#204 – Centenarians, metformin, and longevity | Nir Barzilai, M.D.

Nir Barzilai, Director of the Institute for Aging Research at the Albert Einstein College of Medicine, is back for his third appearance on The Drive. In this episode, Nir divulges insights into lifespan and healthspan through the lens of his extensive research on centenarians as well as the latest from the TAME trial (Targeting/Taming Aging with Metformin), a multi-center study investigating the concept that the multi-morbidities of aging can be delayed in humans. He discusses common gene variants found in centenarians, important pathways for longevity, and ultimately what we can learn from centenarians about extending lifespan while also trying to improve healthspan. Additionally, Nir goes into depth on metformin as a longevity tool for humans, including studies with positive and negative results. He discusses the impact metformin can have on exercise for both strength training and cardiovascular training, as well as future research facilitated by data from the TAME Trial. He also touches on epigenetic clocks and concludes with his take on the usefulness of NAD precursors as a potential gero-protective agent.

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We discuss:

• Insights from genetic studies of centenarians and twins [3:00];
• Genes with protective variants that aid longevity [13:00];
• The relationship between growth hormone and IGF-1 [22:45];
• Use of growth hormone as a longevity tool [34:00];
• Longevity genotypes: the role of APOE e2, Lp(a), Klotho, and CETP [41:45];
• The correlation between high TSH and longevity [46:30];
• Important pathways for longevity [52:00];
• Insights from centenarian studies, nature vs. nurture, and more [59:00];
• The contraction of morbidity that comes with improved healthspan [1:08:00];
• Defining healthspan [1:13:13];
• Unique perspectives and positive attitudes of centenarians [1:17:30];
• Lessons to take away from centenarians [1:24:00];
• Metformin overview: history, studies, and potential for gero-protection [1:28:45];
• The TAME trial (Targeting Aging with Metformin) [1:39:00];
• The challenge of studying metformin in animals models [1:46:45];
• How data from the TAME trial could provide insights into biomarkers of aging and facilitate a future study on proteomics [1:53:30];
• The search for biomarkers to identify who can benefit from treatment [2:00:30];
• The impact of metformin on exercise, and finding the right indication for the use of metformin [2:10:30];
• Are NAD precursors geroprotective? [2:21:30]; and
• More.

Insights from genetic studies of centenarians and twins [3:00]

Centenarians

It is hard to compare generations

• Peter notes that genes don’t seem to play a big role in people living to 70 versus 80, but when you start to talk about living to 90 versus a 100, genes play a pretty big role
• Nir notes that genetics don’t have a large impact in people living to 70 or 80
• It is problematic to compare the lifespan of fathers and sons (or mothers and daughters, or sons), consider this example:
  • Nir’s grandfather had a heart attack at 68 and died
  • Nir’s father had a heart attack at 68 and had a triple bypass; he died at 84
• Let’s say the correlation between age of death in different cohorts is 20%
  • If we really understand that 20%, we can use that to prevent the 80% impact of the environment

Twin studies

• Twin studies looking at the discordance and concordance of traits can help discern the role of genes in separate environments
• There are problems with twin studies
  • Twins are usually born small for their gestational age
    • Further, 1 twin is usually smaller than the other
  • Studies in rats where you ligate the uterine artery and make them small, they get diabetes, which they never get at 3 months
  • We know that babies that are born small for age, develop age related disease very rapidly; it’s called the Barker’s hypothesis
    • This stems from the observation in Holland during World War II
    • Epigenetic effects / imprinting are involved
    • healthspan is decreased in the small twin
    • Many genes are involved but this hypothesis is not definitive
  • Nir doesn’t think twins are the right model unless you understand that and account for these effects

Generics of centenarians

• Compare a cohort of individuals who live to 80 to a cohort who lives to 100
  • What genes seem to offer protection to the group living to 100?
• There are 3 hypothesis:
  • 1) Longevity can be explained completely by the environment
  • This is the hypothesis that centenarians did everything exactly right
    • This is not true because 60% of men (30% of women) centenarians are smokers
    • 50% of centenarians are obese, don’t exercise, they’re not vegetarians
  • 2) Longevity is due to genetics
  • This is the hypothesis that centenarians have the perfect genome
    • Whole genome sequencing was performed for the first 44 centenarians in his study 
    • There wasn’t a control (so we don’t know what the average person has)
    • They looked at ClinVar (database of clinical variants / alleles responsible for disease)
    • They found 15,000 clinical variants in this initial analysis
    • To put this in perspective, there are around 20,000 coding genes in the human genome
    • Each centenarian had 5-6 bad variants (alleles responsible for disease); so this hypothesis isn’t true either
    • 2 centenarians were homozygous for APOE4; this confers one of the best known risks for Alzheimer’s, but they had no dementia at age 100 
    • We know a lot of genotypes that put us at risk for age-related disease so maybe 1 out of 10,000 don’t have these alleles
    • This is the absence of bad genes (alleles) not the presence of good genes
  • 3) There are genes that slow aging, we call them longevity genes
  • This is the hypothesis that the presence of genes that protect against disease and slow aging are the reason for longevity
• Nir’s research has found a decrease also in bad genotypes in centenarians (some decrease), but really the majority of the study shows that it’s not the perfect genome, it’s something else
• Peter notes that the 3rd hypothesis is harder to demonstrate because there is probably a much smaller library of disease-sparing variants (alleles) as opposed to disease-causing variants

