Episode Summary
Executive Summary: Peter Atiyah interviews Lloyd Klickstein about mTOR biology and the clinical development of rapamycin/rapalogs for aging-related immune decline. They trace the science from basic mTOR signaling to human trials showing that carefully timed, low-dose mTOR inhibition can improve vaccine responses and reduce respiratory infections, while excessive or continuous inhibition risks mTORC2-related metabolic toxicity.
Main Topics: Lloyd Klickstein’s background and translational medicine career: Klickstein explains his physician-scientist path from Harvard/Brigham to Novartis, emphasizing how translational medicine bridges basic biology and clinical need. mTOR biology and rapamycin mechanism: The discussion covers mTOR as a nutrient/growth sensor, the distinction between mTORC1 and mTORC2, and how rapamycin/rapalogs act through FKBP binding to preferentially inhibit mTORC1. Why intermittent dosing matters: A major theme is that short-course or intermittent dosing can preserve beneficial mTORC1 effects while avoiding longer-term mTORC2 inhibition, which is associated with hyperglycemia and hypertriglyceridemia. 2014 human proof-of-concept study on immune aging: They review the landmark Novartis study using everolimus (RAD001) in older adults, showing improved influenza vaccine responses at low doses and a surprising reduction in infections. Follow-up RTB101/BEZ235 studies and RestoreBio: The conversation explains how later studies with RTB101 (BEZ235) and combinations with RAD001 led to RestoreBio, with phase 2 data supporting reduced respiratory tract infections and a phase 3 program. Mechanisms beyond vaccine response: They discuss possible mechanisms including enhanced innate antiviral gene expression, autophagy, altered antigen presentation, and broader links to fasting, inflammation, and immune surveillance. Open questions and future directions: The episode closes with unresolved issues around tissue selectivity, selective mTORC1 inhibitors, epigenetic clocks, and whether similar strategies could help aging, infection prevention, or other diseases.
Key Arguments: mTOR is a master integrator of nutrient and growth signals, making it a plausible target for aging and age-related disease interventions. Rapamycin/rapalogs are not simply immunosuppressive; at the right dose and schedule they can improve immune function in older adults. Intermittent dosing is critical because sustained exposure can eventually inhibit mTORC2, producing undesirable metabolic effects. The 2014 study showed that low-dose everolimus improved influenza vaccine responses and reduced infections, providing a human proof-of-concept for mTOR modulation in aging. The benefit seen in later RTB101 studies may be mediated by innate antiviral gene upregulation rather than improved vaccine antibody responses. Aging likely changes how tissues respond to nutrient sensing and fasting, which may explain why older organisms respond differently to mTOR inhibition. Selective mTORC1 inhibition remains an active drug-development goal, but dosing strategy may already capture much of the benefit without needing a new molecule.
Data Points: 2014 proof-of-concept study size: 218 participants - Older adults enrolled in the RAD001 influenza vaccine study Age threshold in 2014 study: Over 65 years old - Eligibility criterion for the immune-aging trial RAD001 dosing arms: 0.5 mg daily; 5 mg weekly; 20 mg weekly - Everolimus schedules tested in the 2014 study Treatment duration before vaccination: 6 weeks treatment + 2 weeks washout - Designed to test residual immune effects after drug clearance Primary vaccine-response target: 1.2-fold improvement - Pre-specified threshold for clinically meaningful flu vaccine benefit Infections observed in 2014 study: Fewer respiratory tract infections and fewer UTIs - Secondary observations from adverse-event listings over 1 year Respiratory tract infection reduction in phase 2B: 30% decrease - Reported for RTB101 in the larger RestoreBio study Phase 2B study size: 652 patients - Study spanning Southern and Northern Hemisphere cold/flu seasons Phase 3 first study size: 1,024 patients - Protector program trial mentioned as fully enrolled Phase 3 second study size: About 1,600 patients - Planned companion trial in the Protector program Phase 2B responder subgroup: Patients with asthma and diabetes responded; smokers/COPD did not - Differential efficacy by comorbidity Adverse events in placebo arm: 21 total; 12 people affected - Baseline adverse-event burden in the 2014 study Adverse events in 0.5 mg daily arm: 35 total; 22 people affected - Low-dose everolimus arm in the 2014 study Adverse events in 5 mg weekly arm: 46 total; 20 people affected - Intermediate weekly dosing arm in the 2014 study Adverse events in 20 mg weekly arm: 109 total; 27 people affected - Highest weekly dose arm in the 2014 study Mouth ulceration rate at 0.5 mg daily: 11.5% - Noted as a characteristic rapalog side effect Mouth ulceration rate at 5 mg weekly: ~4% - Lower-frequency dosing arm Mouth ulceration rate at 20 mg weekly: ~17% - Higher weekly dose arm RTB101 phase 2B dosing: 10 mg once daily - Dose associated with reduced respiratory tract infections Phase 2B treatment duration: 16 weeks - Extended through cold and flu season Phase 2B total enrollment: 264 patients - Larger follow-up study with multiple arms Phase 2B overall effect: 30% decrease in respiratory tract infections - Primary clinical outcome for RTB101 Phase 2B vaccine response: No increase with RTB101 alone - Helped distinguish innate antiviral effects from vaccine-antibody effects
