The Peter Attia Drive

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Eric Ravussin is a world-renowned expert on obesity, metabolism, and aging whose pioneering research has shaped much of what we understand today about energy balance and caloric restriction. In this episode, Eric shares insights from his cutting-edge work on energy expenditure—a critical factor in understanding how our bodies regulate weight and appetite. He discusses methods for measuring energy output, energy balance, food intake, and appetite regulation, and explores key studies on macronutrient manipulation. Eric then delves into the CALERIE study on caloric restriction, highlighting insights related to biomarkers of both primary and secondary aging. The conversation also covers the potential of GLP-1 agonists to replicate these effects and looks ahead to how AI and technology could transform metabolic research in the coming years.

We discuss:

• Eric’s background and current work metabolism and measuring energy expenditure [3:00];
• The science behind metabolic chambers for measuring energy expenditure, and the complexities of indirect and direct calorimetry [8:00];
• The body's regulatory systems for maintaining energy balance and the primary influence of energy intake on body weight [18:30];
• The epidemic of obesity and a discussion of resting metabolic rate [24:45];
• The impact of exercise, appetite, gut hormones, and eating patterns on weight regulation [28:45];
• Experiments looking at how macronutrient composition affects energy expenditure [38:45];
• The challenges of studying diet in real-life settings, the potential of personalized nutrition, and how public health policy could play a role in guiding nutritional habits [51:00];
• The importance of protein in the diet, the limitations of dietary data collection, and how AI could potentially transform nutrition science [1:08:15];
• How Eric’s interest in caloric restriction (CR) began with Biosphere 2, metabolic efficiency's role in aging, and goals of the CALERIE study [1:15:15];
• The CALERIE study: exploring the real-world impact of caloric restriction [1:28:00];
• Notable findings from the CALERIE study after two years: sustained weight loss, participant retention, and more [1:40:00];
• The effect of caloric restriction on the hallmarks of aging [1:47:00];
• The challenge of applying CR to the general population, the potential of drugs and exercise to mimic the effects of CR [1:55:45];
• Upcoming study comparing caloric restriction to time-restricting eating, and Peter’s takeaways from the discussion [2:02:45]; and
• More.

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Feng Zhang, a professor of neuroscience at MIT and a pioneering figure in gene editing, joins Peter to discuss his groundbreaking work in CRISPR technology, as well as his early contributions to optogenetics. In this episode, they explore the origins of CRISPR and the revolutionary advancements that have transformed the field of gene editing. Feng delves into the practical applications of CRISPR for treating genetic diseases, the importance of delivery methods, and the current successes and challenges in targeting cells specific tissues such as those in the liver and eye. He also covers the ethical implications of gene editing, including the debate around germline modification, as well as reflections on Feng’s personal journey, the impact of mentorship, and the future potential of genetic medicine.

We discuss:

• Feng’s background, experience in developing optogenetics, and his shift toward improving gene-editing technologies [2:45];
• The discovery of CRISPR in bacterial DNA and the realization that these sequences could be harnessed for gene editing [10:45];
• How the CRISPR system fights off viral infections and the role of the Cas9 enzyme and PAM sequence [21:00];
• The limitations of earlier gene-editing technologies prior to CRISPR [28:15];
• How CRISPR revolutionized the field of gene editing, potential applications, and ongoing challenges [36:45];
• CRISPR’s potential in treating genetic diseases and the challenges of effective delivery [48:00];
• How CRISPR is used to treat sickle cell anemia [53:15];
• Gene editing with base editing, the role of AI in protein engineering, and challenges of delivery to the right cells [1:00:15];
• How CRISPR is advancing scientific research by fast-tracking the development of transgenic mice [1:06:45];
• Advantages of Cas13’s ability to direct CRISPR to cleave RNA and the advances and remaining challenges of delivery [1:11:00];
• CRISPR-Cas9: therapeutic applications in the liver and the eye [1:19:45];
• The ethical implications of gene editing, the debate around germline modification, regulation, and more [1:30:45];
• Genetic engineering to enhance human traits: challenges, trade-offs, and ethical concerns [1:40:45];
• Feng’s early life, the influence of the American education system, and the critical role teachers played in shaping his desire to explore gene-editing technology [1:46:00];
• Feng’s optimism about the trajectory of science [1:58:15]; and
• More.

