metformin

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In this special edition celebrating 300 episodes of The Drive, Peter discusses a variety of popular topics and health interventions and classifies them based on their level of evidence and relevance using the following categories: proven, promising, fuzzy, noise, and nonsense. Peter first delves into the topic of geroprotective molecules, covering rapamycin, metformin, NAD and its precursors, and resveratrol. Next, he explores the significance of metrics like VO2 max and muscle mass, as well as emerging concepts like blood flow restriction and stem cells. The conversation extends to nutrition, addressing questions surrounding long-term fasting, sugar consumption, sugar substitutes, and the contentious role of red meat in cancer. Peter not only provides his current stance on each topic—most of which have been covered in great detail in the previous 300 episodes—but also reflects on how his opinion may have evolved over the years.

We discuss:

• Defining the categories of “proven, promising, fuzzy, noise, and nonsense” [3:15];
• Rapamycin [9:30];
• Metformin [17:00];
• NAD and its precursors [24:30];
• Resveratrol [32:45];
• The importance of VO2 max, muscle mass, and muscular strength for lifespan [38:15];
• Blood flow restriction (BFR) training [44:00];
• Using stem cells to treat osteoarthritis or injury [51:30];
• Fasting as a tool for longevity (and why Peter stopped his fasting protocol) [55:45];
• The energy balance theory [1:06:30];
• The idea that sugar is poison [1:12:00];
• The idea that sugar substitutes are dangerous [1:22:15];
• The debate on red meat and cancer [1:28:45]; and
• More.

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Dr. Nir Barzilai is a geroscientist, Chaired Professor of Medicine and Genetics, and the founder and principal investigator of the Einstein Nathan Shock Center and the Glenn Center for Excellence in Biology of Aging. He also studies families of centenarians that have provided genetic and biological insights on the protection against aging—with several drugs developed based, in part, on these paradigm-changing studies. He is also leading the TAME (Targeting/Taming Aging with Metformin) trial to prove to the FDA that aging can be delayed and to allow for next-generation interventions. 

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In this episode we discuss (audio version / Apple Subscriber version):

• The hallmarks of aging (9:01 / 7:10)
• What causes the hallmarks of aging? (15:40 / 13:49)
• Dr. Barzilai’s research on centenarians (23:16 / 21:25)
• Why living to 100+ years is good for the economy (24:54 / 23:03)
• What enables someone to live to 100 years old? (29:30 / 25:20)
• Taking growth hormone and Metformin have different effects based on your age (36:58 / 32:48)
• The connection between HDL cholesterol and longevity (43:36 / 39:26)
• Dr. Barzilai’s research on Metformin (56:23 / 52:13)
• How Metformin works in the body and on muscle growth (1:04:51 / 1:00:41)
• Dr. Barzilai’s personal longevity (1:42:05 / 1:37:55)

Learn more about the Longevity Genes Project and the TAME Trial. 

Get a copy of Age Later: Health Span, Life Span, and the New Science of Longevity

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Andrew Huberman, Professor of Neurobiology at Stanford University and host of the Huberman Lab podcast joins us in a special journal club episode. Peter and Andrew each present a recent paper that sparked their interests, delving into the findings, dissecting their significance, discussing potential confounders and limitations, and exploring remaining questions. Importantly, they share their methodologies for comprehending research studies, providing valuable insights for listeners to navigate this process independently. Peter presents an epidemiological study reevaluating a noteworthy metformin result that intrigued the anti-aging community, leading to discussions on metformin's geroprotective potential (or lack thereof) and the current lack of aging biomarkers. Andrew introduces a paper examining how our beliefs about the medications we take influence their biological effects, distinguishing the "belief effect" from a placebo effect and highlighting its exciting implications for the future.

We discuss:

