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    #31 - Navdeep Chandel, Ph.D.: metabolism, mitochondria, and metformin in health and disease

    enDecember 03, 2018
    What role do mitochondria play in health and longevity?
    How do reactive oxygen species (ROS) contribute positively?
    What are the debated effects of antioxidants?
    Why is mitochondrial DNA inherited maternally?
    How might metformin affect longevity according to researchers?

    Podcast Summary

    • Unraveling the Mysteries of MitochondriaDiscovering the benefits of reactive oxygen species (ROS), exploring the controversy surrounding antioxidants, and understanding the impact of cortisol and metformin on longevity can help improve our overall health and well-being.

      Mitochondria play a crucial role in our overall health and longevity. Navdeep Chandell, an expert in mitochondria and metabolism, provides insights into the complex nature of these organelles. He dispels the misconception that reactive oxygen species (ROS) are entirely harmful and explores their potential benefits in signaling. The discussion also delves into the controversial topic of antioxidants and their potential harm or benefits. Additionally, mitochondrial DNA, which originates from bacteria and is inherited maternally, adds another layer of intrigue to the study of mitochondria. Chandell emphasizes the importance of cortisol and its impact on health, as well as the rising interest in the drug metformin and its connection to longevity. By understanding the role of mitochondria, we can potentially enhance our well-being and longevity.

    • The Connection Between Mitochondria and Metabolism: An Interdisciplinary PerspectiveUnderstanding the connection between mitochondria and metabolism is crucial for improving organ preservation and studying mitochondrial function. Collaboration across disciplines is essential in unlocking the mysteries of these cellular powerhouses.

      Mitochondria and metabolism are intricately connected, and understanding this connection requires a multidisciplinary approach. Navdeep Chandel, a mathematician turned biologist, became interested in mitochondria through his work in a transplant laboratory. He realized that to improve organ preservation, he needed to understand metabolism, which led him to study mitochondria. Chandel's research focused on enzyme kinetics and the role of cytochrome C oxidase in respiration. He also highlighted three significant discoveries in the mitochondria field, including Hans Krebs' work on the TCA cycle and Peter Mitchell's study on ATP production. This conversation emphasizes the importance of interdisciplinary collaboration and the role of metabolism in mitochondrial function.

    • The Role of Mitochondria in Energy Generation and Cellular FunctionsThe mitochondria is responsible for converting glucose into energy in the form of ATP through processes such as the citric acid cycle and electron transport chain. Understanding this energy-generating system is crucial for overall cellular function.

      The mitochondria plays a crucial role in energy generation within cells. Pyruvate, a product of glucose metabolism, can either be converted to lactate in the cytoplasm or be imported into the mitochondria to eventually become acetylcoa. Acetylcoa is important because it can acetylate enzymes, influencing various cellular functions. The mitochondria also houses the TCA cycle, also known as the citric acid cycle or crab cycle, which generates reducing equivalents (NADH and FADH) that feed electrons to the electron transport chain. This chain acts as a battery to produce ATP, the currency that powers cellular functions. The process of converting chemical energy into electrical potential energy, and vice versa, is analogous to a battery. Cyanide is a toxin that disrupts this process and can be lethal at low concentrations. The release of cytochrome C from mitochondria into the cytoplasm is a discovery that sheds light on the importance of this energy-generating system.

    • The Dual Role of Cytochrome c in ATP Generation and Cell DeathThe localization of cytochrome c determines its function, with its release triggering apoptosis. Mitochondria also release reactive oxygen species, which act as signaling mechanisms and emphasize the importance of antioxidants in maintaining cellular function.

      The localization of cytochromes c between the mitochondria and the cytoplasm determines whether it helps generate ATP or triggers cell death. When a cell is under stress or neglect, cytochromes c can escape the mitochondria and start a cascade of apoptosis, which is programmed cell death. This discovery connected mitochondria to more than just energy production and revealed its role in controlling cell biology and the decision of life and death. Additionally, the release of reactive oxygen species like superoxide and hydrogen peroxide by mitochondria was initially believed to be a sign of damage, but it was later found to be a signaling mechanism for cellular functions. This highlights the important role of antioxidants in preserving cellular function.

    • Balancing antioxidants for optimal healthWhile antioxidants can be beneficial in certain situations, too much antioxidant activity can actually be harmful and interfere with immune system responses and exercise benefits. Mitochondria play a vital role in signaling, including in apoptosis and programmed cell death.

      Antioxidants can be beneficial in certain contexts, such as clearing out toxic molecules and promoting immune function. However, it is important to maintain a balance between pro oxidative and anti oxidative stress in the body. In cases where the immune system needs to take action, having too much antioxidant activity can actually be harmful, as seen in trials for sepsis and lung cancer. Additionally, high doses of antioxidants can inhibit the beneficial response of vigorous exercise by turning off beneficial genes. The mitochondria play a crucial role in signaling in both physiological and pathological conditions, releasing molecules like hydrogen peroxide and cytokrom C. Overall, the understanding of the mitochondria's signaling role has expanded over time, particularly in the realm of apoptosis and programmed cell death.

    • The Importance of Apoptosis in Tumor Suppression and Cancer TreatmentManipulating apoptosis is crucial in enhancing the death rate of cancer cells and developing effective cancer treatments, especially by targeting anti-death proteins to sensitize cancer cells to chemotherapy.

      Apoptosis, which refers to the programmed cell death, plays a crucial role in tumor suppression mechanisms. When a cell undergoes an irreparable genetic mutation in the nucleus, it has the ability to kill itself through apoptosis. This process is essential in eliminating cells with genetic defects and preventing the development of cancer. However, cancer cells can upregulate anti-apoptotic proteins, which protect them from apoptosis and make them resistant to chemotherapy. To make chemotherapy more effective, researchers have been targeting these anti-death proteins as a way to sensitize cancer cells and enhance their death rate when exposed to chemotherapy. Understanding and manipulating apoptosis is therefore crucial in developing effective cancer treatments.

    • The Role of Mitochondrial Genes in Energy ProductionMitochondria, known as the cell's powerhouses, have a small number of genes that are crucial for energy production. This suggests that mitochondria may have originated from a symbiotic relationship, providing evidence for evolution.

      Mitochondria, which are often referred to as the powerhouses of the cell, have their own genes that play a crucial role in energy production. While the nucleus contains about 20,000 genes, the mitochondria only have around 13 genes that are essential for the functioning of the respiratory chain. This respiratory chain is responsible for converting oxygen and chemical energy into ATP, the energy currency of the cell. Complexes within the respiratory chain, such as complex 3, have some subunits encoded by the mitochondrial genome. This suggests that mitochondria may have originated from a symbiotic relationship between an archaea and an alpha proteobacteria, with the archaea providing the nucleus and the alpha proteobacteria evolving into the mitochondria. The presence of foreign DNA in every cell is a compelling evidence for evolution.

    • Mitochondria's Unique DNA Protection MechanismMitochondria use antioxidants to protect their DNA from potential damage, despite having fewer repair mechanisms than the nucleus. Inflammation and excess hormones can negatively impact mitochondrial function.

      Mitochondria have a unique way of protecting their DNA, despite its vulnerability. The mitochondria hold onto a small number of essential genes, despite the risks involved. The nucleus, with its multiple mechanisms for DNA repair and protection, would seemingly be a better steward of these genes. However, the mitochondria have an abundance of antioxidants in their matrix, which serve as protection against potential toxins. This high level of antioxidant activity in the mitochondria helps safeguard the exposed mitochondrial DNA. Additionally, it is noted that inflammation can cause the mitochondria to shed DNA, triggering an immune response. Furthermore, the conversation hints at the harmful effects of excess cortisol and other hormones on mitochondrial function.