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Belinda Beck, founder of The Bone Clinic and a leading authority on exercise physiology and bone health, delves into the science of osteoporosis, bone density, and the lifelong importance of maintaining skeletal health. In this episode, she explains how the foundation for strong bones is established during childhood, offering valuable advice for parents on optimizing bone health for their kids. She also explores how bone remodeling occurs throughout life, driven by activity, nutrition, and hormones. Belinda highlights the power of resistance training in improving bone strength, even for those at risk of bone loss, and emphasizes the role of essential vitamins and minerals in maintaining bone health. She shares practical strategies, backed by research, for preventing fractures and combating osteoporosis.

We discuss:

• Belinda’s journey into bone health research and training [2:45];
• The physiology of bone and how bones adapt to mechanical loading [8:15];
• Bone development from birth to adulthood, why early life is a crucial period, the functions of osteoblasts and osteoclasts, and gender differences in BMD [14:00];
• How parents can optimize their children’s bone health through diet (calcium and vitamin D), sunlight exposure, and physical activity [27:30];
• The best sports and activities for promoting bone health, weight training for kids, and advice for parents [36:30];
• The impact of corticosteroid use on bone health in children and strategies to minimize negative effects [48:30];
• Advice for people in middle age to preserve bone density: physical activity and bone-loading exercises [52:00];
• Bone loss during the menopause transition for women: hormone replacement therapy and other strategies to mitigate BMD losses [59:30];
• Interpreting the bone mineral density results from a DEXA scan: T-score, Z-score, and more [1:03:00];
• The LIFTMOR study: testing the effects of heavy weightlifting on bone health in postmenopausal women with low bone density [1:10:15];
• Profound benefits of weight training outside of BMD improvements: exploring the broader impacts on patients in the LIFTMOR study [1:19:30];
• Guidance for people wanting to use exercise designed to improve their bone health [1:29:30]; and
• More.

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Anna Lembke is the Chief of the Stanford Addiction Medicine Dual Diagnosis Clinic and author of Dopamine Nation: Finding Balance in the Age of Indulgence. In this episode, Anna dives deep into the biochemistry and neurobiology of addiction, exploring the critical role of dopamine and the prefrontal cortex. She shares her framework for diagnosing and treating addiction, providing real-world examples involving alcohol, gambling, cannabis, social media, and more. Anna outlines the risk factors for addiction, including inherited and nurture-based risks, explores the rise of addictions in younger generations, and discusses effective ways to address these issues with children. Additionally, she touches on healthy coping strategies, the evolution of the “marshmallow experiment,” and provides insights into GLP-1 agonists as a possible tool for addiction treatment. Finally, she reflects on the value of 12-step programs and how she navigates the emotional challenges of her work.

We discuss:

• The role of dopamine and the prefrontal cortex in addiction [3:00];
• The clinical definition of addiction and the behavioral criteria for diagnosing it [13:00];
• Assessing alcohol use: patterns, risks, and addiction diagnosis [17:15];
• Applying the addiction diagnosis framework using gambling as an example [21:45];
• Exploring addiction variability: how nature, nurture, and access shape individual vulnerability and drug of choice [25:15];
• How abstinence from addictive behaviors can help reset the brain’s reward system and improve mental health [41:15];
• Safely abstaining from addiction substances, drugs needing medical supervision, and other key considerations [51:30];
• Transitioning from abstinence to long-term recovery: tools and considerations [59:00];
• Exploring behavioral addictions like sex addiction, and the gender differences in addiction patterns [1:08:30];
• Factors contributing to the increasing levels of addiction across the world [1:13:45];
• How online pornography can affect young boys' developing brains and lead to addictive behaviors, and strategies for parents to address this issue [1:23:30];
• The link between social media use and declines in mental health, potential solutions, and protective measures [1:34:45];
• How exercise affects brain chemistry, the role of dopamine and endorphins, and how exercise can become addictive [1:44:00];
• Cold-water immersion for mood regulation, and other healthy coping strategies [1:47:15];
• The “marshmallow experiment”: how broken promises affect behavior and trustworthy environments help children develop self-control [1:54:00];
• Can GLP-1 agonists be useful in treating addiction? [1:58:30];
• The benefits of 12-step programs [2:06:00];
• Why understanding a patient’s story is essential for meaningful psychiatric care [2:11:45]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter dives back into the increasingly popular topic of GLP-1 agonists, such as Ozempic and Mounjaro, which have garnered widespread attention for their ability to promote weight loss. Peter covers the latest findings in this rapidly evolving landscape, including new insights into their long-term efficacy, side effects, and what happens when the drug is discontinued. Peter also explores their impact on body composition and how resistance training interacts with these treatments. Additionally, he compares different GLP-1 receptor agonists and discusses promising new drugs in the pipeline. Finally, Peter addresses questions about the role of compounding pharmacies in the GLP-1 agonist market, compares oral vs. injectable options, and provides key considerations for anyone deciding whether to use a GLP-1 agonist for weight loss.

