make nucleic acids grow, or are we gonna circle the wagons, conserve resources, recycle, and wait during times of little for hopefully future times of plenty.

— Lloyd Klickstein

Our approach is to address serious aging-associated diseases, and if we're successful, the side effect will be longevity.

— Lloyd Klickstein

It's how do you take a basic science observation and make something useful for human health out of it and prove it, which is surprisingly challenging.

— Lloyd Klickstein

Inhibition of TORC1 extends lifespan and healthspan in rodents. If you do that to TORC2, it accelerates death.

— Lloyd Klickstein

I think that's one of the beautiful things about folks that come on this podcast is great scientists say, "I don't know," probably more than they, they know the answer.

— Peter Attia

Translational medicine versus basic and clinical sciencemTOR, TORC1 and TORC2 biologyRapalog dosing, trough levels and toxicity2014 everolimus immune function studyRTB101 and the resTORbio phase III programRapamycin versus fasting and caloric restrictionEpigenetic clocks, metformin and ketamine

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