    • Unraveling the Mysteries of Mitochondrial DNA and InheritanceUnderstanding the role of mitochondrial DNA inheritance and its involvement in signaling and immune responses is crucial for further research and exploration of its functions and mechanisms.

      There are still unanswered questions in the field regarding the presence of mitochondrial DNA and why it is inherited from the mother. These questions continue to be a topic of interest and research. Additionally, the conversation touches on the role of mitochondrial DNA in signaling and immune responses. Mitochondrial DNA can be released and trigger an immune response, but it is important to understand how this occurs without causing harm to the cell. The mechanisms behind the release of ATP and hydrogen peroxide in a controlled and benign manner also require further exploration. Overall, there is much to learn about the functions and inheritance of mitochondrial DNA.

    • Unveiling the Influence of Mitochondria on Gene Expression and Cellular Function.Mitochondria's role in gene expression and cellular function is still not fully understood, with citrate playing a crucial role in lipid production and potentially acting as a signaling molecule. Further research is needed to uncover the mysteries of mitochondrial DNA and its impact on cellular processes.

      There is still much to be discovered about the role of mitochondria in controlling gene expression and overall cellular function. The conversation highlights the importance of citrate, a molecule that can be exported from the TCA cycle to the cytoplasm and play a role in the production of lipids and fatty acids. Additionally, it is suggested that citrate may also act as a signaling molecule, influencing gene expression through chromatin modifications. The conversation also emphasizes the complexity and inefficiency of mitochondrial DNA and raises questions about why certain genes are present in mitochondria. The field of study surrounding mitochondria and its impact on cellular processes is still a work in progress, inviting further exploration and the potential for groundbreaking discoveries.

    • The Role of Mitochondria in Aging and the Limitations of SupplementsWhile mitochondrial function is linked to aging, the belief that supplements can boost mitochondrial function and slow down aging may not be supported by evidence. Focusing on understanding mitochondrial DNA and promoting mitochondrial biogenesis is more important.

      There is a growing interest in mitochondria and its role in aging. Mitochondrial function, specifically the decline in ATP generation, is seen as a key factor in the aging process. However, it is important to note that the decrease in ATP generation may not be rate-limiting in healthy individuals. Therefore, the current belief that supplements can boost mitochondrial function and slow down aging may not be supported by evidence. Additionally, some popular supplements targeting mitochondria, such as antioxidant supplements, may not have the desired effect. The focus should be on understanding the changes in mitochondrial DNA and finding ways to promote mitochondrial biogenesis rather than simply relying on supplements to improve mitochondrial function.

    • Metformin: A Versatile Diabetes Drug with Potential Health BenefitsMetformin, besides its role in diabetes management, shows promise in reducing the risk of prostate cancer, breast cancer, and inflammation. Its ability to selectively target specific organs holds therapeutic potential.

      Metformin, an anti-diabetic drug, has demonstrated potential in reducing the risk of prostate cancer, breast cancer, and inflammation. It achieves these effects by inhibiting mitochondrial function to a certain extent, activating stress responses that can fight off diseases. Metformin also lowers glucose production in the liver and has anticancer properties. Despite its wide usage and safety record, the precise mechanisms through which Metformin works are not fully understood. The drug's discovery originated from observing goats that were eating a specific plant in France. Metformin's tissue specificity seems to favor hepatocytes and does not significantly affect the heart. Its ability to selectively target certain organs, like the liver, potentially opens up possibilities for therapeutic applications.

    • Metformin's Effects on Liver, Colon, and Immune CellsMetformin primarily works by reducing glucose production in the liver, affecting the microbiome in the colon, and potentially causing inflammation in immune cells. It also promotes autophagy and downregulates glucose production and lipogenesis in the liver.

      Metformin has multiple effects on the body, including its impact on the liver, colon, and immune cells. It primarily works by shutting down glucose production in the liver and affecting the microbiome in the colon. Additionally, metformin can enter immune cells, such as macrophages, potentially causing high levels of inflammation. One common factor among metformin and other drugs like aspirin and statins is inflammation. Metformin also has anti-inflammatory properties that may be beneficial for certain physiological functions. It blocks complex 1 in the mitochondria, reducing potential energy in electrons and activating a cellular kinase called AMPK. This activation promotes autophagy and signals a decrease in energy levels, leading to various physiological responses, such as the downregulation of glucose production and lipogenesis in the liver. The NAD to NADH ratio is also impacted by metformin, which can be transmitted back to the cell through various mechanisms. Overall, metformin's effects are complex and encompass multiple pathways and cellular processes.

    • Understanding the Importance of NADH to NAD ratio in Medication and Metabolic EffectsMetformin, a common diabetes medication, reduces NAD levels, leading to decreased glucose production and explaining its anti-diabetic properties. Delving into NAD metabolism is crucial for informed decisions in healthcare.

      Understanding the NADH to NAD ratio is crucial in grasping the effects of certain medications and metabolic processes. The conversation highlights how metformin, a medication commonly used to treat diabetes, inhibits complex 1 and slows down the conversion of NADH to NAD. This reduction in NAD availability has implications for various cellular functions, including gluconeogenesis. It is revealed that metformin decreases glucose production due to the decrease in NAD levels. This knowledge helps explain the anti-diabetic properties of metformin. Furthermore, the conversation alludes to a research paper that demonstrates the liver's ability to uptake precursors to NAD, but their inability to reach the cells. In order to make informed decisions about medications and metabolic processes, it is essential to delve into the intricacies of NAD metabolism.

    • The Importance of NAD and NADH Ratio in Biological ProcessesMaintaining the balance between NAD and NADH is crucial for optimal biological functions, and while supplements can increase NAD levels, they do not significantly affect the NAD to NADH ratio. Further research is needed to understand the effects of metformin and its benefits.

      The quantity of NAD and the ratio of NAD to NADH are both important factors in biological processes. While supplements can increase the absolute amount of NAD, they do not significantly change the NAD to NADH redox ratio. As we age, NAD ratios decline in the mitochondria, and this decline may impact complex 1 activity. Metformin, a drug commonly used for diabetes, lowers the NAD to NADH ratio, similar to what naturally occurs with aging. Boosting mitochondria may not be the best approach if the decline in NAD is adaptive. However, using metformin can stress out the mitochondria and activate adaptive responses. Further research is needed to determine the full effects of metformin and whether complex 1 inhibition is necessary for its various benefits.

    • The Mechanism of Action of Metformin in Cancer TreatmentMetformin's anticancer effects are linked to inhibiting complex 1 and activating the TCA cycle, highlighting its potential therapeutic role in cancer treatment.

      Metformin's anticancer properties may be linked to its ability to inhibit complex 1 and activate the TCA cycle. In laboratory settings, metformin has shown the potential to reduce tumor burden in mice. However, it was unclear if these benefits were solely due to complex 1 inhibition or if other mechanisms, such as AMPK activation, were also involved. Through experiments using cancer cells, it was demonstrated that when metformin cannot bind to complex 1, its anticancer effects cease to exist. The NAD to NADH ratio and metabolomic profiling further supported this finding. Additionally, studies in human cancer patients confirmed the altered TCA cycle metabolites when metformin was administered. This information provides insights into metformin's potential role in cancer treatment.

