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Peter Attia MD#123–Joan Mannick & Nir Barzilai: Rapamycin and metformin—longevity, immune enhancement, & COVID-19
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CHAPTERS
- 0:11 – 4:31
Introduction and Why Metformin and Rapamycin Are Discussed Together
Peter Attia introduces guests Joan Mannick and Nir Barzilai and explains why he pairs metformin and rapamycin in one episode. The overlap spans longevity and their potential role in immune resilience and COVID-19.
- •Joan Mannick is co-founder and CMO of Restor Bio and formerly led Novartis's New Indications Discovery Unit
- •Nir Barzilai directs the Institute for Aging Research at Albert Einstein and studies centenarians
- •Metformin and rapamycin are the drugs Peter is asked about most
- •The episode covers background first, then immune response and COVID-19
- 4:31 – 8:45
Joan's Path from Infectious Disease to Aging Research at Novartis
Joan describes how Cynthia Kenyon's work drew her to aging research and how she ended up in Novartis's New Indications Discovery Unit. She explains her father's encouragement and why she chose a rapamycin analog to test immune function in older adults.
- •Cynthia Kenyon's worm longevity papers were transformative for Joan
- •Novartis leadership decided around 2012 to work on aging
- •Joan's father encouraged her to try something new at age 50
- •She picked immune function and flu vaccine response as the readout for an mTOR inhibitor
- 8:45 – 14:34
Designing the 2014 Rapalog Flu Vaccine Study
Peter asks how a drug used for immunosuppression could enhance immunity, and Joan explains the rationale and dosing. Low, intermittent dosing that only partially inhibited mTOR improved flu vaccine response in older adults.
- •Novartis questioned testing an immunosuppressant to boost immunity
- •Preclinical evidence in mice and aging models supported the trial
- •Everolimus was dosed at 0.5 mg daily or 5 mg weekly to partially inhibit mTOR
- •Turning mTOR down rather than off appeared best for immune function in the elderly
- 14:34 – 24:21
Nir's Path to Metformin and the ITP Mouse Data
Nir recounts working on metformin's mechanism as a postdoc and the clinical and association data that convinced him it targets aging. The discussion turns to the Interventions Testing Program results for metformin and why mouse data matter less than human data.
- •Nir's early work showed metformin targets hepatic glucose production
- •Association studies on diabetes, cardiovascular disease, cancer and Alzheimer's pointed to broader benefits
- •ITP uses genetically heterogeneous mice across three centers
- •Metformin alone gave mixed ITP results, while metformin plus rapamycin showed 24% longer life
- •Nir argues human data now outweigh mouse results
- 24:21 – 33:54
Hallmarks of Aging and Mechanisms of Metformin and Rapalogs
Nir describes a paper mapping metformin's mechanisms onto the hallmarks of aging and gives three main arms of its action. Joan then describes how rapalogs act, including reduced protein synthesis, inconsistent autophagy induction and SASP regulation.
- •Evidence shows metformin touches every hallmark of aging, though Nir doubts it hits each independently
- •Metformin's three arms are metabolic (complex I, AMPK, mTOR), reduced ROS and DNA damage, and immune/inflammation effects
- •No clear dose equivalence between metformin and rapalog mTOR inhibition is known
- •Rapalogs reduce protein and lipid synthesis and SASP, but autophagy induction is cell dependent
- 33:54 – 45:32
How Rapalogs and Metformin Enhance Immune Function
Peter explains why immune enhancement now matters to him, and Joan describes the mechanisms behind better vaccine response, including interferon and exhausted T cells. Nir adds the history of metformin as an immune agent and the idea of a host that can withstand severe illness.
- •Older adults have a defect in type I interferon production, which mTOR inhibitors can improve
- •Rapalogs reduced PD-1 positive exhausted T cells by about 25 to 30%
- •Biguanides were used for influenza in the elderly in the 1940s to 1960s per Nir
- •Both drugs may improve immunization, reduce cytokine storm and help the body sustain severe disease
- 45:32 – 59:08
Metformin, Rapalogs and COVID-19 Mortality Data
The group examines early evidence on metformin and COVID-19, including a Wuhan hospital cohort and a Minnesota preprint. They discuss how immune enhancement versus cytokine dampening might explain benefits and how severe respiratory illness kills older people.
- •Nir cites Wuhan data in which diabetic patients on metformin had a quarter of the mortality
- •The Minnesota preprint reported 21% lower mortality in women on metformin and 80% lower TNF-alpha
- •Joan notes elderly respiratory deaths are largely viral, with immune-mediated damage
- •Nir stresses metformin would be for prevention, not treating hospitalized COVID patients
- •Joan suggests mTOR inhibitors boost antiviral gene expression after infection
- 59:08 – 1:07:44
RTB101, Catalytic mTOR Inhibition and the Phase 2 and 3 Trials
Joan explains how the first trial led to Phase 2 studies of RTB101, a catalytic TORC1-selective inhibitor, alone and with everolimus. She describes the infection results and why the Phase 3 failed on its FDA-required symptom endpoint.