• The motivation behind this journal club conversation [2:45];
• Why Peter chose a paper on metformin, how metformin works, and why it generated excitement as a longevity-enhancing agent [9:00];
• Defining insulin resistance and its underlying causes [16:15];
• Metformin as a first-line treatment for type 2 diabetes, and Peter’s evolving interest in metformin as a geroprotective drug [22:00];
• Defining the term “geroprotection” [24:45];
• The 2014 study that got the anti-aging community interested in metformin [26:00];
• Peter presents the 2022 paper that repeats the analytical approach from the 2014 Bannister study [33:15];
• Greater mortality in the metformin group: how results differed between the 2022 paper and the 2014 paper [40:00];
• Understanding statistical significance, statistical power, sample size, and why epidemiology uses enormous cohorts [51:45];
• Interpreting the hazard ratios from the 2022 metformin study, and the notable takeaways from the study [56:45];
• Drugs that may extend lifespan, why Peter stopped taking metformin, and a discussion of caloric restriction [1:08:45];
• Current thoughts on the use of metformin for longevity [1:21:00];
• Could there be any longevity benefit to short periods of caloric restriction? [1:22:45];
• Peter and Andrew’s process for reading scientific papers [1:26:45];
• The biological effects of belief, and how “belief effects” differ from placebo effects [1:32:30];
• The neurobiology of nicotine: a precursor conversation before delving into the paper Andrew chose [1:39:45];
• Andrew presents a paper that demonstrates the impact of belief [1:45:30];
• Analyzing the fascinating results of the Perl paper [1:54:30];
• Exciting implications of the findings about “belief” reported by Perl and colleagues [2:03:15]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter focuses the discussion on two topics getting a lot of attention recently. He first dives deep into GLP-1 agonists, most notably semaglutide and tirzepatide, which originally came to market as diabetes drugs but are now being studied and prescribed for weight loss. He walks through the data and compares the effectiveness of the two drugs, the side effects, and perhaps more importantly, his reservations around wide use of these drugs and who he would consider to be a candidate for them. Next, Peter discusses how metformin, another drug originally brought to market for diabetes management, gained popularity as a potential longevity drug even for non-diabetics. Peter gives his take on this possibility and reviews data from a more recent study investigating the question of whether metformin should be used for general “geroprotection.”

If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #45 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• The hype around semaglutide, tirzepatide, and other GLP-1 agonists for weight loss [2:30];
• Overview of GLP-1 agonists and why these drugs are getting so much attention [6:15];
• Defining the term “geroprotective” [13:30];
• Semaglutide: background, brand names, indications, and more [15:15];
• Tirzepatide: background, brand names, indications, and more [19:15];
• How semaglutide and tirzepatide compare in their efficacy in terms of weight loss and other metabolic health metrics [23:45];
• Data showing sustained weight loss and improved metabolic metrics with after more than a year of using semaglutide and tirzepatide [29:00];
• What happens to body weight when a patient discontinues the medication? [34:45];
• Noteworthy side effects of GLP-1 agonists and similar classes of drugs [40:45];
• Increased resting heart rate and other concerning trends in patients using GLP-1 agonists [45:15];
• Changes in body composition (body fat and lean muscle) in patients on GLP-1 agonists [50:45];
• Possible reasons for the loss of lean muscle mass and tips for protecting lean mass [59:00];
• GLP-1 agonists and thyroid cancer [1:01:30];
• Who might be a candidate for GLP-1 agonists? [1:03:45];
• The large financial cost of this class of drugs [1:08:30];
• Metformin as a geroprotective drug: origin of the idea that metformin could be a longevity agent even for non-diabetic patients [1:11:30];
• A 2022 study on metformin sheds more light on the question of whether metformin should be used for “geroprotection” in non-diabetics [1:21:00];
• Peter’s current approach with metformin for his patients [1:25:15]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter is joined by special guest, Dr. Matt Kaeberlein. Together they answer many questions around the field of aging with an emphasis on three specific molecules—NAD, metformin, and rapamycin—and their purported geroprotective qualities. They first discuss aging biomarkers and epigenetic clocks before breaking down the advantages and limitations of the most common experimental models being used today to study aging and pharmacological possibilities for extending lifespan. Next they dive deep into NAD and the much-hyped NAD precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). They compare data from NAD precursors to studies on metformin and rapamycin, assessing how they stack up against each other and using the comparison as an opportunity to illustrate how to make sense of new experimental data and make smart decisions about how to approach future research.

If you’re not a subscriber and listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or on our website at the AMA #35 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Logic behind comparing NAD precursors to rapamycin and metformin [3:40];
• Aging biomarkers: current state, usefulness, and future promise [7:00];
• Epigenetic clocks: definition, use case, and limitations [14:45];  
• Advantages and limitations of studying aging in non-humans and the strengths and weaknesses of different model systems [26:30];
• Aging studies: importance of control lifespans and the problems with reproducibility [34:15];
• Intro to NAD, potential role in aging, relationship to sirtuins, and more [48:15];
• NAD precursors (NR and NMN): current data [1:10:00];
• Human studies with NAD precursors [1:25:45];
• Comparing NAD lifespan data to data from metformin and rapamycin [1:28:30];
• Defining a “clean drug” and a “dirty drug” [1:38:00];
• Reason for the lack of rapamycin studies in humans compared to NAD and metformin [1:41:00];
• Ranking the geroprotective molecules in terms of risk and reward [1:48:00]; and
• More.