Pivotal Quotes: "Our approach is not necessarily what you might read in the popular press about making medicines for aging. Our approach is to address serious aging-associated diseases. And if we're successful, the side effect will be longevity." — Lloyd Klickstein: Explaining the translational strategy behind mTOR inhibition and aging "The goal of translational medicine is to provide clinical input right at the very beginning of the process, even when you're thinking about what to do." — Lloyd Klickstein: Defining how drug development should start from patient need "In humans, after a week to a month, you can start to see consequences of TOR 2 inhibition with a RAPA log alone, and it's reflected in hyperglycemia and hyperdraglyceridemia." — Lloyd Klickstein: Why continuous exposure can become metabolically problematic
Implications: The episode argues that mTOR modulation may be a practical anti-aging strategy if dosing is carefully timed. It also suggests future therapies may focus on immune rejuvenation and infection prevention in older adults, while selective mTORC1 inhibition and better biomarkers remain key research needs.
From the Episode
Of aging is tractable, but how do we actually make a medicine and develop it? Now, was Joan at Novartis at this time? Yes, she joined our group in part to do this. Her real innovation, beyond just the idea, is that she figured out a way to test a medicine that could alter the biology of aging in humans and find an endpoint that's measurable and modifiable in a reasonable timeframe. Which really is the Achilles. Heel of aging research, which is the ultimate outcome is virtually unmeasurable in the species of interest. Yes. So our approach is not necessarily what you might read in the popular press about making medicines for aging. Our approach is to address serious aging-associated diseases. And if we're successful, the side effect will be longevity. Yeah. So keep going then. Now, Joan Flavi. This idea, which is here's a really good proxy for aging that can be measured out in a time course that's clinically tractable and also, frankly, amenable to the type of research that we can do in humans. And so, what was your aha moment? This is interesting. This is interesting to Lloyd. I needed, and beyond interesting to Lloyd, we then as a team had to persuade the rest of the organization: hey, let's try this idea.
Something new in people. But in any event, that's the way Novartis worked: they separated research from clinical development. Other companies did it a little differently. They had the initial testing in healthy volunteers or the initial testing in patients, depending on the risk-benefit argument, as part of the research organization. But in principle, it's the same thing. You had scientists making medicines and then clinicians testing them. The goal of translational medicine is to provide clinical input right at the very beginning of the process, even when you're Thinking about what to do. And it really helps to focus the drug development process on the patients in the clinical need right from the beginning so that ultimately the drug that's made is the drug that's needed. Not let's make something and figure out what we can do with it. Let's figure out what we need and then make it. Is there evidence, by the way? This is a bit of a tangent, but that transition has rendered pharma more efficient?
One possibility, but I don't think that's the case. I think it's more there's a feedback signaling pathway that down-regulates Torque 2. What you said is very important, and we're going to come back to it in great detail, but there's something temporal about this, isn't there? Yes. Do we know how much exposure to rapamycin or arapa log is necessary, constitutive exposure, before you start to see this dual prong of inhibition? Are we talking about a day? Two days, three days, a month. I know you had David Sinclair on recently, and I listened to your talk with him. He talks about mouse experiments. My bias is to talk about people experiments, given my role. In humans, after a week to a month, you can start to see consequences of TORQ2 inhibition with Arapa log alone, and it's reflected in hyperglycemia and hypertrichlyceridemia. So, biomarkers in the periphery. Blood, you can measure. Why is it that inhibition of mTORC2 leads to that phenotype you just described? I don't think we know exactly. Does it confirm that phenotype exists in healthy volunteers? In other words, we see this for sure in patients who take rapamycin or its analogs in the context of organ transplantation. But if we took non-diabetic, non-immunocompromised, quote-unquote, as normal as possible subjects,
About Peter Attia Drive
Expert insight on health, performance, longevity, critical thinking, and pursuing excellence. Dr. Peter Attia (Stanford/Hopkins/NIH-trained MD) talks with leaders in their fields.