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Peter Attia MD#123–Joan Mannick & Nir Barzilai: Rapamycin and metformin—longevity, immune enhancement, & COVID-19
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At a glance
WHAT IT’S REALLY ABOUT
Rapamycin, Metformin, and Immune Resilience Against COVID-19 and Aging
- Joan Mannick describes her Novartis trials showing that low, intermittent doses of an mTOR inhibitor improved flu vaccine response in older adults and reduced respiratory infections, which led to the catalytic inhibitor RTB101.
- Nir Barzilai explains why he chose metformin as the tool to advance geroscience, citing human association data, its effects across the hallmarks of aging, and the planned TAME trial.
- Early observational data, including a Wuhan cohort Barzilai cites, suggest metformin users had lower COVID-19 mortality, while both guests stress these drugs would work by reinforcing the aging host rather than attacking the virus, and only as prevention, not as treatment.
- The group debates combining the two drugs, Peter Attia's personal experience stopping metformin and taking rapamycin, and the limits of epigenetic and proteomic aging clocks as biomarkers.
- The conversation closes on the need for better biomarkers, more rigorous trial design, regulatory learning, and a COVID-era push for research into immune enhancement.
IDEAS WORTH REMEMBERING
5 ideasPartial mTOR inhibition, not complete, appears to improve immunity in the elderly.
Mannick says very low or weekly dosing of everolimus improved flu vaccine response, with the lowest doses working best, because full inhibition would stop T cell proliferation and suppress immunity.
Rapalogs may boost innate antiviral responses and reduce T cell exhaustion.
Mannick reports enhanced interferon-induced gene expression and a 25 to 30% drop in exhausted PD-1 positive CD4 and CD8 T cells, which may explain better vaccine response and milder infections.
The strategy is to defend the host rather than fight the virus.
Barzilai argues that older people die from COVID-19 because of the biology of aging, so drugs targeting aging could help; both guests say the drugs are for prevention, not treatment of sick hospitalized patients.
The metformin COVID evidence is suggestive but weak.
Barzilai cites a Wuhan retrospective cohort with about four times lower mortality and an unreviewed Minnesota preprint, but admits he lacks details and that these are not clinical trials.
Phase 3 failure stemmed partly from the FDA's endpoint choice.
Mannick says the FDA required symptom-based endpoints rather than lab-confirmed infection, where benefit was seen; the drug appeared to reduce symptom severity but not total symptoms.
WORDS WORTH SAVING
5 quotesWhat it looked like is just turning mTOR down in the elderly, not turning it off, is the best for enhancing immune function.
— Joan Mannick
We're not fighting the virus, we're reinforcing the host. Okay? We're defending the host.
— Nir Barzilai
If we have a vaccine that doesn't protect the elderly, we did nothing.
— Nir Barzilai
When we used to go and try to raise money for, you know, doing this kind of research, investors would just... We'd mention respiratory tract infections, and they would start to yawn. Like, nobody cared.
— Joan Mannick
I'm constantly amazed at how often science actually works out when you consider all of the permutations in which it could go wrong.
— Peter Attia
High quality AI-generated summary created from speaker-labeled transcript.
