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    #24 - Tom Dayspring, M.D., FACP, FNLA – Part V of V: Lp(a), inflammation, oxLDL, remnants, and more

    Assessing APOC3 content in APOBs can provide valuable information on disease risk and treatment effectiveness for individuals with triglyceride-rich lipoproteins.

    enOctober 19, 2018

    About this Episode

    In this five-part series, Thomas Dayspring, M.D., FACP, FNLA, a world-renowned expert in lipidology, and one of Peter's most important clinical mentors, shares his wealth of knowledge on the subject of lipids. In Part V, Peter and Tom talk about inflammation, endothelial health, and oxidative stress as they pertain to cardiovascular disease, and our attempts to monitor them using biomarkers. They also discuss a couple of very important risk factors that too few people (and doctors) know about. Tom closes the five-part series with a tragic story about his good friend that is likely all-too-common for many practicing physicians, that both haunts and motivates Dr. Dayspring to learn as much as he can about the number one killer in the United States.

    We discuss:

    •     Lp(a) [2:30];
    •     Inflammation [17:15];
    •     Oxidative stress markers: Lp-PLA2 and oxLDL [20:45];
    •     Endothelial health markers: ADMA and SDMA [34:30];
    •     Remnants [43:45];
    •     Omega-3 fatty acids (EPA and DHA) and apoC-III [55:30];
    •     Red blood cells and cholesterol transport [1:07:45];
    •     Tom's friend Earl [1:10:00];
    •     Peter's friend JP [1:18:15]; and
    •     More.

    Learn more at www.PeterAttiaMD.com

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    🔑 Key Takeaways

    • Accurate measurement and understanding of LP little a is crucial in assessing its composition and impact on cardiovascular health. Further research is needed to uncover its clearance mechanisms and potential implications.
    • LDL-P and HDL-P provide more accurate information about heart health compared to cholesterol levels, and specific methods may be needed to measure dangerous LP little a particles.
    • The development of a drug to specifically target APO and LP is being researched, but until then, experts are considering alternative treatments and exploring the role of APO in reducing LP particle concentration.
    • Rigorous safety measures are in place during drug development, and personalized interventions based on individual biomarkers are crucial in combating multifactorial diseases.
    • Monitoring relevant biomarkers can help tailor therapeutic suggestions for addressing oxidative states and inflammation, with potential benefits from incorporating omega-3 fatty acids in a nutritional approach.
    • Instead of relying on LP PLA 2 and MPO, focus on biomarkers like F2isoprostanes or oxidized LDL and consider nutrition and lifestyle for preventing cardiovascular disease.
    • Monitoring LP little a levels and assessing other factors is important, and ongoing research may lead to new treatment options for high LP little a in the future. Biomarkers can also provide insights into endothelial function and thrombotic potential.
    • Monitoring markers like ADMA and SDMA can help healthcare professionals understand endothelial function, identify disruptions in arginine levels, and determine the need for interventions and treatment strategies.
    • Biomarkers like SDMA and ADMA can detect early stages of renal impairment, which is often overlooked. Understanding these biomarkers can help address potential health issues before they become severe.
    • The size and density of lipoproteins vary among individuals, but it is the APO B particle that contributes to plaque formation in arteries. Lowering APO B particles is essential for effective treatment.
    • Assessing APOC3 content in APOBs can provide valuable information on disease risk and treatment effectiveness for individuals with triglyceride-rich lipoproteins.
    • Omega-3 fatty acids, specifically DHA, are beneficial for reducing APO B levels and can be an effective adjunct therapy for lowering APO B by 8-10%. Individual conversion abilities and monitoring red blood cell omega-3 levels are important. Further research is needed for optimal levels and long-term effects.
    • Understanding the composition of omega-3 fatty acid supplements is crucial for making informed choices, and further investigation is encouraged to ensure the presence of necessary components and avoid potential harm.
    • The combination of EPA and statins could offer a promising treatment option for improving cardiovascular health, with ongoing trials showing encouraging results.
    • Red blood cells do carry cholesterol but are not primary contributors to atherosclerosis. It is the abundance of LDL particles that pose a higher risk, emphasizing the importance of quantity over individual particles.
    • Early detection, regular cholesterol checks, and following medical guidance can delay heart disease progression and improve overall health outcomes, preventing unnecessary deaths.
    • Seeking guidance from experienced individuals and utilizing curated resources can greatly enhance learning and understanding in any field. Developing a foundation of knowledge and learning from first principles is essential for building deep understanding.
    • In the fields of biology and medicine, a combination of first principles thinking and practical knowledge is essential for effective understanding and decision-making. Continuous learning and integration of theoretical understanding with practical knowledge are crucial in these complex subjects.
    • Continuous learning and open-mindedness are essential for doctors to provide the best care and make informed decisions based on evidence and collaboration.