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

We discuss:

• The rapidly evolving landscape of GLP-1 agonists [2:15];
• The mechanism of GLP-1 agonists, their origin as diabetes treatments, and how they evolved into weight-loss drugs [6:45];
• Overview of new data and open questions related to the benefits and risks of GLP-1 agonists [10:30];
• New insights into the long-term safety of GLP-1 agonists, side effects, and more [16:45];
• The long-term efficacy of GLP-1 agonists, financial barriers, and more [19:45];
• The mechanisms behind GLP-1 agonists' ability to promote weight loss [22:00];
• New data on body weight changes after discontinuing the drug [26:00];
• Effects of GLP-1 agonists on lean mass and body composition, and the role of protein and resistance training in preserving muscle [31:30];
• Semaglutide vs. tirzepatide: comparing benefits and side effects [36:30];
• How compounding pharmacies affect availability of GLP-1 drugs and the types of formulations that are available [39:15];
• How do oral formulations of GLP-1 drugs compare to injectable formulations? [44:15];
• How do sublingual (under tongue) formulations of GLP-1 drugs compare to injectable formulations? [46:15];
• Guidance for using compounding pharmacies to purchase GLP-1 agonists [47:15];
• Data on retatrutide—a promising new triple receptor agonist in the pipeline [50:15];
• Can GLP-1 agonists be beneficial for sleep apnea and immune function? [57:00];
• Potential neuroprotective benefits of GLP-1 agonists: impact on dementia risk [1:00:45];
• Exploring why GLP-1 agonists may reduce the risk of cancer, kidney disease, and cardiovascular disease [1:04:00];
• How GLP-1 agonists might boost fertility in women [1:10:15];
• Early indications that GLP-1 agonists may help treat substance abuse disorders [1:12:00];
• Potential health risks of GLP-1 agonists: addressing thyroid cancer concerns and the unknowns due to lack of data [1:14:00];
• Examining the potential link between GLP-1 agonists and increased depression or suicidal ideation [1:16:00];
• Major remaining questions: the effects of cyclic use, rebound appetite, impact on adolescents' development, and more [1:19:30];
• Key considerations when deciding whether to use a GLP-1 agonist for weight loss [1:23:45]; and
• More.

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In this quarterly podcast summary (QPS) episode, Peter summarizes his biggest takeaways from the last three months of guest interviews on the podcast. Peter shares key insights from each episode, covering diverse topics such as liver health with Julia Wattacheril, heart rate variability with Joel Jamieson, artificial intelligence with Zak Kohane, klotho for brain health with Dena Dubal, and lactate and lactate metabolism with George Brooks. Additionally, Peter shares any personal behavioral adjustments or modifications to his patient care practices that have arisen from these engaging discussions.

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 episode #319 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Overview of topics, and the positive feedback on the quarterly podcast summary format [2:00];
• Julia Wattacheril episode: liver health and disease [4:00];
• Noninvasive methods to diagnose liver conditions, and how to manage and improve liver health [16:00];
• Joel Jamieson episode: heart rate variability (HRV) for training and health [27:15];
• Practical tools for measuring HRV and how it informs training and recovery decisions [37:00];
• Zak Kohane episode: artificial intelligence and medicine [47:15];
• The current role of AI in medicine and how it could revolutionize medicine in the future [53:45];
• The limitations and concerns pertaining to AI [1:00:15];
• Dena Dubal episode: the potential benefits of klotho for brain health [1:05:00];
• Animal studies on klotho and brain health [1:11:00];
• Genetics-based variations in klotho levels in humans and their impact on cognition, disease risk, and longevity [1:14:15];
• Testing klotho levels, the significance of the KL-VS variant, the role of exercise in increasing klotho, and more [1:17:30];
• The potential of klotho as a treatment for cognitive decline and Alzheimer's disease [1:23:15];
• George Brooks episode: a new paradigm to think about lactate and lactate metabolism [1:27:45];
• The potential for lactate infusions to aid in brain recovery following a head injury [1:34:00];
• The relationship between lactate and cancer, and the impact of exercise on lactate levels and cancer risk [1:36:30]; and
• More.