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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.

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.

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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.

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.

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In this episode, originally recorded to be the 100th episode of The Drive, Peter discusses topics that he has changed his mind about since starting the podcast as a result of preparing for interviews as well as from the actual conversations. Peter also reviews some of his favorite moments from the first 99 episodes, shares what books he’s currently reading, and much more. Initially scheduled to be released as episode 100, this was delayed due to recent podcasts covering COVID-19.

We discuss:

• Definition of “strong convictions loosely held,” and the value in trying to shoot down your own hypotheses [2:20];
• Metformin—How Peter’s strong convictions have changed since 2018 [8:00];
  
• Getting a dog—Why Peter caved and how it’s going so far [15:45];
  
• Rapamycin—How Peter’s feelings have evolved, and the questions still needing to be answered [20:45];
  
• Archery, the joy of pursuing mastery, and the importance of stillness [26:50];
  
• Zone 2 training—Why Peter has made it a big component of his exercise regimen [37:30];
  
• Deadlifts—Why Peter now believes it’s extremely beneficial to longevity when done properly [41:45];
  
• Read any good books lately? [50:00];
  
• Baby aspirin for preventing blood clotting—Why Peter no longer takes it, and a few alternative options [53:15];
  
• Generic drugs—How and why Peter’s mind has shifted on generic drugs [55:45];
  
• Omega-3 fatty acids, EPA and DHA—How Peter’s long-held views have changed [58:15];
  
• How Peter got better at saying “no” [1:02:30];
  
• Does Peter have any favorite episodes of The Drive? [1:07:15]; and
  
• More.
  

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In this episode, Nir Barzilai, director of the Institute for Aging Research and expert in the genetics of longevity, discusses the evidence that metformin and rapamycin have anti-aging properties and how his TAME study aims to support this hypothesis in humans. Additionally, he describes the role of genetics in lifespan/healthspan and how it might affect important pathways such as IGF and insulin sensitivity.

We discuss:

• Nir’s background and interest in aging and endocrinology [3:30];
• History of metformin, and understanding the mechanism [11:15];
• Attempting to define insulin resistance [21:15];
• Metformin as a possible anti-aging drug [48:45];
• The TAME trial: Targeting Aging with MEtformin [57:45];
• Why Nir believes metformin can slow aging [1:16:30];
• The genetic gift of centenarians [1:28:00];
• IGF/GH and its impact on aging and chronic diseases [1:34:15];
• Genetics/epigenetics of centenarians, gene sequencing, CETP-VV, Lp(a) [1:49:15];
• Should you be taking HGH? [2:05:30];
• NAD and NAD precursors (NR and NMN) [2:30:00];
• Parting thoughts on metformin [2:36:15];
• Possible blind spots in Nir and Peter’s thinking? [2:43:00]; and
• More.

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In this episode, Nav Chandel, a professor of medicine and cell and molecular biology at Northwestern University, discusses the role of mitochondria and metabolism in health and disease. Nav also provides insights into the mitochondria as signaling organelles, antioxidants, and metformin’s multifaceted effects on human health, among many topics related to well-being.

We discuss:

• What got Nav interested in mitochondria [5:00];
• Reactive oxygen species (ROS) [16:00];
• Antioxidants: helpful or harmful? [20:00];
• Mitochondria as signaling organelles [22:00];
• Hydrogen peroxide (H2O2) [25:00];
• Mitochondrial DNA [28:00];
• Mitochondria and aging [45:00];
• Metformin [52:45];
• Metformin and the gut microbiome [54:00];
• Metformin as complex I inhibitor and the importance of the NADH/NAD ratio [1:01:00];
• Anticancer benefits of metformin [1:07:45];
• Mitochondrial function is necessary for tumorigenesis [1:15:00];
• Are somatic mutations the result of mitochondrial dysfunction? [1:31:30];
• Vitamins and antioxidants [1:37:00];
• Targeting inflammation in disease [1:43:00];
• NAD precursors [1:45:45];
• MitoQ [1:52:00];
• Metabolite toxicity [1:56:30];
• Cortisol and healthy aging [2:02:00];
• Nav turns the tables and asks Peter how he deals with the “So what should I eat?” question during social encounters [2:09:00]; and
• More.

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