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Peter Attia MD#118 – Lloyd Klickstein, M.D., Ph.D.: Rapamycin, mTOR inhibition, and the biology of aging
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CHAPTERS
- 0:11 – 6:31
Episode Preview, Disclosures, and Guest Introduction
Peter Attia introduces Lloyd Klickstein of resTORbio and explains why the 2014 Mannick–Klickstein paper changed his thinking about rapamycin. He discloses Klickstein's company affiliation and notes that the interview was recorded in 2019, before the phase III trial missed its primary endpoint.
- •Klickstein is chief scientific officer at resTORbio and was senior author on the December 2014 paper
- •Attia calls that paper the turning point in his thinking about rapamycin for longevity
- •Klickstein is an employee of a for-profit mTOR-inhibition company, so claims should be weighed with that in mind
- •The interview was recorded in September 2019, and the phase III study later did not meet its primary endpoint
- •A follow-up with Joan Mannick and Nir Barzilai is planned
- 6:31 – 10:38
Klickstein's Path from Brigham to Novartis
Klickstein describes growing up in a family of scientists and doctors, his MD/PhD training, and his years at the Brigham. He explains why he left academia in 2006 for Novartis, citing the difficulty of being a physician-scientist and the pull of translational medicine.
- •Science and medicine are his family business
- •He worked at the Brigham from 1979 and left in 2006 to join Tim Wright's department at Novartis
- •Returning to academia is harder without existing grants
- •Regulation and paperwork on the clinical side made the academic physician-scientist role harder
- •Translational medicine was a new concept that suited him
- 10:38 – 18:05
What Translational Medicine Is and How Novartis Applied It
Klickstein distinguishes basic science, clinical medicine, and translational medicine, using restriction enzymes and CRISPR as examples of basic science. He describes how Novartis moved away from throwing compounds over the wall to bringing clinical input in at the start, and explains what an IND is.
- •Basic science examples include restriction enzymes and CRISPR
- •Translational medicine turns a basic observation into something useful for human health and proves it
- •Novartis used to separate research from clinical development
- •An IND is the application to the FDA to begin clinical trials
- •Starting from clinical need aims to make the drug that is needed
- 18:05 – 21:42
The New Indication Discovery Unit and the Aging Idea
Klickstein explains how Mark Fishman challenged him to build a unit asking what Novartis wasn't doing, and how Joan Mannick brought forward the idea of targeting the biology of aging. Her innovation was a measurable, modifiable endpoint in humans, and the team framed aging-related disease as the goal with longevity as a side effect.
- •The unit started around 2008–2009 around medical need and scientific tractability
- •Joan Mannick proposed that the biology of aging was tractable
- •Her key innovation was an endpoint measurable in a reasonable timeframe
- •The approach targets serious aging-associated diseases rather than longevity directly
- •Preclinical data show mTOR inhibition extends healthspan in all species tested
- 21:42 – 33:16
mTOR, TORC1/TORC2, and How Rapamycin Acts
Klickstein explains mTOR as the master integrator of nutrient and growth-factor signals and why it sits on the lysosome. He then covers TORC1 versus TORC2, how rapamycin works through FKBP, and its differential effects on S6K, 4E-BP1, and ULK1.
- •mTOR integrates amino acids, glucose, energy, and growth factors to decide whether cells grow
- •Evolutionary history explains its location on the lysosome
- •TORC1 (raptor) governs protein and lipid synthesis; TORC2 (rictor) governs cytoskeleton
- •Rapamycin–FKBP binds TORC1, inhibiting S6K strongly and ULK1 less so
- •TORC2 is not inhibited directly but is affected by longer-term feedback
- 33:16 – 39:02
TORC2 Inhibition, Side Effects, and Genetic Evidence
The discussion turns to timing: with continuous rapalog exposure, TORC2 inhibition emerges after a week to a month and shows up as hyperglycemia and hypertriglyceridemia. They review RAD001 dosing equivalence and mouse knockout data suggesting that TORC1 inhibition is beneficial while TORC2 inhibition is harmful.
- •TORC2 effects appear after one week to one month of continuous rapalog dosing
- •Hyperglycemia and hypertriglyceridemia seen in non-transplant patients, e.g. in polycystic kidney disease
- •Immunosuppressive rapamycin doses of 2–8 mg/day are comparable to 5–10 mg of RAD001
- •Raptor knockout is embryonic lethal, but adult conditional TORC1 knockout is tolerated
- •TORC1 inhibition extends rodent lifespan, while TORC2 inhibition accelerates death
- 39:02 – 51:03
Dose, Exposure, and Why Low-Dose Rapalog Might Help Immunity
Attia explains his confusion over reconciling mouse longevity data with transplant immunosuppression. They discuss exposure, half-life and trough versus peak toxicity using Cialis, rapamycin, and gentamicin as examples. Klickstein explains the early clues that low-dose rapalogs might improve immune function.
- •Higher rodent doses can produce exposures comparable to transplant doses
- •Half-life explains why dosing schedules differ from presence of drug in the body
- •Rapamycin and gentamicin toxicities are driven by trough levels, so drug-free time matters
- •Fewer CMV infections on rapalogs than on calcineurin inhibitors was an early clue
- •Cell experiments showed far lower exposures could inhibit TORC1 targets
- 51:03 – 1:06:13
The 2014 Study: Design and Safety Findings
Klickstein and Attia walk through the 2014 everolimus (RAD001) trial, from how the team prepared the design to the four-arm randomized structure with six weeks of dosing and a two-week washout before flu vaccination. They review the adverse-event table, including mouth ulcers.