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Tadej Pogačar is a three-time Tour de France champion and one of the most dominant cyclists of his generation. In this episode, he shares insights into his 2020 Tour de France victory, his historic 2024 season winning both the Giro d’Italia and Tour de France, and the struggles he faced in 2022 and 2023. He also dives into his training regimen, nutrition, and the key metrics he tracks, like power, VAM, and heart rate variability. Tadej offers a glimpse into his goals for the future and what it takes to stay at the top of the sport.

We discuss:

• 2020 Tour de France win [4:30];
• Learning from previous mistakes [8:45];
• Training: simulating steep climbs and other challenging race conditions [10:30];
• Tadej’s historic 2024 season and what contributed to his success [12:30];
• Nutrition for optimal performance: offseason diet and carbohydrate intake during intense training sessions [15:30];
• Training metrics: heart rate, power output, VAM, and HRV, and his approach to zone 2 training [18:15];
• Epic climbs in the Tour de France, mindset after challenging stages, and rebuilding confidence after the 2023 Tour [25:45];
• Racing dynamics, media criticism, and Tadej’s reflections on racing records [32:15];
• Training in the off-season [39:00]; and
• More.

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Marty Makary, a Johns Hopkins surgeon and New York Times bestselling author, returns to The Drive to discuss his latest book, Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health. In this episode, Marty explores how a new generation of doctors is challenging long-held medical practices by asking critical new questions. He discusses the major problems of groupthink and cognitive dissonance in the medical community and delves into several of the "blind spots" raised in the book, including treatments for appendicitis, the peanut allergy epidemic, misunderstandings about HRT and breast cancer, antibiotic use, and the evolution of childbirth. He explains the urgent need for reform in medical education and the major barriers standing in the way of innovative medical research. Throughout the conversation, Marty offers insightful reflections on where medicine has succeeded and where there’s still room to challenge historic practices and embrace new approaches.

We discuss:

• The issue of groupthink and cognitive dissonance in science and medicine [2:30];
• How a non-operative treatment for appendicitis sheds light on cognitive dissonance [7:00];
• How cognitive dissonance and effort justification shape beliefs and actions [13:15];
• How misguided peanut allergy recommendations created an epidemic [17:45];
• The enduring impact of misinformation and fear-based messaging around hormone replacement therapy allegedly causing breast cancer [25:15];
• The dangers of extreme skepticism and blind faith in science, and the importance of understanding uncertainty and probability [28:00];
• The overuse of antibiotics and the rise of antibiotic resistant infections and poor gut health [33:45];
• The potential correlations between early antibiotic use and chronic diseases [40:45];
• The historical and evolving trends in childbirth and C-section rates [50:15];
• Rethinking ovarian cancer: recent data challenging decades of medical practice and leading to new preventive measures [1:05:30];
• Navigating uncertainty as a physician [1:19:30];
• The urgent need for reform in medical education [1:21:45];
• The major barriers to innovative medical research [1:27:30];
• The dogmatic culture of academic medicine: why humility and challenging established norms are key for progress [1:38:15];
• The major successes and ongoing challenges of modern medicine [1:51:00]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter dives deep into the topic of hair loss, exploring its relationship with aging and its impact on quality of life. The conversation focuses on androgenic alopecia, the most common form of hair loss in both men and women, and covers the differences in patterns and causes between the sexes. Peter delves into the right timing for treatment, breaking down various options such as minoxidil and finasteride, low-level laser therapy, platelet-rich plasma injections, and more. Additionally, Peter outlines the pros and cons of the two primary hair transplantation methods and concludes with practical advice on selecting the right specialist or treatment team for those facing hair loss.

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

We discuss:

