Premium Subscriber Show Notes: Centenarian Longevity & Metformin | Dr. Nir Barzilai

Exclusive Show Notes: Live Longer World Podcast #08

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Live Longer World Podcast Episode #8 Show Notes

Dr. Nir Barzilai Introduction

Dr. Nir Barziali is well-known in the field of longevity and beyond and is the director and chair of several institutes focused on Aging research. Just to name a few, he is the director of the Institute for Aging Research at the Albert Einstein College of Medicine and of the National Institutes of Health’s (NIH) Nathan Shock Centers of Excellence in the Basic Biology of Aging.

Dr. Barzilai’s research interests are in the biology and genetics of aging, so he has done extensive work studying centenarians and supercentenarians some of which he discusses in today’s episode and also in his book Age Later.

He is currently leading an international effort to approve drugs that can target aging. Targeting Aging with METformin (TAME) is a specific study designed to prove the concept that multi-morbidities of aging can be delayed by metformin, working with the FDA to approve this approach which will serve as a template for future efforts to delay aging and its diseases in humans.

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Time Stamps:

0:00 Live Longer World Intro, Receive Show Notes + Release Updates

2:15 Dr. Nir Barzilai Intro

3:33 Nir's interest in studying centenarians

5:38 Centenarian Longevity Genes; Growth Hormone

10:24 Sex differences in longevity effects of growth hormone IGF-1

13:40 Cholesterol & CETP genes in Centenarians

16:00 How can we apply the findings from centenarian research?

19:50 How did metformin go from being a diabetes drug to longevity drug?

24:50 Targeting hallmarks of aging with metformin

27:27 TAME Trial & working with FDA

31:15 TAME trial as template for developing drugs for aging

31:58 Race-specific differences with Metformin; Could metformin increase risk for Alzheimer's for some?

34:41 Other studies being done on Metformin; No negative effects of Metformin

36:30 Metformin & COVID

37:11 Metformin & Immune System Robustness

38:12 Does Metformin blunt Muscle Mass?

44:45 Metformin Dosage

46:16 Does Metformin cause Hypoglycemia?

49:40 Singapore & Longevity

52:40 SGLT-2 inhibitors for longevity

57:02 What else should we be doing in the longevity field?

58:45 Metformin or Rapamycin?

1:01:00 Support Live Longer World, Social Media, Premium Subscriber Benefits

Extensive Show Notes & Transcript | Nir Barzilai:

CENTENARIAN LONGEVITY

What got you interested in studying centenarians? [3:33]

• It’s when we went from hope that we can do something about aging and to realizing the promise. The way we realize this promise is by looking at long-lived models

• And by looking at the biology of aging in centenarians, it gave us a really good head start

• He did animal studies, Caloric restriction etc.

• But he realized that let’s take the people who age the slowest, have the lowest biological age as compared to chronological age, and what is unique about them whether it’s genetically or environmentally. Let’s see what we can learn from them

You note an interesting point in your book Age Later. That while for the rest of us, genetics matter about 20-30% for longevity, for centenarians it matters 70-80%. But its also the case that they don’t have perfect genes. It’s just that they have some longevity genes. What are the genes that are protecting them and what do we know about the mechanisms by which they work? [5:38]

• Let’s discuss the major example which is growth hormone IGF-1

• 60% of centenarians have some genomic alteration in the growth hormone IGF-1 pathway

  • Low IGF-1 is typically better for longevity

• We all know that small dogs live longer than large dogs

• Dwarf models also live longer

• The main hypothesis: You need to shift from growth when we are younger to managing the breakdown that happens with aging. You cannot spend energy on growth when older

• Recently used UK biobank data and showed that high growth hormone is good in young people in preventing death, but it’s exactly the opposite in older people, it creates diseases

  • This is antagonistic pleiotropy

  • Things that are good when we are younger is antagonistic when older

    • This might apply to metformin too. Maybe metformin is not good for young people, but good for older people

What are the sex differences observed on IGF-1? [10:24]

• We missed a lot with sex differences

• Women on average live 6 years longer which is a lot

  • Even is we cure cardiovascular disease, we will live max of 2 years

• And when we flex around with the IGF-1 growth hormone pathway, we get better results in females than males

• But Nir would caution that if males think they can get growth hormone injection safely, he wouldn’t say that

• The effects are statistically more significant in females than males

  • For every 100 centenarians, 85 are women

  • So there are fewer male centenarians so can’t be so conclusive about male results yet

Can you speak to the connection between cholesterol & the CETP gene in the case of centenarians? [13:40]

• There are 2 genes that have functional mutations in centenarians

  • One is functional mutation in CETP gene: when you inhibit it you get high levels of HDL cholesterol

  • 2nd is a APOC3 gene and when you inhibit that you get lower triglycerides and higher HDL cholesterol

• Pharma came to see results of this study and wanted to develop drugs to target cardiovascular disease

  • Merck developed CETP inhibitor, Phase 3 trials

  • Ionis developed an antagonist to APOC3, also Phase 3

How can we apply some of the findings from Centenarians to our lives right now? [16:00]

• Let’s discuss an example and the challenge

• Many pharma develop an IGF-1 receptor antibody which prevents the action of IGF-1

  • They developed it because cancers have a lot of reception in IGF-1 and they thought it could be anti-tumor or anti-cancer

  • But all of them failed because cancers were smarter and getting over hurdles

• Derek Hoffman at Albert Einstein got the IGF-1 receptor antibody to female mice and they live 10% longer

• And not only do the live longer but their healthspan increased significantly

• And not only that, their healthspan increased significantly

• Let’s pause on the healthspan point. Because if you look at centenarians, you wonder, wait a minute, did the centenarians become sick when everybody got sick and they are just sick for longer? That’s not what we want to do.

• And in fact, centenarians get their diseases 20-30 years later. And it’s important that lifespan and healthspan go together

• In fact, centenarians are sick for a very short period of time, it’s a compression of morbidity

• When Aastha asks people if they want to live to be 120, most people say no. But when she re-frames the question and asks, would they still want to be 100 if they could feel healthy when they are older? And most people say, yes of course!

• Dr. Barzilai would initially use the word aging, but changed it to longevity because he was studying centenarians

• Healthspan is the label on the medicine and longevity is the side-effect

METFORMIN

Metformin’s history is that it was used for treating malaria & influenza. And then diabetes which its still used for. How did researchers come to find out that it could be used as a longevity drug? [19:50]

• Metformin was in Europe decades before it came to the U.S. It was approved in 1993 by the FDA

• Nir was interested in aging but never thought of metformin as a geroprotective then

• But over the years as there were clinical controlled blinded studies with metformin, it showed that metformin prevents cardiovascular disease, prevents diabetes in non-diabetics, people on metformin have less cancers, have less Alzheimers, less cognitive decline

• Nir’s 2016 Paper Metformin as a Tool to Target Aging: https://pubmed.ncbi.nlm.nih.gov/27304507/

• Metformin had specific effects on many other diseases of aging which is our definition of aging as aging drives these diseases