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

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?

• Because of all the data that mTOR inhibition has beneficial effects on aging and every organism tested
• The ITP (interventions testing programs) run through NIH showed inhibition of mTOR could extend the life of mice (Harrison et al., 2009; Miller et al., 2011)
• This was enough for Joan to feel that “Someone’s just got to do the trial in humans and see if this is true in humans”

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

ITP studies

What is the ITP?

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