#123 - Joan Mannick, M.D. & Nir Barzilai, M.D.: Rapamycin and metformin—longevity, immune enhancement, and COVID-19

Episode Summary

Executive Summary: Peter Attia hosts Joan Mannick and Nir Barzilai to compare rapalogs/rapamycin and metformin as geroprotective drugs that may improve immune resilience, reduce respiratory infections, and potentially lower COVID-19 severity. The discussion covers mechanisms, human and animal evidence, dosing, trial design, and the need for better biomarkers and phase 3 studies before broad clinical use.

Main Topics: Rapalogs and immune enhancement in older adults (Priority: 5/5): Joan Mannick explains how low-dose, intermittent mTOR inhibition (everolimus/RTB-101) improved flu vaccine responses and reduced respiratory infections in older adults, despite rapamycin’s transplant-era reputation as an immunosuppressant. Metformin as a geroscience drug (Priority: 5/5): Nir Barzilai traces metformin from diabetes therapy to a candidate aging intervention, citing animal lifespan data, epidemiology, and human studies suggesting benefits for mortality, cardiovascular disease, cancer, and cognition. COVID-19 and host resilience (Priority: 5/5): The guests argue these drugs may help by strengthening host defenses rather than directly attacking the virus, potentially reducing infection severity, cytokine storm, and mortality in older adults. Mechanisms: mTOR, AMPK, inflammation, and autophagy (Priority: 4/5): The conversation compares how metformin and rapalogs affect mitochondrial signaling, mTOR, oxidative stress, SASP, protein synthesis, and immune function, while emphasizing that mechanisms are tissue- and dose-dependent. Clinical trial design and regulatory challenges (Priority: 4/5): They discuss the limitations of current endpoints, the need for better biomarkers, why phase 3 trials are hard, and how FDA expectations may not fit geroscience or immune-resilience outcomes. TAME and the future of aging trials (Priority: 4/5): Barzilai updates the TAME metformin trial, describing its scale, funding, and goal of proving that aging-related disease can be delayed, while also using it to develop biomarkers and ancillary immune studies. Biomarkers, epigenetic clocks, and proteomics (Priority: 3/5): The speakers debate the usefulness and limitations of methylation clocks, proteomic aging signatures, and other omics as surrogate endpoints for aging interventions.

Key Arguments: Low-dose, intermittent mTOR inhibition can enhance rather than suppress immune function in older adults, improving flu vaccine responses and reducing respiratory infections. Rapalogs may work by boosting innate antiviral responses, reducing exhausted T cells, and lowering SASP-driven inflammation. Metformin likely acts through multiple aging-related pathways, including complex I inhibition, AMPK activation, reduced oxidative stress, and immune modulation. Human observational data suggest metformin is associated with lower mortality and possibly lower COVID-19 severity, but causality remains unproven. The most useful framing is not direct antiviral action but improved host resilience: better immune response, less hyperinflammation, and better tolerance of severe illness. Animal data are supportive but imperfect; the ITP is rigorous, yet human evidence should carry more weight for these drugs now. Better biomarkers are essential because current aging clocks and surrogate measures can be noisy, context-dependent, and sometimes misleading. Future trials should focus on clinically meaningful outcomes such as infection severity, hospitalization, and mortality in older adults, especially during respiratory virus season.

Data Points: Rapalog dose in 2014 study: 0.5 mg daily or 5 mg weekly (everolimus/RAD001) - Lower intermittent doses were used to partially inhibit mTOR and avoid immunosuppression while testing flu vaccine response. Higher rapalog dose in 2014 study: 20 mg weekly - Compared against lower doses; produced more mTOR inhibition but was not the best immune-response dose. Flu vaccine study duration: 6 weeks on drug, then 2-week break before vaccination - Older adults received mTOR inhibitor pulses before flu vaccination. Immune response finding: Lower doses improved flu vaccine response - The best responses were seen with 0.5 mg daily or 5 mg weekly everolimus. PD1-positive T-cell change: ~20-30% decrease - Rapalog treatment reduced exhausted PD1+ CD4 and CD8 T cells in older adults. ITP metformin result in male mice: ~10% longer lifespan at two centers; ~1% less at one center - Barzilai noted mixed results across the three ITP sites. ITP metformin + rapamycin result: 24% longer lifespan - Combination arm in one ITP cohort produced the longest-lived animals discussed. Rapamycin solo ITP result: ~16% and 9% lifespan increase by gender - Referenced as a strong comparator in the ITP discussion. Metformin COVID cohort mortality: 4-fold lower mortality (25% of control mortality) - Chinese hospitalized diabetic patients on metformin had substantially lower mortality than diabetic controls not on metformin. Metformin use in China: 60-70% of diabetic patients - Barzilai used this to argue fewer metformin users appeared among hospitalized COVID patients than expected. Minnesota preprint finding: 21-22% lower COVID mortality in women on metformin - Preprint data also reported an ~80% reduction in plasma TNF-alpha. TNF-alpha change: ~80% decrease - Reported in the Minnesota preprint discussed as supportive of anti-inflammatory effects. RTB-101 half-life: 4-6 hours - Explained as a reason for daily dosing and shorter TORC1 inhibition. Protector study timing: Enrollment finished November 2019 - Raised the possibility of retrospective analysis for COVID-era outcomes. TAME budget: $78 million - Barzilai described the overall budget for the metformin aging trial. TAME primary-outcome budget: ~$35 million - Funding for the FDA-style endpoint of preventing age-related disease and mortality. TAME sample size: 3,000 planned; possibly 3,500 - Large multicenter trial across 14 centers. TAME dose: 1,500 mg extended-release metformin daily - Participants will take three 500 mg ER tablets. Metformin exercise study age: 75 years old - Older adults in a study showed blunted muscle-mass gains but preserved function with metformin plus exercise. Transcriptomic effect: 516 transcripts differed - Metformin altered many aging-related muscle transcripts in the exercise study. Proteomics cohort: 1,000 people aged 65-95 - Barzilai described a proteomic aging study identifying breakdown-related proteins. Centenarian offspring sample: 500 offspring of centenarians - Used to compare proteomic signatures associated with longevity. Sex difference in proteome: ~560 proteins changing in men vs ~200 in women - Suggested aging biomarkers may need sex-specific interpretation.

Pivotal Quotes: "“We are reinforcing the host. We are defending the host.”" — Nir Barzilai: Barzilai’s central framing of metformin/rapalogs in COVID-19 and aging: host resilience, not direct antiviral therapy. "“Turning mTOR down in the elderly, not turning it off, is the best for enhancing immune function.”" — Joan Mannick: Summary of the 2014 rapalog flu-vaccine study and its dose-response lesson. "“If we have a vaccine that doesn't protect the elderly, we did nothing.”" — Nir Barzilai: Barzilai’s warning that vaccine development must account for age-related immune dysfunction.

Implications: The episode argues for a geroscience approach to infectious disease: test aging-targeted drugs to improve immune resilience in older adults. It also calls for better biomarkers, smarter trial endpoints, and more rigorous phase 3 studies before routine use.