Neurobiology professor Andrew Huberman joins Peter Attia for a journal club discussing metformin's potential as a geroprotective drug and the power of belief. They analyze metformin's role in glucose regulation, compare it to berberine, and explore the Targeting Aging with Metformin trial. They also delve into how beliefs influence performance and weight loss, and the impact of beliefs on the brain's response to nicotine. They discuss the influence of beliefs on drug side effects and highlight the benefits of becoming a premium member.
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Quick takeaways
The Banister study sparked interest in metformin as a geroprotective drug, but its limitations call for further research.
The Keys study replicated the Banister study findings, indicating higher mortality rates in individuals with type 2 diabetes taking metformin.
Epidemiological studies have limitations, but they provide insights into the potential effects of metformin on mortality rates.
The TAME trial aims to determine the geroprotective effects of metformin through a randomized clinical trial.
Our beliefs about drugs influence their biological effects, as seen in a study on nicotine and its cognitive enhancing properties.
Deep dives
Metformin as a possible geroprotective drug
The Banister study in 2014 initially sparked interest in metformin as a potential geroprotective drug, as it showed a reduction in all-cause mortality in individuals with type 2 diabetes who were taking metformin compared to controls without diabetes. The effects of metformin were thought to go beyond glucose regulation, possibly involving inhibition of mTOR, reduction of inflammation, and targeting senescent cells. However, key limitations of the study included the exclusion of individuals who progressed to other medications and the lack of randomization. Newer studies, such as the Keys study, aim to replicate and expand on these findings.
Reassessing the evidence in a larger study
The Keys study, using a larger sample size of half a million subjects from a Danish health registry, replicated the findings of the Banister study. Individuals with type 2 diabetes who were taking metformin had a higher crude mortality rate compared to controls, even after adjusting for age. The study also employed a discordant twins analysis, which provided further evidence of increased mortality in individuals with diabetes taking metformin. However, the study is limited by the lack of randomized assignment and the confounding effects of medications taken by the participants.
Limitations of epidemiological studies
Epidemiological studies have inherent limitations, such as confounding factors and informative censoring, which complicate the interpretation of results. For example, differential medication use between study groups can affect outcomes. Nonetheless, these studies provide valuable insights into the potential effects of metformin on mortality rates.
Future prospects and ongoing trials
The TAME trial is a proactive clinical trial aiming to investigate the potential geroprotective effects of metformin through random assignment. This trial will provide more conclusive evidence on the long-term effects of metformin on aging. Meanwhile, additional research is needed to assess other potential geroprotective mechanisms of metformin beyond glucose regulation.
Belief effects in drug response
This study explores how our beliefs about drugs impact their effects on us at a biological level. It focuses on nicotine and its cognitive enhancing properties. Participants were given a vape pen with different doses of nicotine and then underwent functional magnetic resonance imaging (fMRI) to observe brain activity. The study reveals that the participants' beliefs about the nicotine dose significantly influenced both their subjective experiences and the activation patterns of brain regions related to attention and cognitive control. The findings highlight the importance of belief effects in understanding the complex relationship between drugs, beliefs, and their physiological effects.
Nicotine's impact on brain circuits and performance
This study explores the impact of nicotine on brain circuits involved in attention and cognitive control, as well as its effects on cognitive performance. The research shows that nicotine, when administered in different doses, can enhance cognitive performance by increasing signal-to-noise ratios in sensory information processing areas, improving focus and attention. The study also highlights the role of nicotine in activating the reward centers of the brain and releasing dopamine. These findings provide valuable insights into the mechanisms behind nicotine's cognitive enhancing properties.
Differentiating belief effects from placebo effects
This study distinguishes between belief effects and placebo effects, showcasing how our beliefs about drugs go beyond simple category effects. Belief effects demonstrate the influence of knowledge and belief systems on the physiological and psychological responses to a drug. The research demonstrates that the brain's response to nicotine is influenced not only by the drug itself but also by the individual's expectations and beliefs. It underscores the importance of considering belief effects in drug response research and highlights the complex interplay between cognitive factors and drug effects.
Implications for understanding drug response
This study's findings have important implications for understanding drug response and the influence of beliefs on drug effects. The research suggests that our expectations and beliefs can shape our physiological and cognitive responses to drugs. These belief effects can have significant impacts on drug performance, highlighting the need for further exploration of the mind-body connection in drug response research. By considering belief effects, researchers can gain a more comprehensive understanding of how drugs interact with the body and provide insights into potential strategies for enhancing their therapeutic outcomes.
Belief in Nicotine Strength Influences Brain Activation
The podcast episode discusses a study that explored the impact of belief on brain activation in response to nicotine. The study involved giving participants vape pens containing the same amount of nicotine, but telling them they received a low, medium, or high dose. The participants then played a stock market game while their brain activity was measured using fMRI. The results showed that participants' subjective feelings about nicotine strength matched what they were told. Moreover, the activation of brain areas involved in attention and reward, such as the thalamus and ventral medial prefrontal cortex, scaled with the belief about nicotine dose. This suggests that what we believe about the effects of a drug can affect how our brain responds to it.
Dose-dependent Response to Belief Effects
The podcast episode highlights the significance of dose-dependent belief effects. The study demonstrated that people's belief about the strength of a drug, in this case nicotine, influenced the activation of specific brain areas. Even though all participants received the same low amount of nicotine, those who believed they received a higher dose showed greater brain activation in regions associated with attention and reward. Interestingly, these belief effects were not just subjective experiences, but there was an actual change in how the brain responded. This research opens up intriguing possibilities for understanding the role of belief in various drug interventions and its implications for clinical practice.
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];