    📝 Podcast Summary

    Understanding LP little a: A Potentially Pathogenic Particle in Cardiovascular Health

    LP little a is an LDL-like particle that carries an extra APO protein called APO little a. This particle is potentially pathogenic and atherogenic. It is important to use the correct terminology when referring to this particle to avoid confusion. Current lab tests measure LP little a mass, which is the weight of all the LDL particles in the plasma, including their triglycerides, cholesterol ester, and other lipid components. However, measuring the molecular weight of APO little a is challenging due to its variability. Therefore, LP little a mass may not provide accurate information regarding the specific composition and pathogenicity of this particle. Further research is needed to better understand the clearance mechanisms and impact of LP little a in cardiovascular health.

    Accurate measurement of LDL and HDL particles is crucial for assessing cardiovascular health.

    The best metric for measuring LDL particles is low density lipoprotein particle number (LDL-P) and for HDL particles, it is HDL particle number (HDL-P). These metrics are more accurate than relying on HDL cholesterol or LDL cholesterol levels. To accurately measure LDL particle count, lipoproteins must be separated electrophoretically and then counted. LP little a particles, which are dangerous, can only be measured using this method. Taking a statin may lower LDL particles without LP little a, but it won't reduce LP little a particles. To target LP little a particles, niacin or PCSK9 inhibitors may be considered, although the cost can be a major barrier. It is difficult to prove that reducing LP little a particles directly reduces cardiovascular events.

    Current efforts to develop a targeted drug for high APO and LP are underway, while experts debate the use of alternative treatments and explore the impact of different drugs on HDL particles.

    There are ongoing efforts to develop a drug that specifically targets APO or LP without impacting LDL particles. Such a drug is currently under investigation, and its effectiveness in genetically inherited conditions involving high APO 8 production is being studied. However, until this drug becomes available, there is debate among experts in lipidology regarding the use of other treatments. Some argue that lowering APO and LP through interventions like Nisin can be beneficial, while others are skeptical about its potential toxicity. Additionally, the impact of different drugs on HDL particle counts and function is still a subject of discussion. The main focus in reducing LP particle concentration lies in inhibiting APO a production in the liver, as clearance alone does not determine particle concentration. The role of APO a and its significance in human life is still being explored.

    Drug Development, Safety, and Personalized Interventions in Combating Multifactorial Diseases.

    Drug development and safety considerations involve extensive evaluation and examination of various aspects. While concerns may arise during the development of a new drug, rigorous safety measures are in place to address them. Lowering APO and LP levels is possible with certain medications, yet it may not be necessary to bring them down to zero to reduce risk. Clinical trials typically focus on individuals with higher LP particle counts, akin to the initial statin trials that targeted specific patient populations. Moreover, there are ongoing drug trials exploring different components of the atherosclerotic mechanism pathway, particularly the inflammatory pathway. By reducing inflammation, the potential for improved vascular health seems promising. However, it is essential to balance inflammation reduction with the body's need for an immunological response. Personalizing interventions based on individual biomarkers and identifying existing pathologies are crucial in combating multifactorial diseases.

