← The Peter Attia Drive

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

Aug 10, 2020 2h 17m 16 insights
<p>In this episode, Joan and Nir discuss their extensive research into rapamycin (including the category of analogs to rapamycin known as rapalogs) and metformin, respectively. Based on his work with metformin, Nir shares how he believes it could be a pro-longevity drug and the clinical trial he's leading to test this belief. Joan discusses her work with rapalogs, their ability to suppress the immune system as well as provide immune-enhancement, and the clinical trials she has led that inform her insights. We also talk about the potential beneficial roles of both metformin and rapamycin in reducing mortality from COVID-19, reducing the risk of neurodegenerative diseases, and delaying aging as well as its related diseases.</p> <p>  </p> <p>We discuss:</p> <ul type="disc"> <li>Joan's career, interest in aging, and work with rapamycin analogs [3:45];</li> <li>When Nir became convinced metformin could be a pro-longevity agent [15:00];</li> <li>How metformin and rapamycin impact the hallmarks of aging and extend lifespan [24:15];</li> <li>Enhancing the immune system with rapalogs and metformin [34:15];</li> <li>Potential of metformin and rapamycin in reducing mortality from COVID-19 [41:30];</li> <li>Insights from Joan's studies investigating the immune-enhancing effects of rapalogs [59:30];</li> <li>Vaccines and treatments strategies for COVID-19, and the likelihood of long-term immunity [1:08:15];</li> <li>The potential role of rapalogs and metformin in neurodegenerative disease [1:14:30];</li> <li>Nir's TAME trial—primary objectives and latest updates [1:18:00];</li> <li>Potential synergistic effect when combining metformin with rapamycin [1:25:45];</li> <li>Why Peter stopped taking metformin and started taking rapamycin [1:27:30];</li> <li>Story from Nir's book that demonstrates the challenge of doing good scientific studies [1:37:30];</li> <li>The biology of aging—epigenetic clocks, proteomics, and Nir's centenarian data [1:42:00];</li> <li>Joan's dream experiment to test immune-enhancing effect of RTB101 [1:57:15];</li> <li>Concluding thoughts on COVID-19 [1:59:45]; and</li> <li>More.</li> </ul> <p>Learn more: <a href="https://peterattiamd.com/">https://peterattiamd.com/</a><br /> <br /> Show notes page for this episode: <a href="http://peterattiamd.com/joanmannick-nirbarzilai/">http://peterattiamd.com/joanmannick-nirbarzilai/</a><br /> <br /> Subscribe to receive exclusive subscriber-only content: <a href="https://peterattiamd.com/subscribe/">https://peterattiamd.com/subscribe/</a><br /> <br /> Sign up to receive Peter's email newsletter: <a href="https://peterattiamd.com/newsletter/">https://peterattiamd.com/newsletter/</a><br /> <br /> Connect with Peter on <a href="http://Facebook.com/PeterAttiaMD"><u>Faceboo</u></a><u>k</u> | <a href="http://Twitter.com/PeterAttiaMD"><u>Twitter</u></a> | <a href="http://Instagram.com/PeterAttiaMD"><u>Instagram</u></a>.</p>
Actionable Insights

1. Metformin Reduces COVID-19 Mortality

Consider metformin use, especially if diabetic, as it was associated with significantly reduced COVID-19 mortality and potentially lower hospitalization rates in observed cohorts. This suggests a protective effect against severe outcomes.

2. Enhance Elderly Immune Response

Older adults can consider low-dose, intermittent mTOR inhibitors (rapalogs) to enhance their immune function and improve response to flu vaccinations. This approach aims to ’turn down’ mTOR, not turn it off, for beneficial effects.

3. Metformin for Aging Prevention

Consider metformin as a tool to target aging and prevent age-related diseases, given its observed ability to increase healthspan and lifespan in animals and its association with reduced incidence of various age-related conditions in humans.

4. Rapalogs Reduce Respiratory Infections

mTOR inhibitors can upregulate antiviral gene expression and reduce the incidence and severity of common coronavirus and other respiratory tract infections in older people. This suggests a role in bolstering the body’s defense against viral pathogens.

5. Metformin for Vaccine Efficacy

Older individuals may benefit from using metformin to enhance their immune system, potentially leading to a better response to vaccines, including those for influenza and new viruses like SARS-CoV-2. This addresses the challenge of vaccines not adequately protecting the elderly.

6. Rapalogs for Seasonal Immune Support

Consider taking RTB-101 (an mTOR inhibitor) during the four months of peak winter cold and flu season, particularly for individuals aged 70 and older. This seasonal dosing may decrease hospitalizations and severe symptoms during periods of high viral incidence.

7. Metformin & Exercise for Muscle

For elderly individuals, combining metformin with exercise may lead to less muscle mass gain but maintain muscle function and preserve a ‘young profile’ of muscle at a transcriptional level. This suggests independent benefits of metformin beyond exercise alone.

8. Rapalogs for Neurodegenerative Diseases

Explore mTOR inhibitors (RTB, rapalogs, or combinations) to enhance autophagy, which may help with neurodegenerative diseases like Parkinson’s and Alzheimer’s. This mechanism could aid in clearing toxic protein aggregates in the brain.

9. High-Dose Rapamycin for Over-Reaction

For severe immune over-reactions, such as a cytokine storm in critically ill patients, consider high, immunosuppressive doses of rapamycin. This is a distinct application from the low doses used for prevention and aims to temper an excessive immune response.

10. Metformin’s Lasting Cellular Effects

Understand that metformin’s cellular effects on the aging phenotype may persist even after stopping the drug. This implies that using metformin for prevention, rather than acute treatment, can have sustained benefits.

11. Centenarian Mindset: Delay Disease

Adopt a mindset focused on delaying the onset of age-related diseases to emulate centenarians, whose ‘superpower’ is slowed aging and delayed disease onset. This approach prioritizes preventing diseases rather than merely surviving them once they strike.

12. Consider Career Change at 50

If you are around age 50, consider it a opportune time to try something new with your career. This perspective suggests that it may be the last significant chance to make a transformative professional change.

13. Advocate for Immune Research

Support and advocate for rigorous, large-scale scientific studies to definitively determine the impact of various interventions (e.g., sleep, vitamin D, vitamin C) on immune function. This is crucial for preparedness against future pandemics and understanding foundational health drivers.

14. Support Better Biomarker Development

Advocate for and contribute to the development of better biomarkers that can quickly predict the effectiveness of aging interventions. This will allow for more efficient and adaptable clinical trials, accelerating the safe delivery of therapies.

15. Rapamycin Side Effects Awareness

If considering rapamycin, be aware of potential side effects such as apthous ulcers and slower fingernail growth. These are observed effects that users may experience.

16. Metformin Affects Lactate Levels

Be aware that metformin, by inhibiting mitochondrial complex one, can increase baseline lactate levels, which may impact aerobic efficiency metrics during exercise. However, this increase has also been associated with better glucose control.