    • Exploring Complex 1 Inhibition for Cancer TherapyTargeting complex 1 inhibition, specifically with metformin, shows promise in cancer therapy. However, further research is needed to understand the broader implications and potential dietary choices for effective treatment.

      Targeting mitochondria inhibition may be a potential strategy for cancer therapy. The discussion highlights the importance of complex 1 inhibition and its potential anticancer effects. Metformin, a drug that lowers glucose, insulin, and IGF, shows promising results in inhibiting complex 1. However, it is crucial to distinguish between tumor-specific effects and global metabolic impacts to understand the broader implications for cancer treatment and dietary choices. The conversation also sheds light on the significance of mitochondria and their role in tumor genesis, challenging previous beliefs. This contrarian viewpoint suggests that mitochondrial function is necessary for tumor formation. Overall, this discussion calls for further research and exploration of complex 1 inhibitors as a potential avenue for cancer therapy.

    • The Role of Glycolysis and Mitochondrial Respiration in Cancer MetabolismCancer cells rely on glycolysis not only for energy production but also to increase the availability of building blocks for cell division. However, mitochondrial respiration still plays a significant role in tumor formation, emphasizing the need for understanding both processes for effective treatment strategies.

      The Warburg effect, which states that cancer cells rely on glycolysis rather than mitochondrial respiration, may not solely be driven by energetic reasons but also by the need for building blocks for cell growth. While Otto Warburg believed that cancer cells switch to glycolysis to optimize energy production, recent research suggests that it is actually a strategy to increase the availability of building blocks for cell division. However, it is important to note that mitochondrial respiration still plays a significant role in tumor genesis. Genetic experiments have shown that when respiratory function is knocked out, tumors become smaller, indicating the necessity of mitochondria in tumor formation. This highlights the complexity of cancer metabolism and the importance of understanding the role of both glycolysis and mitochondrial respiration in developing effective treatment strategies.

    • Importance of Correlation versus Causality in Complex DiseasesUnderstanding the difference between correlation and causality is crucial in medicine, as complex diseases have multiple underlying factors and a causal factor may not be necessary or sufficient for a disease to occur.

      In biology, there are often things that are necessary for a certain outcome, but not sufficient on their own. The conversation highlighted the importance of understanding correlation versus causality and the complexity of diseases like cancer and Alzheimer's. It emphasized that while something may be causal, it doesn't necessarily mean it is necessary or sufficient for a disease to occur. This understanding is crucial in the field of medicine, where misconceptions can arise when people forget the logic taught in basic science classes. Complex diseases have multiple underlying factors, and even if causality can be inferred, it may not be clear whether a certain factor is adaptive or maladaptive.

    • Targeting mitochondria in cancer treatment: A promising approach with challenges in drug development and compatibility with immunotherapy.Inhibiting the respiratory chain in mitochondria can decrease tumor formation, but finding a therapeutic window for effective targeting of cancer cells without toxicity in other organs remains a challenge. Further research and clinical trials are needed.

      There is a growing interest in targeting mitochondria in cancer treatment. The initial paper by Navdeep Chandel and his team faced challenges getting published due to a lack of focus on mitochondria, which led to misconceptions about the role of glycolysis in cancer. However, further research has shown that inhibiting the respiratory chain in mitochondria can decrease tumor formation. Currently, there are potentially two drugs that target mitochondria, including a complex one inhibitor and an alpha keto TCA cycle enzyme inhibitor. The challenge now is to find a therapeutic window where these drugs can effectively target cancer cells without causing toxicity in other organs. Additionally, the compatibility of these drugs with immunotherapy is still under investigation. There is promising potential in this area, but further research and clinical trials are needed.

    • A multi-pronged approach for effective cancer treatmentCombating cancer requires a combination of therapies targeting different vulnerabilities of the tumor, such as mitochondrial function and immunotherapy, emphasizing the need for a comprehensive and adaptable strategy.

      A multi-pronged approach is necessary for effective cancer treatment. Both Navdeep Chandel and Peter Attia agree that relying on a single modality of therapy is not sufficient to combat cancer. Instead, they advocate for a combination of therapies that target different vulnerabilities of the tumor. Chandel suggests that attacking mitochondrial function, either through BRAF inhibitors or cisplatin, may be effective during a specific phase of tumor growth. Attia highlights the potential of immunotherapy, which he considers the most elegant approach to cancer treatment. He suggests that weakening the tumor with successive blows and making it more identifiable from an immune perspective may enhance the effectiveness of immunotherapy. Overall, this conversation underscores the importance of a comprehensive and adaptable strategy in combating cancer.

    • Metformin's Impact on Mitochondrial Function and Cancer DevelopmentMetformin's role in extending lifespan may not be solely due to its inhibition of mitochondrial function. It may also have anti-inflammatory properties and disrupt cancer cells' reliance on robust mitochondrial function. Inhibiting the TCA cycle could potentially be a treatment strategy for certain cancers. The effectiveness of antioxidants in aging and disease prevention is uncertain.

      The inhibition of complex 1, which inhibits mitochondrial function, may not be the reason why metformin makes you live longer. It could be that metformin survives despite inhibiting complex 1, not because of it. Additionally, it is argued that metformin is anti-inflammatory. Cancer cells rely on a robust mitochondrial function, and if that function is disrupted, tumors may not form. While there are rare cancers with TCA cycle mutations, they are exceptions rather than the rule. Viral research suggests that cancer is primarily caused by nuclear DNA rather than mitochondrial DNA. Inhibiting the TCA cycle could potentially be a treatment strategy for certain cancers. The ultimate proof would be to inhibit the TCA cycle and assess the impact on immunotherapy or chemotherapy. The effectiveness of antioxidants in aging and disease prevention remains inconclusive.

    • The Benefits and Risks of Consuming AntioxidantsConsuming natural antioxidants from fruits like oranges can support gene expression and enzyme function. However, excessive intake or high-dose supplements may not be necessary. Cancer patients should be cautious with antioxidants, and further research is needed to understand the full relationship.

      Consuming natural quantities of antioxidants in our food can have benefits for our health. While there may not be a significant benefit in taking antioxidant supplements, eating fruits like oranges, which contain antioxidants like vitamin C, can support proper gene expression and enzyme function. The recommended intake is about one orange a day or a glass of orange juice. It is not necessary to consume excessive amounts of oranges or high-dose supplements. Additionally, the conversation also touches on the suggestion that cancer patients may need to avoid antioxidants, as some trials have shown negative effects. However, more research is needed to fully understand this relationship. Personal biases aside, it is important to evaluate the balance between benefits and risks when considering supplementation.

    • The Potential Anti-inflammatory Effects of MetforminMetformin has the potential to reduce inflammation over time by inhibiting the respiratory chain, lowering the production of reactive oxygen species and cytokines. This could be particularly beneficial for individuals living in highly polluted areas.

      Metformin may have potential anti-inflammatory effects and could be beneficial in reducing inflammation over a long period of time. Metformin works by inhibiting the respiratory chain, which decreases the production of reactive oxygen species and cytokines. Lowering inflammation has been shown to have wonderful health benefits, as seen in trials targeting pro-inflammatory agents. However, the data on the immune-modulating or inflammatory-modulating benefits of metformin is relatively limited at this point. Additionally, metformin may be particularly beneficial for individuals living in highly polluted areas like Beijing or Delhi, where pollution is known to increase inflammation. Overall, while metformin's anti-inflammatory properties are still being studied, it may hold promise as an agent for reducing inflammation and potentially slowing down the aging process.