    Exploring Biomarkers for Oxidative States and Inflammation

    There are various biomarkers that can help us understand different aspects of oxidative states and inflammation in the body. By measuring these biomarkers, we can individualize our therapeutic suggestions and determine the appropriate nutritional and pharmacological interventions. It's important to recognize that not all biomarkers are equal in terms of relevance and significance. For example, oxidized LDL particles in the plasma are a reflection of a pro-oxidative state, but they only represent a small fraction of the total LDL particles. Other markers, such as myeloperoxidase and isoprostanes, provide a more comprehensive assessment of oxidative stress. While there may not be a definitive drug or supplement to directly address oxidative states, incorporating omega-3 fatty acids as part of a nutritional approach may have potential benefits. Overall, understanding and monitoring these biomarkers can guide our efforts in reducing inflammation and optimizing health.

    Biomarkers like LP PLA 2 and MPO may not predict outcomes for cardiovascular disease.

    Certain biomarkers, such as lipoprotein phospholipase a 2 (LP PLA 2) and myeloperoxidase (MPO), may not be helpful in predicting outcomes or assessing risk for cardiovascular disease. LP PLA 2, an enzyme produced by macrophages, is involved in the oxidation of phospholipids on LDL particles within the arterial wall. However, measuring LP PLA 2 activity or mass does not seem to have a significant impact on patient outcomes. Similarly, MPO data has shown to be unimpressive in providing valuable information. Therefore, it may be more beneficial to focus on other biomarkers, such as F2isoprostanes or oxidized LDL, which can provide clearer insights into the atherosclerotic process. Additionally, considering the overall nutrition and lifestyle factors can play a crucial role in preventing and managing cardiovascular disease.

    Measuring LP little a particles and their attributes for cardiovascular risk assessment

    Measuring LP little a particles and their attributes is crucial in assessing the risk of certain cardiovascular events. LP little a is known for carrying enzymes and oxidized lipid moieties, which can contribute to inflammation and thrombosis in the arteries. While not everyone with high LP little a will experience negative outcomes, it is important to monitor levels and assess other factors such as oxidized APO B phospholipids. Currently, there is no specific drug to address high LP little a, but ongoing research and the development of antisense drugs may provide new treatment options in the future. Additionally, biomarkers like asymmetric or symmetric dimethalargine can provide insights into endothelial function and thrombotic potential.

    Measuring ADMA and SDMA for insights into endothelial function and vascular health

    Measuring markers like ADMA and SDMA can provide valuable insights into endothelial function and potential vascular pathology. These markers are related to the synthesis and catabolism of arginine, which is crucial for the production of nitric oxide. Elevated levels of ADMA and SDMA indicate a disruption in arginine pools, leading to reduced nitric oxide synthesis. This can be detrimental to vascular health. By measuring these markers, healthcare professionals can gain a better understanding of endothelial function and the potential need for interventions. Additionally, high levels of ADMA and SDMA may suggest the need for aggressive nutritional interventions, especially in cases where other approaches have been maximized. These markers can serve as indicators for further investigation and potential treatment strategies.

    Biomarkers for Renal Function and Vascular Health

    There are important biomarkers, such as SDMA and ADMA, that can provide valuable information about renal function and vascular health. These biomarkers can detect early stages of renal impairment, which are often overlooked in the medical community. It is essential to address mild degrees of renal impairment to lower the risk of vascular disease. Use of biomarkers like SDMA and ADMA can provide more accurate assessments of renal function compared to traditional methods like creatinine. Additionally, incorporating cystatin c along with creatinine can further enhance the accuracy of renal clearance measurements. Understanding these biomarkers and their pathways can help identify and address potential health issues before they become more severe.