Genes with protective variants that aid longevity [13:00]

• How are these protective variants discovered?
• Nir began to study this in 1998; one of the things he had to do is establish the phenotype
  • One of the phenotypes that came up is a very high level of HDL cholesterol
    • This was more obvious in the offspring of the studied centenarians, more so than the centenarians
    • The offspring had HDL cholesterol levels 130, 140, fold higher than it should be
  • They got very compelling data on 2 genotypes that seemed to be functional important; they both were involved in controlling lipid metabolism
    • 1) A CETP genotype 
    • 2) An APOC3 genotype
    • A homozygous genotype for these variants occurred in 8-9% of controls and almost 20% of centenarians
• If a genotype is killing you then those genotypes will decrease in 80-90-year-olds

{end of show notes preview}

Nir Barzilai, M.D.

Born in Israel, Dr. Barzilai graduated from The Ruth and Bruce Rappaport Faculty of Medicine at the Technion-Israel Institute of Technology in Haifa and completed his residency in internal medicine at Hadassah Medical Center in Jerusalem. He served in a refugee camp during the war in Cambodia (1979-1980) and built a nutritional village in the homeland of the Zulu (1983 – Kwazulu). He has completed 2 fellowships at Yale (metabolism) and Cornell (Endocrinoology and molecular Medicine). He  served as chief medic and physician in the Israel Defense Forces. He was an invited speaker to the 4th Israeli President Conference (2012) and a Vatican conference on efforts to enhance cures (2013, 2016). He has also taken part in Global initiatives and spoke at The Milken Global Institute, Asian Megatrends and is an advisor for the Prime Minister of Singapore on Aging. Dr. Barzilai has been on the ‘Forward 50, top 50 influential Jews in the US (2011). His work has been profiled by major outlets, including the New York Times, the BBC and PBS’ NOVA science now, TEDMED and several TEDx talk is the leading feature on the Ron Howard/Jonathan Silberberg/National Geographic film about the Age of Aging. He authored Age Later (2019).

Dr. Nir Barzilai is the director of the Institute for Aging Research at the Albert Einstein College of Medicine and the Director of the Paul F. Glenn Center for the Biology of Human Aging Research and of the National Institutes of Health’s (NIH) Nathan Shock Centers of Excellence in the Basic Biology of Aging. He is the Ingeborg and Ira Leon Rennert Chair of Aging Research, professor in the Departments of Medicine and Genetics, and member of the Diabetes Research Center and of the Divisions of Endocrinology & Diabetes and Geriatrics at Albert Einstein College of Medicine.

Dr. Barzilai’s research interests are in the biology and genetics of aging. One focuses on the genetic of exceptional longevity, where we hypothesize and demonstrated that centenarians have protective genes, which allows the delay of aging or for the protection against age-related diseases. In a Program he is leading we take full advantage of phenotypes, DNA, and cells from the Ashkenazi Jewish families with exceptional longevity and the appropriate controls and his group have established at Einstein (over 2600 samples of which ~670 are centenarians) and discovered underling genomic differences associated with longevity. Longevity Genes Project (LGP) is a cross-sectional, on-going collection of blood and phenotype from families with centenarian proband. LonGenity is a longitudinal study of 1400 subjects, half offspring of parents with exceptional longevity, validating and following their aging in relationship to their genome. The second direction, for which Dr. Barzilai is holding an NIH Merit award that focuses on the metabolic decline of aging, and his team hypothesize that the brain leads this decline. His lab has identified several central pathways that specifically alter body fat distribution and insulin action and secretion by intraventricular or hypothalamic administration of several peptides that are modulated by aging including: Leptin, IGF-1, IGFBP3, and resveratrol.

He has received numerous grants, among them ones from the National Institute on Aging (NIA), American Federation for Aging Research, the Ellison Medical Foundation, and The Glenn Medical Foundation. He has published over 280 peer-reviewed papers, reviews, and textbook chapters. He is an advisor to the NIH on several projects and serves on several editorial boards and is a reviewer for numerous other journals. Dr. Barzilai is in the Scientific Director and on the board of the American Federation for Aging Research, is its co-scientific director, and has served on several NIA study section. He is also a founder of CohBar Inc., a biotech that develops mitochondrial derived peptides as therapy for aging and its diseases and of Life Biosciences biotech. Dr. Barzilai has been the recipient of numerous prestigious awards, including the Beeson Fellow for Aging Research, the Ellison Medical Foundation Senior Scholar in Aging Award, the Paul F. Glenn Foundation Award, the NIA Nathan Shock Award, the 2010 Irving S. Wright Award of Distinction in Aging Research and the IPSEN Longevity Prize (2016).

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. 

[Albert Einstein College of Medicine]