    • Boosting NAD Levels and Gene Regulation in AgingIncreasing NAD levels can restore sirtuin activity and improve gene regulation, potentially reducing inflammation and promoting metabolic health.

      Boosting NAD levels can have important benefits, especially for aging and gene regulation. The de novo pathway, along with precursors given to cells, allows for increased NAD production and its transportation to the mitochondria. NAD serves as a crucial co factor for sirtuins, which control gene expression. As NAD levels decline with aging, there is a loss of sirtuin activity and the ability to regulate gene expression. By increasing NAD levels, it is possible to restore some sirtuin activity and improve gene regulation. These NAD supplements have the potential to reach various tissues, including the liver and immune cells, where they can have metabolically healthy effects and potentially reduce inflammation.

    • The potential connection between supplements, immune cells, and inflammation.While there is a potential link between supplements and immune cells as anti-inflammatory agents, it is still uncertain if these supplements can effectively deliver necessary nutrients intravenously and the potential benefits may not outweigh potential harm.

      There is a potential connection between supplements working as mild anti-inflammatory agents and immune cells. The enzyme CD38, which affects NAD levels, is most abundant on immune cells, suggesting an immune connection. However, it's still uncertain if NAD can be effectively delivered to the cells intravenously. The NAD to NADA ratio and the role of coenzyme Q (co q) in antioxidant function are also discussed. Mito Queue, a version of co q with a cation attached to it, may increase its affinity for cells but has a narrow therapeutic window. Overall, the availability and potential benefits of antioxidants like co q remain uncertain and may not outweigh potential harm.

    • Metabolite Toxicity: A New Perspective on Disease MechanismsIncreased levels of certain metabolites, such as L2AG, can contribute to major pathology in diseases like neurodegeneration and diabetes. Exploring metabolite toxicity opens doors for potential therapeutic interventions.

      There is a possibility of metabolite toxicity in various diseases, such as neurodegeneration and diabetes. While the prevailing theory focuses on protein misfolding and aggregation, the idea of metabolites reaching pathological levels and causing harm is gaining attention. Evidence from genetic mutations and altered metabolic pathways supports the notion that certain metabolites can lead to major pathology. By screening metabolites in mice, rats, and humans, researchers can identify potential signatures of metabolite toxicity. One specific metabolite of interest is L2 hydroxyglutarate (L2AG), which has been associated with neuropathology. This alternative perspective on disease mechanisms provides an avenue for further exploration and potential therapeutic interventions.

    • The role of metabolite L2AG and dysfunctional mitochondria in diseases like Parkinson's and the complex challenge of understanding metabolomics.Understanding the impact of specific metabolites, like L2AG, on mitochondrial function is a promising approach in identifying potential links to diseases and pathologies. Excessive stress and regimentation may also impact overall health.

      The ratio between NADH and NAD levels plays a crucial role in the production of L2AG. Under certain physiological conditions like hypoxia, L2AG levels increase and act as a signaling molecule. Dysfunctional mitochondria, specifically the loss of complex one, have been correlated with diseases like Parkinson's, where L2AG levels are elevated. Furthermore, the conversation highlights the potential link between metabolites and pathologies. However, the identification of specific patterns and variables within metabolomics remains a complex challenge. Despite this complexity, focusing on understanding the impact of specific metabolites, like L2AG, tied to mitochondrial function is a promising approach. Additionally, the discussion touches upon the potential interaction between cortisol and mitochondria, suggesting that stress and excessive regimentation may impact overall health.

    • The Importance of Managing Cortisol Levels for Overall HealthManaging stress and cortisol levels is essential for maintaining good health, as high levels of cortisol can lead to negative effects on sleep, blood pressure, and overall well-being.

      Cortisol, the stress hormone, plays a significant role in our overall health and should not be overlooked. While many people focus on controlling their diet and exercise, managing stress is equally important. High levels of cortisol can lead to various negative effects, including increased blood pressure, impaired sleep, and inhibition of melatonin secretion. It may even impact the mitochondria and affect neuro-regeneration. Therefore, it is crucial to pay attention to cortisol levels and find effective ways to cope with stress. Understanding our individual response to stress and finding ways to manage it can greatly improve our overall well-being.

    • The underestimated impact of stress on health and the potential toxicity of alcohol.Meditation can help regulate stress levels, while alcohol should be consumed in moderation due to its potential liver toxicity. It is important to understand and prioritize overall health and the significance of metabolism science.

      Stress and cortisol levels are often overlooked in discussions about health and longevity. While many people focus on insulin, glucose levels, and testosterone, the impact of stress on our bodies is underestimated and not well understood. There is a lack of target and pharmacologic ways to manipulate cortisol levels, and measuring cortisol levels is not easily accessible. However, meditation has been found to be a valuable tool in regulating stress. Additionally, the discussion touches on the consumption of alcohol and its potential toxicity. While alcohol can be enjoyable in moderation, there is no dose of ethanol where it becomes valuable, and its hepatic toxicity should not be ignored. Finally, this conversation highlights the interest and fascination people have with metabolism science and the importance of sharing its significance in promoting overall health.

    • Navigating social situations and questioning research studies are crucial skills.Creative approaches to social interactions and critical thinking in evaluating research studies are valuable skills in personal and professional contexts.

      Both Navdeep Chandel and Peter Attia have found clever ways to avoid discussing their professions at social events. Peter Attia, an introvert, creates alter egos to leave people hanging and divert the conversation elsewhere. On the other hand, Navdeep Chandel, as an extrovert, still gives an answer about the Mediterranean diet but adds his personal touch by mentioning curry. However, the conversation also touches upon the Pradimed study, which evaluated the impact of different diets on patients and found that the Mediterranean diet with high levels of extra virgin olive oil and nuts outperformed the low-fat diet. However, there were concerns about randomization and potential biases in the study. Overall, the key takeaway is that finding creative ways to navigate social situations and being critical of research studies are important skills in both personal and professional settings.

    • Importance of Study Design and Diet Descriptions in Validity of ResultsThe design of diet studies, including proper randomization and clear definitions of diets, is crucial for reliable results and meaningful dietary recommendations.

      The design and implementation of diet studies play a crucial role in determining the validity of their results. In the case of the predimed study, it was found that certain patients were not randomized correctly, which can introduce biases into the outcomes. However, even when accounting for these inconsistencies, the overall results of the study were not significantly changed. The conversation also highlights the need for more specific descriptions of diets, such as the Mediterranean diet, which may vary across different regions. Additionally, the discussion touches upon the potential benefits and drawbacks of high protein, high carb, and ketogenic diets, emphasizing the importance of understanding the context and long-term effects of insulin resistance. Overall, careful study design and clear terminology are essential for reliable and meaningful dietary recommendations.

    • The significance of fasting and calorie deprivation for longer periods of time in achieving optimal well-being.Focusing on complete calorie deprivation and incorporating a 15-hour daily fast can have significant benefits for overall health and exploring different aspects of nutrition and metabolism is crucial for well-being.

      Both Peter Attia and Navdeep Chandel emphasize the importance of fasting and calorie deprivation for longer periods of time. They believe that fixating less on the exact amount of specific macronutrients and focusing more on complete calorie deprivation can have significant benefits. Additionally, they discuss the importance of incorporating a 15-hour daily fast into their eating habits. While Navdeep consumes a fair amount of protein, they acknowledge the need to possibly lower it. The conversation also highlights the importance of being knowledgeable about metabolism and mitochondria, as they play a crucial role in overall health. Overall, this conversation underscores the significance of exploring different aspects of nutrition and metabolism for optimal well-being.