    Understanding Lipoproteins and Their Role in Plaque Build-up

    Lipoproteins, such as LDL and VLDL, come in various sizes and densities. Every individual has a mixture of different lipoprotein subfractions, and there is no one-size-fits-all diameter or density for each. The important factor to consider is the APO B particle, which can contribute to the build-up of plaque in the artery walls. While LDL particles are responsible for most of the cholesterol delivery to the artery wall, VLDL particles can also contribute to this process. Estimating VLDL cholesterol can be done by dividing triglyceride levels by 5 or subtracting LDL cholesterol from non HDL cholesterol, but the accuracy of these estimates varies. Lowering APO B particles, including remnants, is crucial for effective therapy, which may involve nutritional changes and medication.

    Understanding the complexity of VLDL cholesterol and its remnants

    The measurement of VLDL cholesterol and its remnants is complex and not always indicative of disease or treatment outcomes. While fibrates can be effective in reducing remnants, statins may also clear them to some extent. However, fibrates offer additional benefits for individuals with triglyceride-rich lipoproteins. The availability of laboratory tests for identifying remnants has changed, with some labs now only reporting large VLDL particles. It is important to note that while VLDL particles may contain extra cholesterol, their clearance by APOB100 receptors is rapid. The presence of APOC3, a pro-inflammatory protein, can delay the clearance of VLDL particles and lead to pathologies such as increased cholesterol enrichment. Therefore, assessing the APOC3 content of APOBs may provide valuable information on disease risk and treatment effectiveness.

    The impact of Omega-3 fatty acids on cardiovascular health.

    Omega-3 fatty acids, specifically DHA, have a significant impact on APOC3 levels and can be beneficial in reducing APO B, a predictor of cardiovascular disease. Previously, omega-3s were disregarded as useless supplements, but recent findings suggest otherwise. High-dose prescription strength EPA can be an effective adjunct therapy for lowering APO B by an additional 8-10%. However, it is important to consider individual conversion abilities and measure red blood cell omega-3 levels, as not everyone can efficiently convert EPA to DHA. Monitoring and aiming for a red blood cell EPDHA level of at least 10% can be a prudent approach. Further research is needed to determine the optimal levels and potential long-term effects.

    The Importance of Considering the Delivery of Omega-3 Fatty Acids

    The vehicle in which omega-3 fatty acids are delivered to the body is important to consider. Whether it is a supplement or a prescription product, understanding the composition of the omega-3 fatty acids is crucial. Most supplements on the market use monoglycerol with two other fatty acids plus one omega-3 fatty acid, rather than try acylglycerides. The presence of these additional fatty acids may not be necessary or could potentially be harmful. It is also worth noting that there is currently no pharmaceutical-grade DHA available. However, an FDA-approved product combining statins with EPA is expected to be brought to market soon, offering potential benefits for those at risk. Further investigation into the composition of omega-3 supplements is encouraged to make informed choices.

    Exploring the Potential Benefits of Adding EPA to Statins for Cardiovascular Health

    There is a high expectation that EPA (eicosapentaenoic acid) added to statins will have a positive effect on cardiovascular health. The conversation revolves around the potential benefits of EPA and the ongoing trial to determine its efficacy. The company Amarin has developed Vascepa, a free omega-3 fatty acid product, which has shown promising results. The hope is that adding Vascepa to a statin will provide a combined treatment option for patients. Another company, AstraZeneca, is conducting its own study with the combination of Rosuvastatin and free fatty acids. If the first trial with EPA is successful, it is believed that combining it with a potent statin could further enhance its benefits. This has important implications in the lipid world, and the trial results are eagerly anticipated in November.

    Differentiating the role of red blood cells and lipoproteins in atherosclerosis risk

    Red blood cells do carry cholesterol molecules, but they do not cause atherosclerosis like lipoproteins do. This is because red blood cells are not able to invade the arterial walls and are not subject to oxidative forces. While red blood cells can enter plaque through the veins, they are not the primary delivery method for oxidized phospholipids and sterols into the artery. It is the LDL particles and remnants that pose a greater risk due to their ability to easily penetrate the arterial walls. Although red blood cells carry more cholesterol molecules, there are far more LDL particles in the bloodstream. So, while a single LDL particle may be a troublemaker, there is safety in numbers.

