August 10, 2020

Podcast

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

“I think what the mTOR inhibitors are doing is not stopping people from getting infected [with a virus], but if you get infected, there's a better immune response and your symptoms will be milder.” — Joan Mannick

Read Time 34 minutes

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.

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We discuss:

  • Joan’s career, interest in aging, and work with rapamycin analogs [3:45];
  • When Nir became convinced metformin could be a pro-longevity agent [15:00];
  • How metformin and rapamycin impact the hallmarks of aging and extend lifespan [24:15];
  • Enhancing the immune system with rapalogs and metformin [34:15];
  • Potential of metformin and rapamycin in reducing mortality from COVID-19 [41:30];
  • Insights from Joan’s studies investigating the immune-enhancing effects of rapalogs [59:30];
  • Vaccines and treatments strategies for COVID-19, and the likelihood of long-term immunity [1:08:15];
  • The potential role of rapalogs and metformin in neurodegenerative disease [1:14:30];
  • Nir’s TAME trial—primary objectives and latest updates [1:18:00];
  • Potential synergistic effect when combining metformin with rapamycin [1:25:45];
  • Why Peter stopped taking metformin and started taking rapamycin [1:27:30];
  • Story from Nir’s book that demonstrates the challenge of doing good scientific studies [1:37:30];
  • The biology of aging—epigenetic clocks, proteomics, and Nir’s centenarian data [1:42:00];
  • Joan’s dream experiment to test immune-enhancing effect of RTB101 [1:57:15];
  • Concluding thoughts on COVID-19 [1:59:45]; and
  • More.

§

Joan’s career, interest in aging, and work with rapamycin analogs [3:45]

Early career

  • Started career in academic medicine after training in infection disease
  • She was running a basic science lab when she had a transformative moment—
  • She read a review by Cynthia Kenyon in which she pointed out that genetic mutations in worms that cause doubling of lifespan suggests that organisms have the capacity to live longer than they normally do

“I just thought that was the coolest piece of research and the coolest idea that sort of threw medicine on its head.” —Joan Mannick

Foray into aging research

  • She began doing aging research in her lab after that
  • Eventually moved to Novartis in a group called the New Indications Discovery Unit
  • Despite reservations at first, Novartis agreed to let Joan “work on aging”
  • Novartis already had a rapamycin analog, and there was data that mTOR inhibitors have beneficial effects on aging and lifespan
  • Joan thought the immune function was an area where you could see improvement in a relatively short period of time
  • In 2014, Joan did a trial giving older adults an mTOR inhibitor to see if they could make their immune function better

Given that the clinical application for rapamycin was immune suppression—what made Joan think that you could actually use the same drug to enhance the immune response to a vaccine?

Joan’s 2014 paper at Novartis

  • Knowing that the only way this will ever move forward is if the drug was safe and did not suppress the immune system, they started with a very low dose with intermittent dosing 
  • They were looking to see if the patients had an enhanced immune response to the flu vaccine 

-Study details 

  • The drug used was RAD001 (a.k.a. everolimus)
  • The doses given to the 4 different arms—
    • 1) Placebo arm 
    • 2) 0.5 mgs of RAD001 daily
    • 3) 5 mgs once a week 
    • 4) 20 mgs once a week
  • The goal was to partially inhibit mTOR, because when you completely inhibit mTOR, you stop T cells from proliferating and you’ll get immunosuppressed

-The ending observations

    • The two lower doses (0.5 mgs daily and 5 mgs once a week) were the best
    • Turning mTOR down (not off) in the elderly is the best for enhancing immune function

 

When Nir became convinced metformin could be a pro-longevity agent [15:00]

  • The normal clinical indication of metformin is an early-line treatment for patients with type 2 diabetes
  • While at Yale doing his first postdoc with Ralph DeFronzo, Nir spent the year looking for the mechanism of action of metformin (which wasn’t yet being used in the US)
  • In 1991, Nir’s study was the first to show that metformin specifically targets hepatic glucose production — aka the insulin sensitivity of the liver much more so than the muscle
  • Metformin finally began gaining more interest in the US after the DPP found metformin was people from developing diabetes
  • There were also many association studies with all kinds of cancer as well as Alzheimer’s disease and MCI
  • The turning point for Nir came when he read a paper showing that people on metformin, even those who were diabetic and obese, had less mortality when compared to control patients without diabetes who were not taking metformin

⇒ Nir’s 2016 paper talking about the UKPDS and DPP papers: Metformin as a Tool to Target Aging

“And all of a sudden we have everything. We have all ages, all the old age-related disease, clinical association studies, we’d have mortality. That just made metformin the perfect tool for us to push geroscience ahead.” —Nir Barzilai

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11 Comments

  1. All these scientific experiments could be shortened if you go to areas that have centenarians. Dominica, NW Costa Rica. Just ask indigenous people why they live longer! They say it’s because their food is pesiticide free soil filled with microbiomes, eating fresh food, no junk food! Gosh what an easy answer. Maybe too easy for scientists! My mom lived to be 100. Why? She ate fresh food, limited amounts of food, no sugar, no white flour, no junk! Didn’t have much money, but completely content with life. Slept 8 hours. A Happy Person!