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    • Finasteride for treating hair loss: efficacy, potential side effects on libido, and the need for careful PSA monitoring in men to avoid missing early signs of prostate cancer [37:15];
    • Other effective hair loss treatments for women: boosting hair density with spironolactone gel and ketoconazole shampoo as part of a comprehensive strategy [41:30];
    • Low-level laser therapy: effectiveness, costs, practicality, and a comparison of in-office treatments with at-home devices [49:00];
    • Platelet-rich plasma (PRP) as a treatment for hair loss: potential effectiveness, varying protocols, and significant costs [53:45];
    • Hair transplant for advanced hair loss: criteria and considerations [58:00];
    • Types of hair transplants: follicular unit transplantation (FUT) vs. follicular unit extraction (FUE) [1:02:00];
    • The financial cost of hair transplant surgery, and what to consider when seeking affordable options [1:06:15];
    • The potential risks and downsides of the various hair transplant procedures [1:09:30];
    • Post-procedure care for hair transplants and whether the procedure must be repeated periodically [1:16:30];
    • Combining different hair loss treatments: benefits, risks, and considerations [1:18:30];
    • Emerging hair loss treatments with limited data [1:21:00];
    • Key considerations for selecting the right treatment plan for hair loss [1:22:00];
    • A summary of the different considerations for men and women facing hair loss [1:24:30];
    • Practical advice on selecting the right specialist or treatment team [1:26:15]; and
    • More.

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    The Peter Attia Drive
    enSeptember 09, 2024

    Improve your decision-making, frameworks for learning, backcasting, and more | Annie Duke (#60 rebroadcast)

    Improve your decision-making, frameworks for learning, backcasting, and more | Annie Duke (#60 rebroadcast)

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    In this episode, former World Series of Poker champion and author Annie Duke explains how poker is a pertinent model system for decision-making in the real world, a system which blends imperfect information with some unknown percentage of both luck and skill. Annie breaks down the decision-making matrix, revealing how we often focus too narrowly on just one of the four quadrants, missing out on valuable learning opportunities in the remaining 75% of situations. She delves into how our tendency to evaluate only negative outcomes leads to a culture of risk aversion. This mindset, she argues, stifles the kind of bold decision-making necessary for progress and innovation across various fields, from poker and sports to business and medicine. Annie also introduces a robust framework for learning and the levels of thought required to excel in any domain. Finally, she discusses a strategy called “backcasting”, a concept that resonated deeply with Peter in terms of how he thinks about extending healthspan.

    We discuss:

    • Annie’s background, favorite sports teams, and Peter’s affinity for Bill Belichick [1:30];
    • Chess vs. poker: Which is a better metaphor for decision-making in life (and medicine)? [6:45];
    • Thinking probabilistically: Why we aren’t wired that way, and how you can improve it for better decision-making [12:30];
    • Variable reinforcement: The psychological draw of poker that keeps people playing [19:15];
    • The role of luck and skill in poker (and other sports), and the difference between looking at the short run vs. long run [32:15];
    • A brief explanation of Texas hold ‘em [41:00];
    • The added complexity of reading the behavior of others players in poker [47:30];
    • Why Annie likes to “quit fast,” and why poker is still popular despite the power of loss aversion [52:45];
    • Limit vs. no-limit poker, and how the game has changed with growing popularity [55:15];
    • The advent of analytics to poker, and why Annie would get crushed against today’s professionals [1:04:45];
    • The decision matrix, and the “resulting” heuristic: The simplifier we use to judge the quality of decisions —The Pete Carroll Superbowl play call example [1:10:30];
    • The personal and societal consequences of avoiding bad outcomes [1:21:45];
    • Poker as a model system for life [1:31:30];
    • How many leaders are making (and encouraging) status-quo decisions, and how Bill Belichick’s decision-making changed after winning two Super Bowls [1:35:15];
    • What did we learn about decision-making from the Y2K nothingburger? And how about the D-Day invasion? [1:39:30];
    • The first step to becoming a good decision maker [1:43:00];
    • The difference between elite poker players and the ones who make much slower progress [1:49:45];
    • Framework for learning a skill, the four levels of thought, and why we hate digging into our victories to see what happened [1:52:15];
    • The capacity for self-deception, and when it is MOST important to apply four-level thinking [2:00:30];
    • Soft landings: The challenge of high-level thinking where there is subtle feedback and wider skill gaps [2:11:00];
    • The benefits of “backcasting” (and doing pre-mortems) [2:13:30];
    • Parting advice from Annie for those feeling overwhelmed (and two book recommendations) [2:21:30]; and
    • More.

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    The Peter Attia Drive
    enSeptember 02, 2024

    #315 ‒ Life after near-death: a new perspective on living, dying, and the afterlife | Sebastian Junger

    #315 ‒ Life after near-death: a new perspective on living, dying, and the afterlife | Sebastian Junger

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    Sebastian Junger is an award-winning journalist, bestselling author, and previous guest on The Drive. In this episode, Sebastian returns to discuss his latest book, In My Time of Dying: How I Came Face to Face with the Idea of an Afterlife. This episode delves into Sebastian's profound near-death experience and how it became the catalyst for his exploration of mortality, the afterlife, and the mysteries of the universe. They discuss the secular meaning of what it means to be sacred, the intersection of physics and philosophy, and how our beliefs shape our approach to life and death. He also shares how this experience has profoundly changed him, giving him a renewed perspective on life—one filled with awe, gratitude, deeper emotional awareness, and a more engaged approach to living.

    We discuss:

    • How Sebastian’s near-death experience shaped his thinking about mortality and gave him a reverence for life [3:00];
    • The aneurysm that led to Sebastian’s near-death experience [6:30];
    • Emergency room response, his subsequent reflections on the event, and the critical decisions made by the medical team [16:30];
    • Sebastian’s reaction to first learning he nearly died, and the extraordinary skill of the medical team that save his life [26:00];
    • Sebastian’s near-death experience [37:00];
    • The psychological impact of surviving against overwhelming odds [48:00];
    • Ignored warning signs: abdominal pain and a foreshadowing dream before the aneurysm rupture [54:30];
    • Sebastian's recovery, his exploration of near-death experiences, and the psychological turmoil he faced as he questioned the reality of his survival [58:15];
    • A transformative encounter with a nurse who encouraged Sebastian to view his near-death experience as sacred [1:03:30];
    • How Sebastian has changed: a journey toward emotional awareness and fully engaging with life [1:08:45];
    • The possibility of an afterlife, and how quantum mechanics challenges our understanding of existence [1:15:15];
    • Quantum paradoxes leading to philosophical questions about the nature of reality, existence after death, and whether complete knowledge could be destructive [1:26:00];
    • The sweet spot of uncertainty: exploring belief in God, post-death existence, and meaning in life [1:37:00];
    • The transformative power of experiencing life with awe and gratitude [1:53:00]; and
    • More.

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    The Peter Attia Drive
    enAugust 26, 2024

    #314 ‒ Rethinking nutrition science: the evolving landscape of obesity treatment, GLP-1 agonists, protein, and the need for higher research standards | David Allison, Ph.D.

    #314 ‒ Rethinking nutrition science: the evolving landscape of obesity treatment, GLP-1 agonists, protein, and the need for higher research standards | David Allison, Ph.D.