    Addressing Cholesterol: Preventing Heart Disease for a Longer, Healthier Life

    Heart disease is a serious and preventable condition that is often overlooked or misunderstood. The tragic story of Earl, who died at a young age due to a heart attack, highlights the importance of early detection and appropriate treatment. It is crucial for individuals to seek medical advice and get their cholesterol levels checked regularly, especially if they have risk factors or a family history of heart disease. By addressing cholesterol-related issues and following medical guidance, it is possible to delay the progression of heart disease and extend life expectancy. Education and awareness about the significance of managing cholesterol levels can help prevent unnecessary deaths and improve overall health outcomes.

    The Power of Learning from Experts and Curated Resources

    Having access to knowledgeable experts and curated resources can greatly accelerate learning and understanding in any field. Thomas Dayspring expresses his gratitude for having connections to experienced individuals who can provide insights and guidance. By reaching out to these "lipid gods," as he calls them, Dayspring has been able to deepen his knowledge and benefit from their expertise. Peter Attia shares a similar experience, highlighting the value of having mentors who can streamline the learning process by providing curated curriculum. Moreover, Attia shares an anecdote from his college days, where he learned the importance of first principles and deriving formulas, rather than purely relying on memorization. This conversation underscores the importance of seeking wisdom from experts and leveraging foundational knowledge to build understanding.

    Balancing first principles thinking and practical knowledge in understanding biology and medicine.

    Understanding complex subjects, such as biology and medicine, requires a balance between first principles thinking and practical knowledge. While Peter Attia, who had a background in engineering and mathematics, initially believed he could apply first principles thinking to biology, he quickly realized that certain foundational knowledge is necessary to navigate the subject effectively. Similarly, Thomas Dayspring, a lipid expert, acknowledges that even with expertise, there is always a need to continue learning and verifying ideas against scientific foundations. This highlights the inherent complexity of biology and the importance of recognizing the limitations of first principles thinking in this field. As clinicians and learners, we must approach medicine with curiosity, a commitment to ongoing education, and a willingness to integrate theoretical understanding with practical knowledge.

    Navigating the complexities of medicine for better patient care

    The field of medicine, specifically lipidology, is incredibly complex and requires continuous learning and understanding. While it may be difficult to grasp all the information presented in discussions and research, it is important for doctors to invest time in better understanding the nuances to provide the best care for their patients. Doctors who genuinely care about their patients are not simply motivated by financial gain or influenced by pharmaceutical companies. It is crucial to approach medical knowledge with an open mind and not dismiss theories or ideas without considering the evidence and clinical trials behind them. Moreover, continuous learning and collaboration, like the one between Peter Attia and Thomas Dayspring, can lead to valuable insights and personal growth.

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    • The relationship between VO2 max, power output, and endurance performance in different sporting contexts [34:45];
    • How VO2 max is measured in the lab, and why it’s a crucial predictor of both lifespan and quality of life [44:45];
    • Absolute vs relative VO2 max, the significance of functional threshold power in cycling, and the importance of longer duration tests for accurate assessments [54:00];
    • Portable VO2 testing devices as a practical alternative to lab-based tests [1:05:15];
    • The complexities of measuring ventilation and its impact on performance metrics like VO2 max and heart rate [1:15:45];
    • Training interventions to increase VO2 max, and factors that impact performance outcomes [1:23:30];
    • The respiratory exchange ratio (RER) and endurance sports, and how factors such as diet composition and exercise intensity influence RER values and performance [1:32:45];
    • Science-guided training for versatile athletes: maximizing VO2 max, power, torque, and cadence in cycling, and the importance of incorporating diverse stimuli to enhance performance [1:41:00];
    • Physiological limitations on VO2 max [2:02:15];
    • The different energy systems used during work, and other things to monitor like VCO2 and heart rate [2:06:00];
    • Lactate threshold and other metrics to guide your training [2:10:30];
    • Analysis of a lactate power curve: exploring lactate dynamics in endurance training and performance [2:23:15]; and
    • More.