- •Rapalog recipients reported fewer respiratory infections as adverse events
- •RTB101 mostly inhibits TORC1 at clinical concentrations and has a short half-life
- •RTB101 alone reduced infections in both Phase 2 studies, while the combination worked in only one
- •FDA required a symptom-based endpoint for Phase 3, which did not show reduced total symptoms
- •The data suggest milder illness rather than prevention of infection
- 1:07:44 – 1:12:44
Defending the Aging Host, Vaccines and Durable Immunity
Nir argues the strategy is to reinforce the host rather than fight the virus and warns that vaccines may fail in the elderly. Peter raises the likelihood of short-lived coronavirus immunity and the need for better immune enhancement strategies.
- •Nir equates multimorbidity with biological age and says vaccines are not being designed for the older host
- •A vaccine that fails to protect the elderly would be a disaster, in Nir's view
- •Peter notes coronavirus immunity is often short-lived and herd immunity may not be reached naturally
- •Joan agrees that finding ways to generate persistent immunity will be important
- 1:12:44 – 1:17:41
Neurodegeneration: Rapalogs in Parkinson's and Metformin in Alzheimer's
Joan explains the rationale for combining a rapalog and RTB101 in Parkinson's disease through enhanced autophagy. Nir reviews the metformin evidence for MCI and Alzheimer's and why association studies can mislead.
- •COVID-19 is increasing interest in immune enhancement, which investors previously found boring
- •Combining RTB101 with a rapalog lowers the RTB concentration needed for autophagy, easing the brain-penetration problem
- •Metformin MCI studies showed less decline in some domains
- •Association studies may be confounded by metformin users living longer
- 1:17:41 – 1:27:21
Combining Metformin and Rapamycin and the TAME Trial
Peter asks about combining the drugs, and Nir explains why TAME uses metformin as a tool to establish an aging indication. He details TAME's funding, budget, size and planned ancillary immune studies, while Joan cautions about combined side effects.
- •Nir chose metformin because it would not kill anyone on the road to an FDA indication
- •TAME is budgeted at $78 million, with about $35 million for the primary outcome via AFAR
- •The study plans 3,000 subjects across 14 centers, with ancillary immunity studies
- •Joan says there is not enough data on synergy and two active drugs mean more side effects
- •Nir notes that if both enhance autophagy, that is undesirable in a patient with cancer
- 1:27:21 – 1:36:59
Peter's Experience: Stopping Metformin, Taking Rapamycin, and the Exercise Trial
Peter explains why he stopped metformin (higher lactate during Zone 2 exercise) and describes his rapamycin use and side effects. Nir discusses the MASTERS exercise trial, in which metformin blunted mTOR transcripts and muscle mass but not function in elderly participants.
- •Peter saw higher lactate during exercise on metformin and reproduced it by stopping and restarting
- •Nir describes a trial in which metformin blunted exercise-induced mTOR transcripts in 75-year-olds
- •Muscle function was the same despite less muscle mass, and about 500 aging-related transcripts were preserved
- •Peter takes about 6 mg of rapamycin weekly in cycles and reports aphthous ulcers and slower nail growth
- •TAME will test 1,500 mg of extended-release metformin
- 1:36:59 – 1:41:31
Monkey Caloric Restriction Story and the Difficulty of Clinical Trials
Nir tells how, as a reviewer, he spotted that Wisconsin caloric-restriction monkeys' weights converged because someone was feeding them. Peter uses it to illustrate how fragile studies are.
- •Nir noticed weight differences between groups vanished in the last year
- •The cause was a person feeding the monkeys out of compassion
- •Nir later talked to his own animal caretakers about not feeding calorically restricted animals
- •Peter says operational choices can undermine even the best theories
- 1:41:31 – 1:56:49
Epigenetic Clocks, Proteomics and Centenarian Biology
The guests and Peter discuss what epigenetic clocks measure and their limitations as biomarkers. Nir describes his proteomic work on breakdown products, sex differences in aging, and what his centenarian studies show about slowed aging.
- •Methylation clocks predict mortality but Peter finds commercial clocks hard to interpret
- •Joan notes some age-related changes may be compensatory and beneficial
- •Nir's proteomic study found breakdown products as promising biomarkers; offspring of centenarians had about a third of the proteome change
- •Men showed far more changing proteins than women, suggesting sex-specific aging
- •Nir says centenarians have delayed aging and their offspring have 40% of the heart disease of controls
- 1:56:49 – 2:16:11
Dream Experiment, Ethical Dilemmas and Pandemic Preparedness
Joan describes the Phase 3 trial she would run with RTB101 and a rapalog in winter, and the discussion moves to whether to use these drugs before trial proof during a pandemic. Peter calls for rigorous research on immune resilience, while Joan and Nir stress the need for data and science-led decisions.
- •Joan's dream trial would run RTB101 and a rapalog head-to-head against placebo during four winter months, with severity as the main outcome
- •Joan believes benefit is greatest while patients are on drug
- •Nir frames the situation as a war and asks if unrandomized studies are justified
- •Joan does not take either drug and wants the data to decide; low doses may prevent while high doses might help hyperinflammation
- •Peter argues for rigorous research on immune enhancement and better biomarkers