    • Did she eat food from animals? I’m very interested in centenarians who indeed eat/ate animal products in a regular basis!

  2. I am 66 year old female who is athletic, very healthy nutrition, and optimal lifestyle. Formerly did research with Burroughs Wellcome and SmithKline. I am taking low dose met form in and other anti-aging protocols. I would be very interested in participating in one of your clinical trials. Hope to hear from you. Thanks

  3. Rapamycin has significant negative renal effects. Yes? Not sure of my use until we have valid DBPC trials. Thanks, tom md.

  4. I get more and more surprised after every episode on why you have not interviewed Dr. Valter Longo yet! Attia dialog with Longo is literally something the world needs! Please invite him soon!

  5. Dr Attia, vis-a-vis your conjecture that metformin (possibly) has no benefit for a maximum exerciser — are there any benefits of metformin or rapalogs that we think periodic multi-day water fasting does not confer? That is, if a person is doing X days of water fasting every Y weeks (imagine ideal dose values for X and Y) would metformin and/or rapalogs confer any benefit for this person or are the drugs only helpful for the average western lifestyle?

    When are we going to see funding for studies thab begin to answer the question of “what benefits do various doses of fasting confer”?

    I see that mental health uses of psycodelics are finally getting research funding. How about fasting research next?

  6. “The turning point for Nir came when he read a paper showing that people on metformin, even those who were diabetic and obese, had less mortality when compared to control patients without diabetes who were not taking metformin”.

    First, you linked the wrong paper: the linked paper is from the UKPDS study, in which all patients were diabetic. I’m pretty sure you meant this one:
    http://dx.doi.org/10.1111/dom.12354

    There was a fatal flaw in this paper (and there are similar problems in the design of nearly all other papers purporting to show better outcomes in metformin-treated patients, especially when compared to the general population): a form of survivors’ bias. As soon as metformin-treated subjects’ diabetes progressed to the point where another drug was added, they were censored out of the metformin-treated group — in other words, progressively enriching the remaining metformin-treated group with healthier and healthier people, compared to the general population that is stably composed of the same people and that only gets sicker (due to aging). See:
    https://www.sciencemediacentre.org/expert-reaction-to-study-looking-at-type-2-diabetes-metformin-and-lifespan/

    https://hypothes.is/search?q=tag%3APubMedCommonsArchive+25041462

  7. Dr. Barzilai said that diabetic patientswho were taking metformin immunized better against the flu. However, the press report you guys link, and the underlying study:
    https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19494812/

    … are about a MOUSE study. I can find no human study finding that metformin enhances vaccine response in humans: in fact, the only study I can find found that “a *delayed* response in the [haemagglutination-inhibition] titre against the influenza B antigen, wherein the maximum response was recorded at 90 days instead of 30 days post-vaccination in [diabetic] patients prescribed metformin or glibenclamide” and that these drugs *suppressed* the avidity of the antibodies raised upon immunization, and that metformin *suppresses* the interferon response to immunization (with inconsistent results for glibenclamide)— the same defect that Dr. Mannick thinks is targeted by mTOR inhibitors to enhance immune response. “Reduced IFN-α expression via decreased mTORC1 signalling in individuals with T2DM who were prescribed metformin may lead to reduced selection of germinal centres and affinity maturation.”
    https://www.nature.com/articles/s41598-020-60213-0

  8. “A paper from China looked at 283 diabetic patients with COVID-19
    104 of them came to the hospital already taking metformin
    179 of them were not taking metformin
    Just 2.9% of people on metformin died versus 12.3% of the to no-metformin group who died”

    A new “retrospective study in a cohort of 1,213 hospitalized individuals with COVID-19 and pre-existing T2D indicated that metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but *not* with 28-day COVID-19-related mortality.” The full text makes it clear that this actually means all-cause mortality in their COVID cohort. On the other hand, “metformin use was significantly associated with reduced heart failure and inflammation.” “The incidence of ARDS was also significantly lower in the metformin group compared to the non-metformin groups (adjusted HR, 0.66; 95% CI, 0.46–0.96; p = 0.028) ”

    This seems beneficial, but apparently not beneficial enough to save anyone’s life.

    They note that “This finding is in agreement with a Korean population-based cohort study, which also showed no significant association was indicated between metformin therapy and 30-day mortality in individuals with ARDS and pre-existing diabetes (Oh and Song, 2020).”

    Also, in this study, 678 patients were on metformin, vs. 535 who were not; in commenting on the previous, smaller study, Dr. Barzilai noted that “the use of metformin in China for diabetic people is between 60 and 70% — yet, the most people who were hospitalized [in the earlier study] were NOT using metformin. The implication of this observation is potentially that the diabetics on metformin were less likely to need to go to the hospital (or maybe even get COVID-19 at all).” This new, larger study seems to undermine that speculation.

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