Key Moments
Journal Club with Dr. Peter Attia | Metformin for Longevity & The Power of Belief Effects
Andrew HubermanKey Moments
Metformin may not offer longevity benefits as previously thought; belief effects modify drug impacts.
Key Insights
The banister study in 2014 suggested Metformin provided a survival advantage for type 2 diabetics, sparking interest in its longevity (geroprotective) potential.
A more recent study by Keyes et al. using a larger Danish registry and twin analysis found no survival advantage for Metformin users with type 2 diabetes compared to controls.
The Keyes study highlighted limitations in epidemiological research, particularly confounding factors like concurrent medication use, despite attempts at adjustment.
Belief effects, distinct from placebo effects, demonstrate that what individuals believe about a drug's dosage and effects can alter physiological responses, even changing brain activation patterns.
A study involving nicotine showed that belief in taking a high, medium, or low dose (despite all participants receiving the same low dose) altered thalamus activation and its connection to the prefrontal cortex.
Metformin's potential geroprotective mechanisms (mTOR inhibition, anti-inflammation, senescent cell reduction) are debated, and its failure in the ITP intervention testing program for mice raises further questions.
METFORMIN: FROM PROMISING GEROPROTECTOR TO QUESTION MARK
The discussion begins with Metformin, a long-standing drug for type 2 diabetes. Initial excitement, fueled by a 2014 study by Banister, suggested Metformin might offer 'geroprotection'—benefits beyond treating disease that potentially extend lifespan by targeting aging hallmarks. This prompted widespread interest in its use for longevity by non-diabetics. However, the conversation shifts to a more recent, larger study by Keyes et al., which re-examined Metformin's survival advantage in type 2 diabetics using a Danish health registry and a novel discordant twin analysis.
REASSESSING METFORMIN'S SURVIVAL BENEFITS
The Banister study, using UK Biobank data, observed a 15% reduction in all-cause mortality for type 2 diabetics on Metformin compared to controls. A key limitation identified in retrospect was 'informative censoring,' where patients who progressed to needing stronger medications were excluded, potentially skewing results. The Keyes study aimed to address these limitations with a larger sample size and a twin design to control for genetic and environmental factors. Despite these methodological improvements, the results were starkly different.
EPIDEMIOLOGY'S CHALLENGES AND KEYES'S FINDINGS
The Keyes study, analyzing half a million individuals, found no survival advantage associated with Metformin use in type 2 diabetics. When comparing diabetics on Metformin to non-diabetics, the Metformin group showed increased mortality. Adjustments for medication use, education, and other factors, while attempted, could not fully account for the significant confounding factors inherent in observational studies. The twin analysis, theoretically purer, also indicated a higher mortality risk in the diabetic twin, even when on Metformin, challenging the earlier optimistic conclusions.
THE POWER OF BELIEF EFFECTS ON PHYSIOLOGY
Shifting focus, the discussion explores 'belief effects,' distinct from placebo effects, which highlight how our expectations and knowledge about interventions profoundly influence biological outcomes. This concept is illustrated by studies showing that framing stress as performance-enhancing or detrimental, or believing a milkshake is high-calorie versus low-calorie (when it's the same), can alter physiological responses like stress hormone levels, ghrelin secretion, and even weight loss from exercise. These effects demonstrate the brain's active role in modulating bodily functions based on anticipated outcomes.
NICOTINE STUDY: BELIEF DIRECTLY IMPACTS NEURAL ACTIVITY
A key study presented investigates belief effects using nicotine. Participants, all experienced smokers receiving the same low dose of nicotine via vaping, were told they received either a high, medium, or low dose. Those told they received a higher dose exhibited altered brain activation, particularly in the thalamus and its connection to the prefrontal cortex, areas involved in attention and reward processing. This differential neural response, directly tied to belief rather than actual dose, suggests that our expectations can shape the physiological impact of substances.
IMPLICATIONS AND NEW VISTAS FOR RESEARCH
The findings on belief effects carry significant implications across medicine, from drug efficacy to behavioral interventions. They suggest that subjective beliefs can modulate objective physiological responses, altering dopamine release and cognitive performance. The studies underscore the complexity of drug responses, suggesting that belief systems, dosage expectations, and the perceived nature of side effects (nocebo vs. enhanced effect) can significantly influence outcomes. The lack of reliable biomarkers for aging and drug efficacy remains a critical challenge, highlighting the need for further research into these nuanced interactions.
Mentioned in This Episode
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●Studies Cited
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Common Questions
A Journal Club brings together students, typically in graduate or medical school, to discuss and critique scientific papers. Its purpose is to compare individual conclusions with authors' findings and identify key takeaways, fostering scientific and clinical thinking.
Topics
Mentioned in this video
Medical doctor and expert in health and lifespan, author of 'Outlive', and host of 'The Drive' podcast. Co-host of this journal club.
Likely the senior Principal Investigator (PI) on the TAME trial.
A sports physiologist and coach known for his work on zone 2 training and lactate testing, influencing Peter Attia's personal testing protocols.
A researcher in the psychology department at Stanford and former podcast guest, known for her work on belief effects, including studies on stress and milkshakes.
Author of 'The 4-Hour Body' and proponent of the Slow Carbohydrate Diet.
Host of the Huberman Lab podcast and Professor of Neurobiology and Ophthalmology at Stanford School of Medicine.
The CEO of Berkshire Hathaway and legendary investor.
A researcher at Yale who performed extensive work elucidating the mechanisms of intramuscular fat accumulation and insulin resistance.
Nominated Acarbose to be studied in the Interventions Testing Program (ITP).
