Journal Club with Dr. Peter Attia | Metformin for Longevity & The Power of Belief Effects

Dr. Peter Attia, Journal Club (00:00:00)

• Dr. Peter Attia, a health and lifespan expert, collaborates with Professor Andrew Huberman on a journal club episode discussing scientific research papers.
• They question the conclusions drawn by the researchers and compare them to their own findings.
• They discuss two papers, one on the possible role of the drug Metformin in longevity and the other about the placebo effect in relation to cognitive enhancement.
• The aim is to provide an insight into how science and medicine are conducted, and encourage listeners to critically examine scientific material on their own.

Dreams (00:06:11)

• The discussion also includes some personal anecdotes and talks about dreaming.
• They discuss their experiences with vivid and transformative dreams, their impact, and the role of subconscious processes in these experiences.
• The dream discussion highlights the intersection of scientific investigation, personal experience and personal belief systems.
• The anecdote about a dream involving a special therapeutic drink and its impact on behaviors and habits in the dream serve to underline Dr. Attia and Professor Huberman's wider discussion on the influences on health outcomes.

Article #1, Metformin, Mitochondria, Blood Glucose (00:12:36)

• The longevity benefits of metformin, a drug used for type 2 diabetes treatment, are highlighted.
• Metformin tends to inhibit complex one of the mitochondria, which impacts how the body stores energy.
• Metformin decreases glucose production in the liver, an issue common in type 2 diabetics.

Type 2 Diabetes & Causes, Insulin Resistance (00:19:47)

• Type 2 diabetes is primarily caused by insulin resistance in the muscles.
• There’s an increase in intramuscular and intracellular fat, that hinders the functioning of insulin, leading to insulin resistance.
• Insulin resistance means more insulin is needed to transport glucose into the cell.
• Increasing insulin resistance can lead to type 2 diabetes.
• Other factors that cause insulin resistance include energy imbalance, lack of exercise, sleep deprivation, and hypercortisolemia.
• Metformin is the first-line treatment for type 2 diabetes, which helps manage blood glucose levels.

Type 2 Diabetes Medications, Metformin, Geroprotection, Bannister Study (00:25:30)

• Metformin, a drug for type 2 diabetes, doesn't just increase insulin but rather tackles the problem from another angle by suppressing glucose and addressing the hepatic glucose output channel.
• Perceptions on Metformin started to shift in 2011, with interest not only in its effect on buffering glucose but also in its potential to be 'geroprotective', that is, offering protection from aging.
• Geroprotective agents are believed to target hallmarks of aging such as decreased autophagy, increased senescence, defective nutrient sensing, proteomic instability, and genomic instability.
• In 2014, the Bannister Study found that people with type 2 diabetes on Metformin had a crude death rate of 14.4 per thousand patient years versus a control group with 15.2.
• This finding was surprising because typically, type 2 diabetes reduces life expectancy by six years on average, yet the Metformin group had a slightly better death rate than the non-diabetic group.
• This led to the theory that Metformin may be doing more than just managing glucose – it may be working as a geroprotective agent by inhibiting mTOR, reducing inflammation, and possibly calming senescent cells and their secretory products.
• There is still ongoing debate on the geroprotective properties of Metformin due to certain constraints and conditions in the Bannister study.

TAME Trial; Demographics, Twin Cohort (00:37:15)

• Most people consider the banister study as primary evidence for the benefits of metformin.
• The TAME (Targeting Aging with Metformin) trial seeks to ask if metformin's benefits on aging can be established through random assignment.
• The study referenced utilized half a million subjects from a Danish Health Registry.
• Two groups were studied: one was a standard replication of what banister did, and the second included discordant twins where only one twin had diabetes.
• Medicine intake can't be matched in these studies; patients with one health issue taking metformin likely have other health issues, complicating results.