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    David Allison, a leading expert in obesity and nutrition, quantitative genetics, clinical trials, and research methodology, returns to The Drive to explore the evolving landscape of nutrition science and obesity treatment. In this episode, David begins by discussing the intricate relationship between nutrition, obesity, and body composition, emphasizing the multifaceted impacts of food beyond mere calorie intake. David provides a critical analysis of the complexities in nutrition research and their practical implications for tackling obesity. He critiques historical public health policies, addresses the trust issues plaguing nutrition science, and underscores the need for a paradigm shift to more effectively combat obesity. The conversation also delves into the rise of GLP-1 receptor agonists like Ozempic and Mounjaro, exploring their ethical and practical considerations in obesity treatment. The episode concludes with an in-depth look at protein intake recommendations and highlights the significant research gaps that remain in the field.

    We discuss:

    • The complex relationship between nutrition, body weight, and body composition [2:30];
    • The slow progress in addressing obesity and public health despite substantial effort and investment [7:30];
    • The very limited success of public health initiatives in curbing obesity [17:15];
    • The evolving landscape of obesity research: public health initiatives and the impact of pharmacological success [26:30];
    • Rethinking obesity solutions: the need for a paradigm shift [32:45];
    • Understanding environmental triggers and embracing a balanced approach to addressing obesity that includes both pharmacological treatments and realistic lifestyle changes [41:45];
    • The need for higher standards in obesity research [51:45];
    • The rapid success of GLP-1 receptor agonists for weight loss: a discussion on the societal impact and controversy of their growing usage [1:02:15];
    • The ethical and practical considerations of obesity drugs: risks, benefits, and motivations for usage [1:11:30];
    • The use of GLP-1 agonists by athletes as performance enhancers [1:23:45];
    • Unanswered questions about protein intake and health [1:30:45];
    • Future research needed to understand basic questions around protein intake [1:45:00];
    • David’s weekly newsletter: “Obesity and Energetics Offerings” [1:50:45]; and
    • More.

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    The Peter Attia Drive
    enAugust 19, 2024

    #313 - AMA #62: Protein’s impact on appetite and weight management, and uric acid's link to disease and how to manage levels

    #313 - AMA #62: Protein’s impact on appetite and weight management, and uric acid's link to disease and how to manage levels

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    In this “Ask Me Anything” (AMA) episode, Peter dives into two important health topics: uric acid and protein, examining them from unique perspectives. For uric acid, he explores its metabolic role and connection to various diseases, focusing on the potential causal link with cardiovascular disease. He also discusses factors influencing uric acid levels, such as diet, genetics, and lifestyle, providing practical tips for effective management. Shifting to protein, Peter delves into its role in appetite and weight management, the consequences of insufficient protein, and the “protein leverage hypothesis” linking protein deficiency to obesity. He covers optimal protein intake and its impact on energy expenditure, and he compares the satiety effects of solid versus liquid protein. Finally, Peter shares his strategy for incorporating protein into a comprehensive weight management plan.

    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 #62 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

    We discuss:

    • Overview of episode topics (and an important discussion on fanny packs) [2:00];
    • Understanding uric acid: its role in metabolic processes, its association with gout and kidney stones, its impact on blood pressure, and more [6:00];
    • Non-modifiable factors that influence uric acid levels [11:00];
    • Modifiable factors that influence uric acid levels [14:15];
    • Association between high uric acid levels and cardiovascular disease [20:00];
    • Evidence suggesting a causal link between high uric acid levels and cardiovascular disease [24:00];
    • Inconclusive evidence about the cardiovascular benefits of lowering uric acid pharmacologically [28:15];
    • Exploring the potential risks of low uric acid levels in neurodegenerative diseases [37:00];
    • Managing uric acid levels: dietary interventions and pharmacological approaches [42:00];
    • The impact of protein on appetite and weight management [44:00];
    • The consequences of insufficient protein on eating behaviors and satiety [52:15];
    • The relationship between protein deficiency and obesity: exploring the “protein leverage hypothesis” [57:15];
    • The impact of protein intake on energy expenditure [1:02:15];
    • Determining optimal protein intake to avoid deficiency and support health [1:05:45];
    • The role of different amino acids and protein sources in promoting satiety [1:08:15];
    • Comparing the satiety effects of solid vs. liquid protein sources [1:10:30];
    • Peter’s framework for incorporating protein intake into a strategy for controlling body weight [1:12:00]; and
    • More.

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    The Peter Attia Drive
    enAugust 12, 2024

    #312 - A masterclass in lactate: Its critical role as metabolic fuel, implications for diseases, and therapeutic potential from cancer to brain health and beyond | George A. Brooks, Ph.D.

    #312 - A masterclass in lactate: Its critical role as metabolic fuel, implications for diseases, and therapeutic potential from cancer to brain health and beyond | George A. Brooks, Ph.D.

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    George A. Brooks is a renowned professor of integrative biology at UC Berkeley. Known for his groundbreaking "lactate shuttle" theory proposed in the 1980s, George revolutionized our understanding of lactate as a crucial fuel source rather than just a byproduct of exercise. In this episode, George clarifies common misconceptions between lactate and lactic acid, delves into historical perspectives, and explains how lactate serves as a fuel for the brain and muscles. He explores the metabolic differences in exceptional athletes and how training impacts lactate flux and utilization. Furthermore, George reveals the significance of lactate in type 2 diabetes, cancer, and brain injuries, highlighting its therapeutic potential. This in-depth conversation discusses everything from the fundamentals of metabolism to the latest research on lactate's role in gene expression and therapeutic applications.

    We discuss:

    • Our historical understanding of lactate and muscle metabolism: early misconceptions and key discoveries [3:30];
    • Fundamentals of metabolism: how glucose is metabolized to produce ATP and fuel our bodies [16:15];
    • The critical role of lactate in energy production within muscles [24:00];
    • Lactate as a preferred fuel during high-energy demands: impact on fat oxidation, implications for type 2 diabetes, and more [30:45];
    • How the infusion of lactate could aid recovery from traumatic brain injuries (TBI) [43:00];
    • The effects of exercise-induced lactate [49:30];
    • Metabolic differences between highly-trained athletes and insulin-resistant individuals [52:00];
    • How training enhances lactate utilization and facilitates lactate shuttling between fast-twitch and slow-twitch muscle fibers [58:45];
    • The growing recognition of lactate and monocarboxylate transporters (MCT) [1:06:00];
    • The intricate pathways of lactate metabolism: isotope tracer studies, how exceptional athletes are able to utilize more lactate, and more [1:09:00];
    • The role of lactate in cancer [1:23:15];
    • The role of lactate in the pathophysiology of various diseases, and how exercise could mitigate lactate's carcinogenic effects and support brain health [1:29:45];
    • George’s current research interests involving lactate [1:37:00];
    • Questions that remain about lactate: role in gene expression, therapeutic potential, difference between endogenous and exogenous lactate, and more [1:50:45]; and
    • More.

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    The Peter Attia Drive
    enAugust 05, 2024

    #311 ‒ Longevity 101: a foundational guide to Peter's frameworks for longevity, and understanding CVD, cancer, neurodegenerative disease, nutrition, exercise, sleep, and more

    #311 ‒ Longevity 101: a foundational guide to Peter's frameworks for longevity, and understanding CVD, cancer, neurodegenerative disease, nutrition, exercise, sleep, and more

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    In this special episode, Peter provides a comprehensive introduction to longevity, perfect for newcomers or those looking to refresh their knowledge. He lays out the foundational concepts of lifespan, healthspan, and the marginal decade. Additionally, Peter discusses the four main causes of death and their prevention, as well as detailing the five key strategies in his longevity toolkit to improve lifespan and healthspan. Detailed show notes provide links for deeper exploration of these topics, making it an ideal starting point for anyone interested in understanding and improving their longevity.