Chair of Ophthalmology at Stanford, who shared an anecdote about the vast vocabulary a physician acquires.
Researcher at Icahn School of Medicine at Mount Sinai, whose lab studies addiction in humans and is an author on the nicotine belief effect paper.
The phenomenon where belief in a treatment can lead to real physiological changes, ranging from subjective feelings to measurable brain activation.
A brain pathway that releases dopamine, associated with reward and reinforcement, activated by nicotine.
A phenomenon where a person's beliefs about the effects of a substance or intervention can modify physiological responses beyond a simple placebo/non-placebo binary, often scaling with the amount and type of information received.
An area of the forebrain involved in limiting focus and attention for learning, showing belief-dependent activation in its connection with the thalamus in the nicotine study.
The phenomenon where negative expectations about a treatment or drug can lead to adverse effects or symptoms.
The primary energy currency of the cell, produced most efficiently through oxidative phosphorylation in the mitochondria.
Nine recognized biological processes that contribute to aging, including decreased autophagy, increased senescence, and genomic instability.
A type of curve used in survival analysis to estimate the survival function from life history data, often used to show mortality over time in clinical studies.
A brain structure that acts as a relay station for sensory information, containing nicotinic receptors and showing belief-dependent activation in the nicotine study.
A common practice in graduate and medical school where students discuss and critique scientific papers.
A condition where cells become resistant to the effects of insulin, requiring more insulin to transport glucose, primarily beginning in muscles and contributing to type 2 diabetes.
A statistical method used in survival analysis to investigate the association between the survival time of a patient and one or more predictor variables.
A type of scan used to measure body composition, including muscle mass, serving as a biomarker for fitness interventions.
A neuroimaging technique that measures brain activity by detecting changes in blood flow, serving as a proxy for neural activity.
The concept of protecting against aging by targeting the fundamental biological hallmarks of aging, rather than specific age-related diseases.
A dietary regimen involving a consistent reduction in calorie intake, explored for its potential to extend lifespan but often difficult to sustain.
A laboratory technique for the separation of a mixture, used for purifying compounds and analyzing mixtures.
A highly rigorous, NIH-funded program that tests molecules for geroprotective effects in animals, using large sample sizes and multiple labs.
A scientific publishing company publishing more than 50 peer-reviewed journals in the life, physical, earth, and health sciences.
A health registry used by Keyes and colleagues for their large-scale retrospective cohort study on Metformin, sampling about half a million people.
A prominent peer-reviewed academic journal published by the American Association for the Advancement of Science.
The institution where Gerald Shulman conducted clinical trials on insulin resistance.
A U.S. government agency that funds biomedical research, including the Interventions Testing Program (ITP).
A British multidisciplinary scientific journal, first published in 1869, considered one of the most prestigious and highest-impact academic journals.
The institution where Dr. Ali Crum conducts research in the psychology department.
A medical school in New York City, where Chaosi Guo runs a laboratory studying addiction.
University of California, San Diego, where Andrew Huberman used to teach a class on neural circuits.
A glucose disposal agent that works in the gut to prevent glucose absorption, found to have a survival benefit in the ITP not related to caloric restriction.
A substance derived from tree bark, sometimes referred to as the 'poor man's Metformin' due to its similar properties of reducing mTOR and blood glucose.
A drug discussed in a paper for its cognitive-enhancing properties, particularly its ability to increase signal-to-noise in sensory information via nicotinic receptors in the brain.
A highly toxic substance that completely blocks complex four of the mitochondria, leading to instantaneous death.
A supplement company partnered with the Huberman Lab podcast, offering supplements for various health goals.
A hormone that signals hunger, measured in studies to assess the physiological impact of belief effects on satiety.
Dr. Peter Attia's popular podcast where he interviews experts in medicine and science.
A neuroimaging technique used in the nicotine study to measure brain activity, specifically blood flow (hemodynamic response) in response to belief effects.
An open access preprint repository for the biological sciences, where researchers can post papers prior to peer review.
A class of drugs that increase insulin sensitivity and initially cause the body to make more insulin, used to treat type 2 diabetes.
A drug that has consistently shown lifespan extension in male mice in the ITP, even when given late in life. It is an mTOR inhibitor.
A drug used for over 50 years to treat type 2 diabetes, known to inhibit complex one of the mitochondria and reduce hepatic glucose output. Its geroprotective effects are debated.
A brand name for Metformin, a generic drug used for type 2 diabetes.
A GLP-1 agonist drug.
A form of estradiol that continues to show geroprotective effects comparable to rapamycin in male mice in the ITP.
A stimulant medication commonly prescribed for ADHD.
An SGLT2 inhibitor that was very successful in the ITP, showing a survival benefit in mice not through calorie restriction but likely through lower glucose and insulin.
A stimulant medication commonly prescribed for ADHD.
A stimulant medication commonly prescribed for ADHD.
An influential 2014 paper that suggested a survival advantage in type 2 diabetics treated with Metformin, which generated significant excitement for its geroprotective potential. Later re-evaluated due to methodological limitations.
A large, long-term national health study in the United States, mentioned as an example of a very expensive large-scale prospective randomized experiment.
A large-scale biomedical database and research resource that provides information for epidemiological studies.
A clinical trial designed to prospectively and through random assignment investigate if Metformin provides a geroprotective benefit to non-diabetics.
A mattress company that creates customized mattresses based on a two-minute quiz to optimize sleep.
A program that provides real-time feedback using a continuous glucose monitor to help understand how diet and behavior affect blood glucose levels.
Warren Buffett's holding company, known for its annual shareholder meeting.
A smart mattress cover that can track sleep metrics, used as an example of a tool that provides biomarkers for sleep supplements.
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