peter attia paul grewal covid-19

Joan Mannick, M.D. & Nir Barzilai, M.D.: Rapamycin and Metformin – Longevity, Immune Enhancement, and COVID-19| The Drive with Peter Attia #123

Key Takeaways

  • When taking rapalog, innate immune function is augmented possibly driving enhanced adaptive immune system when vaccinated
  • Studies have shown that people on metformin who were diabetic and obese still had significantly less mortality than otherwise metabolically healthy individuals
  • Rapalogs and metformin both address a critical piece of fighting a virus: reducing comorbidities  
  • There’s some evidence that a direct antiviral effect between mTor inhibition and SARS-CoV-2 exists
  • “We’re not fighting the virus, we’re reinforcing the host.” – Nir Barzilai


Joan Mannick, M.D. is an expert on rapamycin, rapalogs, and mTor. She is Chief Medical Officer of resTORbio, an offshoot biotech company of Novartis.

Nir Barzilai, M.D. is the director of the Institute for Aging Research at the Albert Einstein College of Medicine and the Director of the Paul F. Glenn Center for the Biology of Human Aging Research. His research focuses on metformin for longevity.

In this episode of The Drive, Joan Mannick, M.D. and Nir Barzilai, M.D. discuss their research into rapamycin, rapalogs, and metformin for health, immunity, and longevity.

Host: Peter Attia (@PeterAttiaMD)

Book: Age Later: Health Span, Life Span, and the New Science of Longevity by Nir Barzilai, M.D.

Epigenetic Clock

  • Epigenetics is the study of heritable changes in gene expression that do not change the DNA sequence
  • With aging, there are epigenetic changes
  • Lifestyle factors such as diet obesity, physical activity, tobacco, alcohol, etc. have been associated with epigenetic changes
  • Methylation of DNA is one way which we see how the environment interacts with genome and could be a cause of aging
  • Methylation of DNA is also associated with predicting biological age
  • We want biomarkers that predict whether we’re accurately targeting aging and biological clock
  • Problem is you can reverse biological clock relatively easy with fasting, but it’s not necessarily stable  
  • There is some debate about whether methylation of DNA is fixed and how accurately it represents biologic age

Joan Mannick’s Foundational Research on Rapamycin

  • Mannick, et al. study dosed rapamycin analog called rapalogs at either low dose once daily or once weekly
  • Category of analogs to rapamycin called rapalogs which inhibit mTor
  • The ability of rapalogs to induce autophagy is cell-dependent
  • Full inhibition of mTor stops T cell function and leads to immunosuppression
  • The goal was to partially inhibit mTor and test immunity
  • Study findings: the lowest dose of rapamycin analog followed by flu shot enhanced immune function in elderly patients
  • Innate immune function is enhanced, possibly enhancing the adaptive immune system when vaccinated
  • Greatest effect of rapalog on longevity: less protein and lipid synthesis, possible effect on autophagy, regulation of inflammatory cytokines secreted by senescent cells

Nir Barzilai’s Foundational Research on Metformin

  • Intervention Testing Program (ITP) was established to have multi-clinical intervention studies to test diet, drugs, and other interventions to test longevity strategies
  • ITP controls for laboratory-specific differences, repeating studies across sites to assess the strength of findings
  • Metformin is a weak mitochondrial toxin which tricks the body into thinking nutrients are scarce which has a downstream effect on inhibition of mTor  
  • Nir study found people on metformin who were diabetic and obese still had significantly less mortality than otherwise metabolically healthy individuals
  • The study also demonstrated immune enhancement with metformin  
  • Evidence that metformin hits the most important targets of aging: metabolic effect on mitochondrial function, decrease in oxidative stress in RAS production and DNA damage, positive relationship to immune function and inflammation

TAME Trial: Targeting Aging with Metformin

  • TAME is a 14-center study which will enroll 3,000-3,500 participants to assess three outcomes
  • TAME dosing will be 1500mg of extended-release metformin per day
  • The primary outcome is FDA approval for alternative use of metformin
  • The secondary outcome is finding biomarkers
  • The tertiary outcome is assessing the impact on geriatric patients  

Can Metformin and Rapamycin Be Used in Combination?

  • Rapamycin is slightly riskier than metformin and requires more careful attention and dosing
  • We can risk mitigate better by assessing both drugs in parallel instead of in combination
  • We need more precise dosing of both

COVID-19: Immunity Enhancement with Rapalogs and Metformin

  • Influenza and rhinovirus can paralyze the immune system, leaving people susceptible to the second wave of infections that lead to fatality in elderly
  • COVID-19 kills in multiple ways partly because it causes more direct damage to organs and induces cytokine storm response by the host
  • Many overlaps between rapamycin and metformin in terms of longevity and potential for reducing infection, including COVID-19 morbidity
  • “We’re not fighting the virus, we’re reinforcing the host.” – Nir Barzilai
  • In the 40s, 50s, and 60s, metformin was used to enhance immunity and fight the flu, malaria, and other viruses
  • Rapalogs and metformin both address a critical piece of fighting a virus: reducing comorbidities  
  • New studies (e.g., 1, 2) show people with COVID-19 had decreased in mortality on metformin regimen
  • “People should take metformin to prevent COVID not treat COVID.” – Nir Barzilai
  • mTor inhibitors enhance innate antiviral gene expression in the presence of viral exposure
  • In previous studies, mTor inhibitors were shown to upregulate antiviral gene expression and reduce incidence and severity of other coronaviruses
  • Some evidence that there’s a direct antiviral effect between mTor inhibition and SARS-CoV-2

The Complexity of a Potential COVID-19 Vaccine

  • “If we have a vaccine that does not protect the elderly, we did nothing.” – Nir Barzilai
  • The probability is low that we’ll have a vaccine that confers lifetime immunity – or even immunity beyond one year
  • “What is the probability this virus is going away? Zero. Somewhere between zero and epsilon.” – Peter Attia
  • We may never naturally acquire herd immunity, so we need a better strategy around the immune enhancement
  • We must be able to think about immune-targeted therapies for the most vulnerable populations

“No Regret” Moves for Future Pandemics

  • There should always be a national stockpile of PPE, reagents for PCR, antiviral therapy
  • When we sequence a new virus, we should have appropriate contact tracing and surveillance
  • We need rigorous research around immune enhancement – for example, how much sleep do we need? Does vitamin D supplementation have the same effect as the sun?
  • Agents such as rapamycin and metformin could have a significant impact on resilience
  • We need improved biomarkers – existing biomarkers are crude and this hinders some of our progress
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Notes By Maryann

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