    We discuss:

    • Key points about starting exercise as an older adult [2:45];
    • Overview of episode topics and structure [1:45];
    • How Peter defines longevity [3:45];
    • Why healthspan is a crucial component of longevity [11:15];
    • The evolution of medicine from medicine 1.0 to 2.0, and the emergence of medicine 3.0 [15:30];
    • Overview of atherosclerotic diseases: the 3 pathways of ASCVD, preventative measures, and the impact of metabolic health [26:00];
    • Cancer: genetic and environmental factors, treatment options, and the importance of early and aggressive screening [33:15];
    • Neurodegenerative diseases: causes, prevention, and the role of genetics and metabolic health [39:30];
    • The spectrum of metabolic diseases [43:15];
    • Why it’s never too late to start thinking about longevity [44:15];
    • The 5 components of the longevity toolkit [46:30];
    • Peter’s framework for exercise—The Centenarian Decathlon [47:45];
    • Peter’s nutritional framework: energy balance, protein intake, and more [58:45];
    • Sleep: the vital role of sleep in longevity, and how to improve sleep habits [1:08:30];
    • Drugs and supplements: Peter’s framework for thinking about drugs and supplements as tools for enhancing longevity [1:13:30];
    • Why emotional health is a key component of longevity [1:17:00];
    • Advice for newcomers on where to start on their longevity journey [1:19:30]; and
    • More.

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    The Peter Attia Drive
    enJuly 29, 2024

    #310 - The relationship between testosterone and prostate cancer, testosterone replacement therapy, and tools for predicting cancer aggressiveness and guiding therapy | Ted Schaeffer, M.D., Ph.D.

    #310 - The relationship between testosterone and prostate cancer, testosterone replacement therapy, and tools for predicting cancer aggressiveness and guiding therapy | Ted Schaeffer, M.D., Ph.D.

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    Ted Schaeffer is an internationally recognized urologist specializing in prostate cancer and a returning guest on The Drive. In this episode, Ted provides insights into the role testosterone plays, or doesn't play, in the initiation and progression of prostate cancer. He unpacks the findings and limitations of the recent TRAVERSE trial, exploring the complex relationship between testosterone and prostate cancer. Ted delves into the molecular nature of prostate cancer, explaining the androgen receptor saturation theory and the potential impact of testosterone on cancer growth. He also discusses the use of the Decipher test to predict cancer aggressiveness and guide targeted treatment. Furthermore, Ted shares how he counsels patients regarding testosterone replacement therapy (TRT), including its safe administration in patients with low-grade prostate cancer. Additionally, he highlights advancements in prostate cancer therapies and biomarkers that help develop precise treatment strategies while minimizing the need for broad androgen deprivation therapy.

    We discuss:

    • Background on the TRAVERSE trial: insights into exogenous testosterone and prostate cancer risk [3:00];
    • The androgen receptor saturation theory: how different organs respond to varying levels of testosterone [10:30];
    • The relationship between testosterone levels and prostate cancer aggressiveness: how aggressive prostate tumors have lower androgen receptor activity and rely on different growth mechanisms [16:15];
    • Using the Decipher score to assess prostate cancer aggressiveness and guide personalized treatment strategies [23:45];
    • Considerations for testosterone replacement therapy: how Ted counsels patients, how TRT can be safely administered in patients with low-grade prostate cancer, and more [31:15];
    • Advancements in prostate cancer therapies and PSA as a biomarker for precise treatment decisions, minimizing the need for broad androgen deprivation therapy [38:30]; and
    • More.

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    The Peter Attia Drive
    enJuly 22, 2024

    #309 ‒ AI in medicine: its potential to revolutionize disease prediction, diagnosis, and outcomes, causes for concern in medicine and beyond, and more | Isaac Kohane, M.D., Ph.D.

    #309 ‒ AI in medicine: its potential to revolutionize disease prediction, diagnosis, and outcomes, causes for concern in medicine and beyond, and more | Isaac Kohane, M.D., Ph.D.

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    Isaac "Zak" Kohane, a pioneering physician-scientist and chair of the Department of Biomedical Informatics at Harvard Medical School, has authored numerous papers and influential books on artificial intelligence (AI), including The AI Revolution in Medicine: GPT-4 and Beyond. In this episode, Zak explores the evolution of AI, from its early iterations to the current third generation, illuminating how it is transforming medicine today and unlocking astonishing possibilities for the future. He shares insights from his unconventional journey and early interactions with GPT-4, highlighting significant AI advancements in image-based medical specialties, early disease diagnosis, and the potential for autonomous robotic surgery. He also delves into the ethical concerns and regulatory challenges of AI, its potential to augment clinicians, and the broader implications of AI achieving human-like creativity and expertise.

    We discuss:

    • Zak’s unconventional journey to becoming a pioneering physician-scientist, and his early interactions with GPT-4 [2:15];
    • The evolution of AI from the earliest versions to today’s neural networks, and the shifting definitions of intelligence over time [8:00];
    • How vast data sets, advanced neural networks, and powerful GPU technology have driven AI from its early limitations to achieving remarkable successes in medicine and other fields [19:00];
    • An AI breakthrough in medicine: the ability to accurately recognize retinopathy [29:00];
    • Third generation AI: how improvements in natural language processing significantly advanced AI capabilities [32:00];
    • AI concerns and regulation: misuse by individuals, military applications, displacement of jobs, and potential existential concerns [37:30];
    • How AI is enhancing image-based medical specialties like radiology [49:15];
    • The use of AI by patients and doctors [55:45];
    • The potential for AI to augment clinicians and address physician shortages [1:02:45];
    • The potential for AI to revolutionize early diagnosis and prediction of diseases: Alzheimer’s disease, CVD, autism, and more [1:08:00];
    • The future of AI in healthcare: integration of patient data, improved diagnostics, and the challenges of data accessibility and regulatory compliance [1:17:00];
    • The future of autonomous robotic surgery [1:25:00];
    • AI and the future of mental health care [1:31:30];
    • How AI may transform and disrupt the medical industry: new business models and potential resistance from established medical institutions [1:34:45];
    • Potential positive and negative impacts of AI outside of medicine over the next decade [1:38:30];
    • The implications of AI achieving a level of creativity and expertise comparable to exceptional human talents [1:42:00];
    • Digital immortality and legacy: the potential to emulate an individual's personality and responses and the ethical questions surrounding it [1:45:45];
    • Parting thoughts [1:50:15]; and
    • More.

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    The Peter Attia Drive
    enJuly 15, 2024

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    We're back for another edition with Dr. Phil Maffetone

    On this show we dive deeper into potential issues holding you back from making progress. So, if you're not seeing results with MAF and/or fat-burning, yet on paper you are doing everything "right" with training, diet, and lifestyle, then take a listen because it could actually be something else. Even if you've had progress the topics covered today could get you too the next level. Of course, the theme of nutrition and what we eat is integral for this episode including a great discussion at the end of the show.

    Be sure to read Phil's new published article titled Athletes: Fit But Unhealthy, and also check this article on Phil's website profiling our very own Tawnee Prazak on her journey in sport and health.