• The impact of hair loss on emotional health [2:15];
• The prevalence, patterns, and causes of hair loss in men and women [5:15];
• The genetic and hormonal causes of hair loss, and the role of dihydrotestosterone (DHT) in androgenic alopecia [8:45];
• The visual differences in hair loss patterns between men and women, and the importance of consulting a specialist to rule out non-genetic causes of hair loss [13:30];
• How genetic predisposition influences the risk of androgenic alopecia, and how early detection through diagnostic tools and blood tests can help manage risk more effectively [16:45];
• Ideal timing for starting treatment: why early treatment is crucial for effectively managing hair loss [19:30];
• The various FDA-approved treatments for androgenic alopecia, their mechanisms, and additional off-label treatments commonly used to manage hair loss [24:30];
• Topical minoxidil—the most commonly recommended starting treatment for hair loss [30:15];
• Oral vs. topical minoxidil: efficacy, ease of use, and potential side effects that must be considered [33:45];
• 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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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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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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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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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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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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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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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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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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Iñigo San-Millán is an internationally renowned applied physiologist and a previous guest on The Drive. His research and clinical work focuses on exercise-related metabolism, metabolic health, diabetes, cancer metabolism, nutrition, sports performance, and critical care. In this episode, Iñigo describes how his work with Tour de France winner Tadej Pogačar has provided insights into the amazing potential of elite athletes from a performance and metabolic perspective. He speaks specifically about lactate levels, fat oxidation, how carbohydrates in food can affect our lactate and how equal lactate outputs between an athlete and a metabolically unhealthy individual can mean different things. Next, he discusses how Zone 2 training boosts mitochondrial function and impacts longevity. He explains the different metrics for assessing one’s Zone 2 threshold and describes the optimal dose, frequency, duration, and type of exercise for Zone 2. Additionally, he offers his thoughts on how to incorporate high intensity training (Zone 5) to optimize health, as well as the potential of metformin and NAD to boost mitochondrial health. Finally, he discusses insights he’s gathered from studying the mitochondria of long COVID patients in the ICU.

We discuss:

• The amazing potential of cyclist Tadej Pogačar [2:00];
• Metrics for assessing athletic performance in cyclists and how that impacts race strategy [7:30];
• The impact of performance-enhancing drugs and the potential for transparency into athletes’ data during competition [16:15];
• Tadej Pogačar’s race strategy and mindset at the Tour de France [23:15];
• Defining Zone 2, fat oxidation, and how they are measured [26:00];
• Using fat and carbohydrate utilization to calculate the mitochondrial function and metabolic flexibility [35:00];
• Lactate levels and fat oxidation as it relates to Zone 2 exercise [39:15];
• How moderately active individuals should train to improve metabolic function and maximize mitochondrial performance [51:00];
• Bioenergetics of the cell and what is different in elite athletes [56:30];
• How the level of carbohydrate in the diet and ketogenic diets affects fuel utilization and power output during exercise [1:07:45];
• Glutamine as a source for making glycogen—insights from studying the altered metabolism of ICU patients [1:14:15];
• How exercise mobilizes glucose transporters—an important factor in diabetic patients [1:20:15];
• Metrics for finding Zone 2 threshold—lactate, heart rate, and more [1:24:00];
• Optimal Zone 2 training: dose, frequency, duration, and type of exercise [1:40:30];
• How to incorporate high intensity training (Zone 5) to increase VO2 max and optimize fitness [1:50:30];
• Compounding benefits of Zone 2 exercise and how we can improve metabolic health into old age [2:01:00];
• The effects of metformin, NAD, and supplements on mitochondrial function [2:04:30];
• The role of lactate and exercise in cancer [2:12:45];
• How assessing metabolic parameters in long COVID patients provides insights into this disease [2:18:30];
• The advantages of using cellular surrogates of metabolism instead of VO2 max for prescribing exercise [2:25:00];
• Metabolomics reveals how cellular metabolism is altered in sedentary individuals [2:33:00];
• Cellular changes in the metabolism of people with diabetes and metabolic syndrome [2:38:30]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter delves into two topics that have generated a lot of questions over the years: skin cancer and sunscreen. He begins by exploring the basics of UV radiation, discussing its effects on vitamin D conversion, photoaging, and its role in skin cancer. He examines various skin types, discussing their implications for sun exposure and vitamin D levels, as well as how to determine where you fall on the skin type scale. He then delves into the various types of skin cancer, with a particular emphasis on melanoma, exploring its complex relationship with UV exposure and other contributing risk factors. Additionally, he covers tanning beds, the importance of early skin cancer detection through regular skin checks, and the often confusing topic of sunscreen. He explains how sunscreen affects UV radiation and skin cancer risk, what SPF levels to choose, the differences between organic and mineral sunscreens, and what to consider when selecting the best sunscreen for your needs.

