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

Jul 6, 2020

Lloyd Klickstein, Chief Science Officer at resTORbio and a former Novartis and Brigham and Women's Hospital scientist, dives into the fascinating world of aging and how rapamycin could revolutionize longevity. He shares insights from his influential research on mTOR inhibition and its potential to enhance immune function, particularly in older adults. The discussion compares rapamycin’s effects to fasting and its implications for healthspan. With a look at innovative clinical applications, Klickstein highlights the significance of bridging basic science and medicine to tackle age-related health issues.

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ANECDOTE

Quick Podcast Setup

Peter Attia was so excited to talk to Lloyd Klickstein about rapamycin that he set up the podcast within a day of learning about him.
Attia had previously only known of Joan Mannick's work, not Klickstein's, despite Klickstein being the senior author.

INSIGHT

Family Business

Klickstein comes from a family of scientists and doctors, making his career path a natural choice.
He chose immunology and rheumatology due to the influence of people he worked with, not solely scientific interest.

INSIGHT

Brigham and Women's to Novartis

Klickstein worked at Brigham and Women's Hospital from 1979 to 2006.
The increasing regulations and paperwork, primarily on the clinical side, prompted his move to Novartis.

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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:

His background and decision to leave academia for translational medicine [6:15];
Translational medicine—bridging the gap between basic science and clinical medicine [10:30];
What prompted Lloyd to focus on mTOR inhibition? [18:00];
Defining mTOR, TORC1, and TORC2, and the consequences of inhibiting them with rapamycin [21:30];
Dose-dependent impact of rapamycin on immune function, mTOR inhibition, and toxicity [42:15];
Lloyd’s 2014 experiment—mTOR inhibition improves immune function in the elderly [53:00];
Insights into autophagy, antigen presentation, and the pleiotropic benefits of a rapalog, and how it compares to fasting [1:13:00];
Lloyd’s 2018 experiment—TORC1 inhibition enhances immune function and reduces infections in the elderly [1:18:45];
Creation of resTORbio, subsequent studies, and takeaways about dosing, TORC2 inhibition, and tissue selectivity [1:29:00];
Comparing the longevity effect of rapamycin, fasting, and caloric restriction [1:40:00];
Excitement around RTB101—resTORbio’s mTOR inhibiting molecule [1:47:00];
Identifying rapalogs selective for TORC1 [1:56:15];
Treating depression with ketamine, an activator of mTOR [2:00:00];
Epigenetic clocks, rapalogs, and metformin [2:03:30]; and
More.

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