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    The Peter Attia Drive
    enMarch 18, 2024

    #293 - AMA #57: High-intensity interval training: benefits, risks, protocols, and impact on longevity

    #293 - AMA #57: High-intensity interval training: benefits, risks, protocols, and impact on longevity

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    In this “Ask Me Anything” (AMA) episode, Peter delves into the topic of high-intensity interval training (HIIT), starting with addressing some common misunderstandings around this type of exercise and breaking down what HIIT truly entails. He examines the correlation between HIIT and VO2 max, a vital metric for overall health and longevity, and describes the beneficial impact of HIIT on longevity when incorporated properly. Additionally, he emphasizes the importance of building a wide base of cardiovascular fitness, reveals the optimal protocols for incorporating HIIT into a balanced routine, and discusses the risk of injury and other potential drawbacks of HIIT.

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

    We discuss:

    • Common questions about high-intensity interval training (HIIT) [1:30];
    • The origins of HIIT [3:15];
    • Defining HIIT training and differentiating it from sprint interval training (SIT) [5:45];
    • Why HIIT is often touted as a more efficient way to exercise [14:00];
    • Navigating the nuances of HIIT research: understanding limitations and the importance of a blended exercise routine [20:30];
    • The four pillars of exercise [24:15];
    • Using HIIT to improve VO2 max [26:00];
    • HIIT training for the untrained individual: impact on VO2 max and the interplay between exercise-induced adaptations and potential weight loss [33:00];
    • Sprint interval training (SIT) vs. HIIT: comparing the relative improvements in VO2 max and the impact of longer duration intervals [40:00];
    • Benefits and limitations of HIIT, drawbacks of overtraining with HIIT, and the importance of a diversified routine to increase total cardiorespiratory capacity [44:15];
    • HIIT protocols Peter recommends [58:45];
    • The risk of injury and other potential drawbacks of HIIT [1:02:15];
    • The importance of incorporating a balance of continuous moderate-intensity cardio and HIIT when aiming for longevity [1:04:00]; and
    • More.

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    The Peter Attia Drive
    enMarch 11, 2024

    #292 ‒ Rucking: benefits, gear, FAQs, and the journey from Special Forces to founding GORUCK | Jason McCarthy

    #292 ‒ Rucking: benefits, gear, FAQs, and the journey from Special Forces to founding GORUCK | Jason McCarthy

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    Jason McCarthy is a former US Special Forces member and the founder of GORUCK, a company specializing in rucking equipment. In this episode, Jason recounts his journey from military service to navigating the challenging transition back into civilian life and ultimately embracing the mission of introducing rucking to the masses. Delving into the significance of rucking in military training and its applicability to the wider population, he discusses the mental and physical benefits of rucking as a mode of training, provides practical tips for beginners, and answers frequently asked questions about packs, weights, footwear, and more.

    We discuss:

    • Jason’s upbringing and what inspired him to join the military [3:15];
    • Jason’s path to becoming a Green Beret, his calling to serve, and staying true to oneself [10:30];
    • About the Green Berets: their role in the military, unique abilities, missions, and more [20:00];
    • The mental and physical challenges of special forces training and selection [25:00];
    • Rucking challenges as a Green Beret [37:00];
    • How Jason trained in his off-time and stayed mentally prepared [46:30];
    • Jason’s difficult decision to leave the army, and the challenges many veterans face returning to civilian life [51:30];
    • Jason’s struggles after leaving the army: loss of identity, feelings of shame, and the how he overcame a period of despair [57:15];
    • The origin of GORUCK [1:10:30];
    • The GORUCK Challenge [1:24:30];
    • The company's evolution from event organizer to manufacturing specialist, spurred by the growing interest in rucking as a form of training [1:35:30];
    • FAQs about rucking: packs, weight, rucksack vs. weighted vest, chest straps, and more [1:38:45];
    • Commemorating Normandy: GORUCK's plans for the 80th anniversary of the Normandy landings [1:51:30];
    • Footwear for rucking, and how GORUCK got into the footwear business [1:57:30];
    • How to avoid the most common injuries from rucking, and the benefits of rucking for VO2 max, strength, and sleep quality [2:05:00];
    • Advice for using rucking as a mode of training, and the advantages of rucking over other forms of training [2:12:45]; and
    • More.