Metformin & Mortality Rate (00:44:27)

• The study included a sensitivity analysis with and without informative censoring to understand if counting metformin patients who progress matters.
• The crude mortality rate in each group is given per thousand person years.
• A notable difference in death rate was observed between people with diabetes and those without.
• In the study, the death rate among non-diabetic dishcordant twins was around 13 per thousand person years, while for those on metformin with diabetes, it was almost 25 per thousand person years.
• However, these numbers need to be interpreted considering that these people were not assigned the drug randomly; it's a comparison between people taking metformin to tackle a major health issue and everyone else.

Kaplan-Meier Mortality Curve, Error Bars & Significance, Statistical Power (00:51:28)

• A Kaplan-Meyer curve is used in all kinds of studies. It is a mortality curve that charts time (x-axis) and cumulative survival (y-axis).
• Such a curve either goes downwards monotonically or stays flat, it cannot increase.
• When analyzing a Kaplan-Meyer curve, it is important to understand that there are mathematical representations and error bars that give a sense of range and potential variables.
• Error bars are used to measure the variability or uncertainty in the data.
• Even when error bars overlap, it doesn't necessarily denote a significant difference between two treatments—it is dependent on the nature of the experiment.
• Statistical power is also vital and not discussed as often as it should be. Statistical power is the probability of a test correctly rejecting a null hypothesis.
• To reduce variability in data, one can increase the sample size. Bigger the sample size, higher is the power of the study to detect the differences.
• The immense data sets of real-world observational studies make up for limitations and biases as compared to experimental lab studies. Epidemiological studies offer infinite duration and a massive number of subjects, while randomized assignment experiments can control for specific variables but are cost and time prohibitive. Both approaches need to be understood in terms of their inherent strengths and weaknesses.

Hazard Ratios, Censoring (01:02:23)

• Hazard ratios, a statistical measurement used in this study, indicate relative harm when the number is greater than one.
• According to the data presented, those on Metformin exhibited a 48% higher chance of dying annually than their non-diabetic counterparts.
• When accounting for factors like other medications, marital status, and educational level, the hazard ratio changes but still remains positive, indicating the increased risk of death remains.
• For the category of twins studied, one with diabetes and one without, the diabetic individual on Metformin had a 115% higher chance of dying than their healthy co-twin.
• The study also took into account censoring, which refers to the practice of excluding Metformin users who have died from the count. This slightly reduced the hazard ratios but did not overturn the general findings.

Metformin Advantage?, Variables, Interventions Testing Program (01:09:00)

• The presented study found no discernible health advantages offered by Metformin in reversing the disadvantages of having Type 2 diabetes.
• The data does not confirm whether the subjects taking Metformin would have been worse without it, nor does it assert that Metformin doesn't offer some level of protection.
• These conclusions underline the need for randomized control trials to establish these results accurately.
• Mentioned also, is the Interventions Testing Program (ITP), funded by NIH for testing molecules for longevity in animal studies. According to it, Metformin failed to provide the expected results.
• The results were contrasted with other medications like Rapamycin and 17 Alpha estradiol, which have shown consistent and promising results in animal trials, while Metformin has not.
• Nevertheless, this doesn't definitively rule out possible benefits of Metformin in humans as it was not a human trial.

Berberine, Acarbose, SGLT2 Inhibitors (01:16:02)

• Dr. Peter Attia stopped taking metformin five years ago. Metformin is traditionally used for diabetes, but Attia took it for blood glucose buffer and potential longevity.
• During lactate tests, Attia noticed high lactate levels at rest.
• According to Attia, a resting, fasted lactate in a healthy person should be between 0.3.6 millimole. It should only go up when exercising.
• Using a lactate threshold of two millimoles as a determinant, Attia noticed that his resting lactate was at 1.6 millimole.
• Applying berberine to a 'slow carb diet' helped to buffer blood glucose and reduce feelings of sickness post high calorie intake.
• The beneficial effects of berberine were only noticed when taken before a high intake of carbohydrates, otherwise it led to headaches.
• Acarbose, another glucose disposal drug, showed a survival benefit in the ITP (Interventions Testing Program). Despite the expectation that acarbose would lead to caloric restriction, mice on acarbose lived longer without weighing any less.
• Speculation suggests that the mice lived longer due to lower glucose and insulin levels.
• Regular exercise is deemed the best method to keep blood glucose and insulin levels in check.
• In addition to exercise, a type of drug used for type 2 diabetes, SGLT2 inhibitors, is taken by Attia due to its promising mechanistic and human trial results.