- •Rapalog terminology: rapamycin/sirolimus, then everolimus (RAD001) and temsirolimus as modified analogs
- •Work began around 2010 and needed modeling to keep trough levels low
- •218 participants over 65 in Australia and New Zealand got placebo, 0.5 mg daily, 5 mg weekly, or 20 mg weekly
- •Dosing was six weeks plus a two-week washout so the drug was gone at vaccination
- •Mouth ulcers were the notable side effect, but no one knows why
- 1:06:13 – 1:18:56
2014 Results: Vaccine Response, PD-1, and Autophagy Questions
The low doses improved flu vaccine response by the prespecified 1.2-fold in two of three strains, while the 20 mg dose did not, likely reflecting immunosuppression at high exposure. They also discuss lower PD-1 on lymphocytes, a pneumococcal vaccine exploratory result, and open questions about autophagy and what other mechanisms might be at work.
- •Both low doses met the 1.2-fold target in two of three strains; the high dose did not
- •PD-1 levels fell by about 10–20% in treated participants
- •Pneumococcal vaccine responses rose modestly in six of seven measured antigens
- •Autophagy is hard to measure clinically, and no banked samples remain
- •Methylation clocks do not seem to be reset by rapalogs, per Klickstein
- 1:18:56 – 1:29:10
Novartis's Reaction and the 2018 TORC1-Selective Study
Klickstein explains that Novartis asked the team to replicate the work in a more TORC1-selective way. He describes the 2018 study, which used BEZ235 (now RTB101) alone and with RAD001, and the observation that infections fell in treated groups. They also discuss whether six weeks was the right duration.
- •The 2014 study was far too small to support broad marketing authorization
- •A catalytic plus allosteric combination was more potent and TORC1-selective
- •The 2014 adverse-event listings showed fewer infections, mainly respiratory and urinary
- •Revaccination a year later showed the improvement had not persisted
- •In 2018, BEZ235 alone worked best against respiratory infections, while the combination best improved flu response
- 1:29:10 – 1:40:10
Founding resTORbio and the Interferon-Mediated Mechanism
Klickstein recounts how the program fell below Novartis's funding line, was out-licensed, and became resTORbio. He explains the phase 2b design and the mechanism, an upregulated interferon-stimulated antiviral gene response, and discusses tissue targeting in drug design.
- •Novartis out-licensed the program and Joan Mannick launched resTORbio, which licensed BEZ235 (RTB101)
- •RTB101 10 mg alone was the best at preventing respiratory infections
- •The proposed mechanism is an interferon-stimulated antiviral gene response
- •Prolonged mTOR inhibition might blunt expression of these proteins
- •Tissue targeting is harder than target targeting, though doable
- 1:40:10 – 1:47:13
Does Rapamycin Overlap with Fasting? Aging and mTOR Suppression
Attia asks how much of rapamycin's benefit comes through immunity versus other mechanisms, and how it relates to fasting and caloric restriction. Klickstein describes work showing that old rats fail to suppress liver mTOR with fasting, raising open questions about humans, tissues, and autophagy.
- •Autophagy, senescent cell clearance, and mitophagy can each extend healthspan preclinically but are unproven in people
- •Fasting suppresses mTOR in young animals but not in old rats' livers
- •Older animals appear to lose responsiveness to nutrient reduction
- •Klickstein's group could not detect mTOR activity in leukocytes of old people
- •Autophagy and mTOR inhibition are overlapping but distinct
- 1:47:13 – 1:56:23
Phase 2b Results and the Phase III Protector Program
Klickstein details the phase 2b study, which tested multiple doses and schedules over two hemispheres and found about a 30% reduction in respiratory infections, with poorer response in smokers and COPD patients. He then describes the phase III program, its enrollment, and dosing through winter cold and flu season.
- •Phase 2b enrolled 652 patients across Southern and Northern Hemisphere seasons
- •Overall there was a 30% reduction in respiratory tract infections
- •Asthma and diabetes patients responded, while smokers and COPD patients did not
- •Phase III Protector Program targets people 65 and over, with 16 weeks of dosing
- •First phase III study fully enrolled at 1,024 patients, with top-line data expected by early 2020
- 1:56:23 – 2:01:24
Selective TORC1 Inhibition, FKBPs, and Ketamine
They discuss a recent paper screening about 90 rapalogs for TORC1 selectivity, which suggests the roles of different FKBPs (12 versus 51) are more complex than assumed. The conversation then covers ketamine's rapid antidepressant effect, rapamycin blocking it, and Navitor's mTOR activator, plus open questions about immunophilins.
- •The screen identified rapalogs selective for TORC1 despite sustained exposure
- •Activity required FKBP12 but not FKBP51
- •Klickstein believes TORC2 inhibition arises from indirect counter-regulatory signaling
- •Intravenous ketamine works in minutes to hours for major depression, and a study showed rapamycin blocked its effect
- •Navitor is using an mTOR activator to treat depression
- 2:01:24 – 2:14:54
Epigenetic Clocks, Growth Hormone Trial, and Metformin
Klickstein explains Horvath-style methylation clocks and suggests methylation changes may be causally linked to aging. They discuss a small uncontrolled study using growth hormone, DHEA, and metformin, with comments on thymic size and metformin's mitochondrial effects, before closing the interview.
- •Methylation patterns predict chronological age within about six months to a year between ages 20 and 80
- •Klickstein thinks DNA methylation may cause, not just reflect, aging
- •A rapalog methylation experiment he knows of was negative and unpublished
- •DHEA replacement has shown no clinical benefit, and growth hormone is expected to enlarge lymphoid tissue
- •Klickstein says it is unknown whether metformin benefits healthy people, given possible mitochondrial effects