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    The Peter Attia Drive
    enMarch 04, 2024

    #291 ‒ The role of testosterone in males and females, performance-enhancing drugs, sustainable fat loss, supplements, and more | Derek, More Plates More Dates Pt.2

    #291 ‒ The role of testosterone in males and females, performance-enhancing drugs, sustainable fat loss, supplements, and more | Derek, More Plates More Dates Pt.2

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    Derek is a fitness educator, the entrepreneur behind More Plates More Dates, and an expert in exogenous molecules commonly used and misused by bodybuilders and athletes. In this episode, Derek returns to the podcast to explore the impact of exogenous molecules on male and female health. He covers testosterone, DHT, DHEA, progesterone, clomiphene (Clomid), hCG, and various peptides, alongside updates from the FDA affecting peptide use. Additionally, he addresses the recent hype around increasing muscle mass through myostatin inhibition via follistatin gene therapy and supplementation. Additionally, Derek discusses the various strategies that bodybuilders use for losing fat while preserving muscle, including insights on weight loss drugs.

    We discuss:

    • Testosterone and DHT: mechanisms of action, regulation of muscle growth, and influence on male and female characteristics [2:15];
    • TRT in women: the complexities and potential risks associated with testosterone use in women [9:00];
    • DHEA supplementation: exploring the benefits and risks for women, and the differing effects on men vs. women [22:00];
    • The role of progesterone in both men and women, pros and cons of supplementation, the importance of tailored doses, and more [28:00];
    • Measuring levels of free testosterone [37:15];
    • The trend towards earlier interest in TRT, and the risks of underground sources of testosterone [42:00];
    • The complexities and considerations surrounding the use of Clomid, E-Clomid, and hCG in TRT [46:00];
    • Low testosterone: diagnosis, potential causes, treatment options, and other considerations [53:45];
    • Growth hormone-releasing peptides: rationale and implications of the recent FDA categorization as high-risk substances [1:03:45];
    • Follistatin gene therapy and myostatin inhibition for increasing muscle mass: the recent hype online, human and animal data, and the need for more research [1:14:45];
    • Simple tips for lowering calorie intake and losing fat [1:32:30];
    • Methods of sustainable fat loss with muscle preservation: insights gleaned from bodybuilders [1:40:00];
    • Could prolonged fasting impact testosterone levels? [1:55:30];
    • High-protein ice cream [1:57:00];
    • Exploring fat loss supplements and drugs: L-carnitine, yohimbine, and more [2:02:15];
    • Potential remedies for individuals experiencing metabolic dysfunction due to hypercortisolemia [2:12:30];
    • The cornerstones of body composition improvement remain nutrition and exercise, even in the presence of exogenous testosterone [2:19:15];
    • The importance of approaching health advice found online with a critical eye and a healthy dose of skepticism [2:23:30]; and
    • More.

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    The Peter Attia Drive
    enFebruary 26, 2024

    #290 ‒ Liquid biopsies for early cancer detection, the role of epigenetics in aging, and the future of aging research | Alex Aravanis, M.D., Ph.D.

    #290 ‒ Liquid biopsies for early cancer detection, the role of epigenetics in aging, and the future of aging research | Alex Aravanis, M.D., Ph.D.