Blood Glucose & Energy Balance; Caloric Restriction, Aging Biomarkers (01:23:48)

• Buffering blood glucose can be separated from the concept of a caloric deficit. With a balanced energy regime, proper sleep hygiene, extensive exercise, and considerate eating, blood glucose can be controlled without a calorie deficit.
• The impact of profound caloric restriction on human life-span extension remains uncertain, and most people find it difficult to maintain.
• Negative energy balance might not necessarily result in a healthier lifestyle if food consumed is primarily unhealthy.
• Satiety and energy balance can be achieved without focusing too much on macros thanks to unprocessed or minimally processed food sources.
• The impact of certain anti-aging approaches such as metformin and rapamycin on large populations has not been thoroughly studied.
• Metformin remains prescribed for patients with insulin resistance, but its efficacy is doubtful for those who are insulin sensitive and exercise frequently.
• Short periods of caloric restriction may offer benefits in terms of discipline, flexibility, and insulin sensitivity, but there is no sure evidence that it contributes to living longer.
• The downside of fasting includes profound misery for a few days and unconsciously lost muscle mass which is hard to regain.
• The field has no concrete biomarkers for aging as of now, thus it is difficult to gauge the success and effectiveness of anti-aging interventions. Invest more resources into finding these biomarkers can lead to a better understanding of aging.
• Incorporating biomarkers could permit the modification of aging-related interventions and provide more insights about their direction and adequacy.

Tool: Reading Journal Articles, 4 Questions, Supplemental Information (01:32:22)

• An advisable method for understanding complex journal articles is to read and re-read them a number of times; comprehension often improves with each subsequent reading.
• First-timers approaching a new research paper are encouraged to note down key points like the general and specific research questions being addressed.
• Understanding the methods used to test these research questions can be beneficial; while fine details aren't always essential, it can be helpful to familiarize oneself with important terminologies or methodologies.
• Key findings and the paper's conclusions should be noted down; it's helpful to evaluate whether the research findings genuinely support the conclusions presented.
• While interpreting research papers can be challenging, it's a skill that can be perfected over time given dedication and practice.
• The reading process often starts with the title and abstract, moving on to the figures and eventually the full text.
• Many modern research papers incorporate supplementary information not included in the main body of the paper, which might need to be consulted for additional insights.

Article #2, Belief Effects vs. Placebo Effect (01:38:10)

• A paper under discussion demonstrates how belief systems about certain drugs influence their impact at both biological and subjective levels.
• Unlike placebo effects, which are either on or off phenomenon, belief effects are influenced by varying degrees of available knowledge.
• Placebo effects illustrate how individuals can be tricked into believing they are experiencing certain effects based on false information relayed to them.
• Belief effects, by contrast, suggest that the quality of performance can vary according to our beliefs about stress; if we believe stress enhances performance, we might perform better, and the opposite if we believe it harms performance.
• These belief effects can either enhance or diminish performance by around 10 to 30 percent.
• The research showed that belief effects can also impact individuals' sense of satiety and their weight, indicating that beliefs can have significant impacts on physical health.

Nicotine Effects (01:45:22)

• Nicotine, regardless of the delivery method, can enhance cognitive performance by increasing the signal-to-noise ratio of sensory information in the brain. This results in improved clarity of conscious perception.
• Nicotine binds with nicotinic acetylcholine receptors in the brain which enhances signal to noise. This explains why individuals often feel clearer after consuming nicotine.
• The brain reacts to nicotine by releasing dopamine within its reward centers, leading to positive reinforcement and cravings for more nicotine.
• The intake of nicotine can also stimulate the ventromedial prefrontal cortex, an area in the brain that enhances focus and attention. This explains the use of substances like Adderall which have similar effects for treating attention deficit disorders.
• While nicotine can enhance focus, it can also cause muscle relaxation in the peripheral body, explaining its calming effects.
• It should be noted that while nicotine has these cognitive benefits, its delivery methods and the resulting vasoconstriction can have detrimental health effects.

