#123 - Joan Mannick, M.D. & Nir Barzilai, M.D.: Rapamycin and metformin—longevity, immune enhancement, and COVID-19
Dr. Joan Manik and Dr. Nir Barzilai discuss their extensive research into rapamycin (rapalogs) and metformin. They explore these drugs' potential as pro-longevity agents, immune-enhancers, and their roles in reducing COVID-19 mortality, neurodegenerative diseases, and delaying aging.
Deep Dive Analysis
15 Topic Outline
Joan Mannick's Background and Rapamycin Research Journey
Nir Barzilai's Metformin Research and Longevity Conviction
Metformin and Rapamycin: Mechanisms and Hallmarks of Aging
Immune-Enhancing Effects of Rapalogs and Metformin
COVID-19 Mortality Reduction Potential of Metformin and Rapamycin
Insights from Joan's RTB-101 Studies and Immune Enhancement
Challenges of COVID-19 Vaccines and Durability of Immunity
Rapalogs and Metformin in Neurodegenerative Diseases
Update on the TAME Trial for Metformin
Synergy and Combination Therapy: Metformin and Rapamycin
Peter Attia's Personal Experience with Metformin and Rapamycin
The 'Feeding the Monkeys' Story: Challenges in Scientific Studies
Epigenetic Clocks and Proteomics as Aging Biomarkers
Joan's Ideal Experiment for RTB-101's Immune Benefits
Ethical Considerations for Accelerating Longevity Research
6 Key Concepts
Rapalogs
Rapalogs are analogs of rapamycin that inhibit the mTOR pathway, specifically mTORC1, by changing its conformation. While clinically used for immune suppression in transplant patients, at lower, intermittent doses, they can paradoxically enhance immune function, particularly in older adults.
mTOR Inhibition
This refers to reducing the activity of the mammalian target of rapamycin (mTOR) pathway. Inhibition can be achieved through allosteric inhibitors (like rapalogs, which alter mTOR's shape) or catalytic inhibitors (which block its active site). Partial or intermittent mTOR inhibition has shown beneficial effects on aging and immune function.
Metformin Mechanism of Action
Metformin primarily targets mitochondrial complex one, leading to an increase in AMP kinase and subsequent indirect inhibition of mTOR. This metabolic effect, combined with a decrease in oxidative stress and an influence on immune function and inflammation, contributes to its potential anti-aging properties.
SASP (Senescence-Associated Secretory Phenotype)
SASP refers to the inflammatory cytokines secreted by senescent cells that accumulate as we age. Inhibiting mTOR has been shown to decrease SASP, thereby reducing systemic inflammation and its associated detrimental effects.
Epigenetic Clocks
Epigenetic clocks are biomarkers that estimate biological age by analyzing specific methylation patterns on DNA. While they correlate with chronological age and can predict mortality, their rapid changes in response to short-term interventions like fasting raise questions about their direct interpretation as true 'rejuvenation' markers.
Proteomics as Aging Biomarkers
Proteomics involves the large-scale study of proteins to identify changes associated with aging. Analyzing specific protein breakdowns (e.g., of collagen, granulocytes) is being explored as a potentially more reactive and informative biomarker of aging compared to DNA methylation, reflecting the body's ongoing degradation processes.
8 Questions Answered
Joan was inspired by research showing organisms' capacity to live longer and joined Novartis, where she initiated a clinical trial to test if an mTOR inhibitor could improve immune function in older adults, despite its known immunosuppressive properties.
Nir's conviction grew from metformin's historical use against influenza, clinical studies showing prevention of diabetes and cardiovascular disease, hundreds of association studies linking it to reduced cancer and Alzheimer's risk, and animal lifespan extension data.
At low, intermittent doses, rapalogs can enhance innate antiviral gene expression and reduce exhausted T cells (PD-1 positive CD4 and CD8 cells), leading to improved vaccine responses and better handling of viral infections in older adults.
Both drugs may reduce COVID-19 mortality by reinforcing the host's immune response, potentially reducing the severity of disease, and mitigating the inflammatory 'cytokine storm.' Metformin also reduces comorbidities, which are major risk factors for severe COVID-19.
Peter stopped taking metformin due to its effect on increasing lactate levels, particularly during zone two exercise, and concerns about potential blunting of muscle hypertrophy, although muscle function was maintained.
The TAME (Targeting Aging with Metformin) trial is a phase three-like study aiming to prevent age-related diseases and mortality using metformin, with a primary outcome focused on FDA-approved endpoints for age-related disease prevention.
Current vaccine development may not adequately consider the older host, potentially leading to vaccines that are less effective or durable in the elderly, who are most vulnerable to severe outcomes and may not generate persistent immunity.
Epigenetic clocks measure biological age through DNA methylation patterns, while proteomics analyzes protein changes. Both are being developed as biomarkers to predict biological age and assess the effectiveness of anti-aging interventions, with proteomics potentially offering more reactive insights.
16 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.
8 Key Quotes
The genetic mutations in worms that cause doubling of lifespan show that organisms have the capacity to live longer than they normally do.
Joan Mannick
What it looked like is just turning mTOR down in the elderly, not turning it off, is the best for enhancing immune function.
Joan Mannick
If metformin targets aging, which we kind of knew from animals, it increased healthspan and lifespan of animals, many animals... And all of a sudden, we have everything.
Nir Barzilai
I don't believe for a second that metformin independently targets all of them. And I think that's what we should note. Metformin, let's say on the cellular level, it fixes aging.
Nir Barzilai
What we are trying to sell out there is that we are reinforcing, we're not fighting the virus, we're reinforcing the host.
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 mentioned respiratory tract infections, and they would start to yawn, like nobody cared.
Joan Mannick
The proteome of women is much more stable.
Nir Barzilai
Science has won. You could see that the Pope is asking people not to go to church, right? And rabbis are asking people not to go to synagogues. And Ramadan was not in mosques. So there was an influence. And the influence was because they saw that we know and that we are responsible.
Nir Barzilai
3 Protocols
Rapalog Dosing for Immune Enhancement (Manick Study 2014)
Joan Mannick- Administer a rapamycin analog (e.g., everolimus) at a very low dose (0.5 mg daily) or once weekly (5 mg weekly) for six weeks.
- Provide a two-week break from the drug.
- Administer a flu vaccination.
Metformin Dosing for TAME Trial
Nir Barzilai- Administer 1,500 mg of extended-release metformin daily.
- Subjects will take three 500 mg extended-release tablets each morning or night, based on their choice.
Seasonal Rapalog Dosing for Respiratory Infection Prevention
Joan Mannick- Administer RTB-101 during the four months of winter cold and flu season, when there is peak incidence and healthcare resource utilization among older adults.
- The goal is to decrease hospitalization and severe symptoms while on the drug.