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    Alex Aravanis is a leader in research and development of technologies and clinical tests utilizing the latest tools in DNA analysis and data science. In this episode, Alex delves into two interconnected topics: liquid biopsies and epigenetics. He begins by tracing the trajectory of genome sequencing and tumor sequencing, setting the stage for a detailed exploration of liquid biopsies as an early cancer detection method. The discussion encompasses key concepts such as cell-free DNA, DNA methylation, sensitivity, specificity, and the predictive values associated with liquid biopsies. Transitioning to epigenetics, Alex examines the intricate interplay of DNA methylation and aging biology and explores the possibility of using cellular reprogramming to reverse epigenetic changes that occur with aging.

    We discuss:

    • Alex’s background in applying engineering to problems in medicine [3:15];
    • A primer on human genetics, and the history and current landscape of DNA sequencing [11:00];
    • The advent and evolution of liquid biopsies for early detection of cancer [23:15];
    • The role of cell-free DNA in cancer detection: how incidental findings in non-invasive prenatal testing led to the development of liquid biopsies [40:15];
    • The development of a universal blood test for cancer detection and a discussion of specificity of tests [46:00];
    • Advancements in cell-free DNA analysis and development of a multi-cancer screening test at GRAIL [51:00];
    • DNA methylation explained [58:15];
    • Optimizing cancer detection with methylation analysis of cfDNA in small blood samples [1:02:45];
    • The importance of understanding sensitivity, specificity, positive predictive value, and negative predictive value in cancer screening [1:08:00];
    • The performance of the GRAIL Galleri test and its ability to detect various types and stages of cancer [1:21:00];
    • Do early cancer detection methods, like liquid biopsies, translate to improvement in overall survival? [1:27:45];
    • The role of epigenetics in aging [1:39:30];
    • How cell-free DNA methylation patterns can help identify a cancer’s tissue of origin [1:45:30];
    • Cellular and epigenetic reprogramming and other exciting work in the field of aging [1:52:30]; and
    • More.

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    The Peter Attia Drive
    enFebruary 19, 2024

    #289 - AMA #56: Cancer screening: pros and cons, screening options, interpreting results, and more

    #289 - AMA #56: Cancer screening: pros and cons, screening options, interpreting results, and more

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    In this “Ask Me Anything” (AMA) episode, the conversation focuses on cancer screening, a topic often shrouded in confusion yet crucial to understand given that early identification of a cancer is an essential part of survival strategy. Peter examines the arguments both for and against cancer screening, including addressing why some trials may show no benefit to screening. He then delves into the various screening modalities available for different cancers, highlights the pros and cons associated with each, and explains how to interpret the results. Additionally, Peter provides guidance for navigating outside of the relatively narrow and confined screening guidelines for various types of screening tests.

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

    We discuss:

    • Why understanding cancer screening is crucial [2:45];
    • The prevalence of cancer diagnosis and mortality rates [4:30];
    • Why cancer screening and early detection is such an important part of the strategy to survive a cancer diagnosis [11:00];
    • Data on how cancer screening impacts survivability of cancer [16:30];
    • Inconsistencies between cancer screening trials regarding benefits to survival rates [25:45];
    • What are some of the reasons why clinical trials don’t always improve cancer-specific mortality? [30:15];
    • What are the arguments against population-level cancer screening? [42:00];
    • Cancer screening outside the recommended guidelines: risks and benefits, interpreting results, and other considerations [46:00];
    • Understanding sensitivity and specificity when reviewing screening results [52:30];
    • Risks and complications associated with colonoscopies [55:45];
    • Cancer screening modalities: options for cancer screening both within standard recommendations and beyond [58:30];
    • The strengths and limitations of various types of cancer screening [1:02:15];
    • Understanding positive and negative predictive value using sensitivity, specificity, and pretest probability [1:11:45];
    • Factors that influence an individual's pretest probability of cancer [1:13:45];
    • How to interpret cancer screening results [1:18:15];
    • The importance of having an advocate when considering out-of-guideline cancer screening tests [1:23:30];
    • How stacking multiple cancer screening modalities can decrease the risk of false positives [1:29:30];
    • Advice and guidance for making decisions related to cancer screening [1:31:15]; and
    • More.

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