    On this show:

    • Creating mighty mitochondria! Without good mitochondria could we be slightly suffering? 
    • Mitochondria are our powerhouse for energy, efficiency and health. They extract energy from nutrients to produce ATP (adenosine triphosphate) which our body uses to create energy for a countless cellular processes. They are also integral in the metabolism of lipids/fatty acids (aka your fat-burning)
    • Help with steroid hormone production (testosterone, estradiol), insulin/glucose regulation, and cellular calcium homeostasis
    • When mito are burdened they produce more free radical damage. Increasing mitchondria takes the demand off mitochondria and disperses the workload. This is when they make fat into ATP and produce less free radical damage
    • Mitochondrial dysfunction is a real thing and serious, and it's at the root cause of many genetic disorders, chronic diseases, etc.
    • But for athletes it may just be poor-functioning mitochondria holding you back from making progress
    • When not functioning well we aren't as good with blood sugar regulation and fat burning during exercise
    • Most common problem in hurting your mitochondria is the use of statins--depletes CoQ10--as wel as most prescription drugs too (consult with your doctor)
    • How to boost mitochondria?
    • Endurance training helps boost mitochondria, but in this case that might not be enough for the population we're addressing.
    • The right diet/nutrition is key for creating highly effective mitochondria! High fat diets, low in refined carbs, sugar and junk, with macro's adjusted to your needs and health.
    • Healthy mitochondria depend on a diet that stabilizes blood sugar levels, normalizes fatty acid ratios, and provides mega-doses of trace minerals and phytonutrient anti-oxidants. This diet consists of fresh vegetables and healthy fat sources.
    • Supplements for better mitochondria?
    • Supplement if deficient, and don't supplement with the false idea that more is better. In some cases certain supplements in abundance are not good for us and have a potential toxic or harmful effect.
    • If you have any deficiencies you're going to affect hundreds if not thousands of functions in the body
    • Supplements discussed that aid in healthy mitochondria: CoQ10, B2 (riboflavin), ALA, Mg, Zinc, iron, PQQ, carnitine
    • Carnitine deficiency in particular: carnitine is required to oxidize fat in the mitochondria. With age, carnitine levels decline. Carnitine supplementation has proven effective in reducing fatigue, enhancing cardiovascular function, improving body composition, lowering blood sugar, and more.
    • Treating people is easy, it's the assessment process that is so hard!
    • We must read and analyze the signs or symptoms and consider the biochemical pathways in what's presenting
    • Can we overdo it on antioxidants and/or recovery protocols and blunt the training response/adaptations?
    • There is evidence that some recovery aids such as ice, anti-inflammatory nutrition and antioxidant supplements blunt the adaption to training. So how do you maximize recovery without erasing the workout and making the training ineffective?
    • Research indicates that antioxidants can impair metabolic processes--dose matters, as well as type (synthetics  especially Vitamins C, E)
    • But we need them to offset free radicals! and boost mitochondria!
    • Are we actually doing more harm than good without antioxidants? Where can we find a happy medium?
    • ROS reactive oxygen species covered in Phil's paper Athletes: Fit But Unhealthy
    • Bottom line:
    • Can too much focus on recovery techniques hold back your fitness?
    • Or, can too little focus on recovery, even with MAF, inhibit adaptations (i.e. fatigue, poor health, etc)?
    • Give the body what it needs
    • Tie back to Phil's mention of spacing his speedwork apart by 4 days.
    • Could it be body composition? Specifically: too low body fat, are there risks?
    • We often discuss risks and harms over being overfat but what about the opposite? 
    • Can we have such low body fat as an endurance athlete--male or female--that it hurts our fitness and health? Obviously the answer is yes for women who are more sensitive to low body fat, but what about men?
    • For men is there risk in closing in on 3% body fat or less? Is it playing with fire?
    • There is a range of healthy body fat, but the range is hard to determine
    • If someone's healthy and doing well but has low body fat assess the symptoms. If this person is truly ok it is not a concern
    • Body fat measuring and its accuracy
    • And more....
    • Hormonal imbalances associated with having poor fat-burning ability
    • Find your ideal carb intake
    • Bob Newhart's "Stop It" mentioned by Phil
    • More on diet and getting real on what we're really eating
    • Inaccurate diet reporting
    • Phil and Tawnee share their difference POV's on "food flexibility"
    • Phil lays out some real risks with even slightly too much intermittent fasting--could be more of a stress on the body and in reality you need to eat more. The only IF you need may be that gap between dinner and breakfast the next dya.
    • Shoutout and giving love to Primal Products: Mayo, Dark Chocolate Almond Bars, Dressings and more

    TWiP 142: Just a virus, go home

    TWiP 142: Just a virus, go home

    The TWiPsids solve the case of the Guatemalan Positive for Rhinovirus, and reveal how to kill all African trypanosomes with a primate apolipoprotein.

    Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin

    Become a patron of TWiP.

    Links for this episode:

    Case Study for TWiP 142

    Woman in 50s, immigrant from rural area with limited resources. Admitted to hospital with iron deficient anemia and eosinophilia. In US. Sent for colonoscopy. Note long slender serpiginous motile object, recovered, 4.5 cm long, one end slender, other large and curled but not blunt. Send worm to parasitology lab for identification. What might fit description? Is this usually associated with eosinophilia? What about anemia, is severe or mild? Would this person have come from outside the US to acquire this, or could they have acquired the infection in the US.

    Send your case diagnosis, questions and comments to twip@microbe.tv

    Music by Ronald Jenkees

    The Truth About Heart Health Part 2

    The Truth About Heart Health Part 2

    Get ready to reconsider everything you thought you knew about heart health!

    This is Part 2 to the previous episode - so make sure you check out Part 1 first!

    Mainstream medicine has failed to stem the rising tide of cardiovascular mortality despite massive spending on drugs and interventions. Now the number 1 killer in the US, with one person dying every 33 seconds, it's time to reevaluate what we have come to be told about heart health and learn the truth about how to get well and prevent it. 

    In this two part deep dive, Dr. Nathan makes the case that the cholesterol theory driving our modern approach to treating heart disease was built on bad science and confirmation bias that ignores contradictory evidence.

    He explains

    • The history of why you're told information that might not actually help you.
    • Helps you understand cholesterol and testing better.
    • Reveals that proper saturated fats actually support heart health.
    • Lifestyle choices like diet, exercise, sleep and stress management are more important than genetics.
    • Provides practical tips to improve circulation, balance the nervous system, and support mitochondrial function.
    •  And most importantly dives deep into the solutions that you can start making today to not only support your body to heal but to support the prevention of heart disease.

    Learn how to take control of your heart health by tuning in to this myth-busting conversation.

    Ready to work with us? Both in-office in Chattanooga, TN and virtually worldwide--> Click here for more information

    Sign up here to receive Dr. Nathan's Heart Health Protocol: https://www.drswarren.com/supplements 

    Facebook: https://www.facebook.com/drswarren/

    Youtube: https://www.youtube.com/channel/UCrKoH9JOZ54D8mU2WpiA9Pg

     

     

     

     

     

     

    Disclaimer: This podcast is for information purposes only. Statements and views expressed on this podcast are not medical advice. This podcast including Drs.Warren disclaim responsibility from any possible adverse effects from the use of information contained herein. Opinions of guests are their own, and this podcast does not accept responsibility of statements made by guests. This podcast does not make any representations or warranties about guests qualifications or credibility. Individuals on this podcast may have a direct or non-direct interest in products or services referred to herein. If you think you have a medical problem, consult a licensed physician.

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