Nicotine Doses & Belief Effects, fMRI Scan (01:51:07)

• In the experiment, smokers were given vape pens with varying doses of nicotine, then observed using functional magnetic resonance imaging (fMRI) to track blood flow patterns in the brain.
• The fMRI machine measures the ratio of oxygenated to deoxygenated blood, visiting active neurons, and observe the changes in blood flow and activity in different brain areas.
• The subjects in the experiment were also assigned a task designed to engage specific brain areas, including the thalamus, reward pathways, and the ventromedial prefrontal cortex.
• The task involved observing a market or stock value and predicting if it would rise or fall, earning or losing points accordingly.
• Subjects were told they were vaping high, medium, or low amounts of nicotine, however, they all received the same amount of low nicotine vape.
• The subject's perceived amount of nicotine influences their feelings, brain activation levels, and performance on the task, creating a belief effect. If subjects were told they received a high amount of nicotine, they reported feeling more stimulated and their brain scans showed a higher level of activation.
• The experiment revealed that what one believes can actually change the brain's response, regardless of the reality of nicotine dosage.

Biological Effects, Dose-Dependent Response & Belief Effects (02:00:07)

• The study mentioned discusses the impact of nicotine and belief effects, indicating that what individuals are told about the dose of a drug changes their physiological responses.
• Research results indicated a connection between the thalamus and the ventral medial prefrontal cortex, a pathway that appeared to be activated according to the perceived dose of nicotine.
• People who believed they had a high dose of nicotine showed a robust activation in this pathway, while low and medium doses resulted in correspondingly lower activations.
• The findings from this study suggest that one’s belief can bypass pharmacology to a degree, implying that the expected effect of a drug can influence an individual's actual response to it.
• A missing element in the research was a control group that received zero nicotine, while still being told that they received a high dose of nicotine.
• This is the first study to analyze the dose-dependence of belief effects helping deepen the understanding of how beliefs can influence pharmacological effects.

Biology & Beliefs, Significance, Dopamine Response, Non-Smokers (02:05:14)

• The degree of activation (beliefs) between the thalamus and the ventromedial prefrontal cortex showed a significant low, medium, and high occurrence of responses.
• Surprisingly, little nicotinic receptor occupancy in the thalamus can activate this pathway, and while there was no raw difference detected in its activation, its output was observable.
• Power and significance differences within the groups were noted and could potentially be statistically significant with a larger sample size.
• Despite the level of nicotine dose, there was no difference in the activation of reward pathways, suggesting the possibility of leveraging this finding for nicotine quitting strategies.
• A predicted challenge in conducting a similar experiment with non-smokers is the lack of previous drug experience to compare, which could make them more susceptible to belief effects.
• A curious side note from the study was the movement artifact caused by smokers coughing during the fMRI scanning process, which could have potentially affected the data's fidelity.

Dose-Dependence & Beliefs, Side Effects, Nocebo Effect (02:10:57)

• The experiment explores dose dependence of belief, which has implications across a range of drugs, interventions, and vaccines.
• The effectiveness of some drugs could be influenced by what we believe about them, including their dosage, and how these beliefs affect our brain's reaction to the drugs.
• Therapeutic effects of drugs such as ADHD medication or GLP-1 agonists, which impact the hypothalamus that is related to satiety, could potentially be enhanced through the belief effect.
• Belief effects could potentially influence a patient's response to drugs such as those for treating hypertension. This is still an area for further exploration.
• The belief about side effects can affect a patient's experience with the drug. If patients are informed that side effects signify that the drug is working, they may tolerate them better and even experience more relief from primary symptoms.
• Belief effects sometimes manifest as a nocebo effect, where patients start experiencing all listed side effects after reading about them.
• There is a need to balance informing patients about possible side effects without instigating a nocebo effect.