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

We discuss:

• The impact of UV radiation on the skin [2:00];
• Understanding solar UV: from the electromagnetic spectrum to skin health [3:45];
• The role of sunlight in vitamin D production [8:30];
• Factors contributing to vitamin D deficiency: insufficient UV exposure, magnesium levels, and more [9:45];
• Sun exposure needs for different skin types, and the limitations of current studies in defining vitamin D deficiency [12:45];
• The acute and long-term effects of excessive UV exposure: sunburn, photoaging, and the increased risk of skin cancer [15:30];
• Types of skin cancer and associations with UV exposure [17:45];
• The complex relationship between melanoma and UV exposure [22:15];
• Why UV exposure alone doesn’t necessarily explain the risk for melanoma [25:15];
• Other risk factors for melanoma [29:15];
• Tanning beds and skin cancer risk [34:45];
• Balancing sun exposure: benefits and risks [38:15];
• Tattoos and sun exposure [40:30];
• The importance of regular skin checks, dermatologists, and emerging technologies showing promise for early detection of cancer [41:45];
• Self-skin checks: what to look for [46:30];
• Prevalence of skin cancer and the importance of early detection [49:30];
• Summary of the major risk factors for melanoma [54:15];
• The role of sunscreen in reducing skin cancer risk [55:45];
• How sunscreen works, the differences between chemical and mineral sunscreens, an explanation of SPF, and more [58:30];
• How to determine the appropriate sunscreen SPF to use based on the UV index [1:04:45];
• Choosing the right sunscreen for your individual needs [1:07:00];
• The impact of water and perspiration on sunscreen effectiveness [1:12:00];
• Chemical vs. mineral sunscreens: safety concerns and recommendations [1:14:00];
• Concerns about hormone effects from chemical sunscreens [1:19:15];
• Sunscreen summary: skin types, key considerations, recommended brands, and more [1:23:15]; and
• More.

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In this special episode, Peter addresses the common questions about starting or returning to an exercise routine over the age of 50. Individuals in this age group have frequently reached out with questions about whether it's too late to start exercising and often express concern over a lack of prior training, a fear of injury, or uncertainty about where to begin. Peter delves into the importance of fitness for older adults, examining all four pillars of exercise, and provides practical advice on how to start exercising safely, minimize injury risk, and maximize potential benefits. Although this conversation focuses on people in the “older” age category, it also applies to anyone of any age who is deconditioned and looking to ease into regular exercise.

We discuss:

• Key points about starting exercise as an older adult [2:45];
• Why it’s never too late to begin exercising and incorporating the four pillars of exercise [5:45];
• The gradual, then sharp, decline in muscle mass and activity level that occur with age [10:00];
• The decline of VO2 max that occurs with age [15:30];
• Starting a training program: exercise variability, movement quality, realistic goals, and more [18:30];
• Improving aerobic capacity: the malleability of the system, the importance of consistency, and setting long-term fitness goals [25:15];
• Starting cardio training: base building, starting with low volume, and zone 2 training [30:45];
• The critical role of VO2 max in longevity [36:45];
• How to introduce VO2 max training to older or deconditioned individuals [46:15];
• Options for performing zone 2 and VO2 max training [53:45];
• The ability to make gains in strength and muscle mass as we age [57:00];
• How to implement strength training for older individuals [1:01:00];
• Advice for avoiding injury when strength training [1:07:30];
• Risk of falls: the devastating consequences and the factors that increase fall risk [1:12:15];
• Mitigating fall risk: the importance of foot and lower leg strength, ankle mobility, and balance [1:19:45];
• Improving bone mineral density through resistance training [1:24:30];
• The importance of protein in stimulating muscle protein synthesis, especially in older adults [1:31:00];
• Parting advice from Peter [1:34:00]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter provides insights on a broad range of important topics. He delves into the prevention of cognitive decline, the link between cardiovascular disease and Alzheimer's disease, and methods to lower blood glucose, insulin, and apoB. He also addresses nutrition-related queries, exploring the impact of dietary habits on weight loss and longevity, how a person can identify the best diet for themselves, and common nutrition myths. Additional discussions include optimal blood pressure, daily step goals, the benefits of standing versus sitting desks, and much more.

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

We discuss:

• Overview of topics and episode format [1:40];
• Preventing cognitive decline [5:00];
• How to lower blood glucose and insulin [13:30];
• The relationship between lipids, CVD, and Alzheimer’s disease, and whether statins can increase the risk of neurodegenerative disorders and AD [23:15];
• Reducing apoB levels through exercise and diet [31:45];
• Pharmacological options for lowering apoB [38:00];
• How nutrition impacts longevity via metabolic health, muscle mass, BMD and more [40:15];
• How can someone determine the best diet for themselves? [43:45];
• Nutrition myth: All weight loss is good [46:45];
• Nutrition myth: Metabolic rates are dramatically different among individuals based on genetics [49:00];
• Nutrition myth: Losing weight after a brief period of overeating is impossible [53:45];
• Nutrition myth: GLP-1 agonists are a replacement for a healthy lifestyle [57:45];
• Nutrition myth: There is a single best diet for weight loss [1:03:00];
• Nutrition oversimplification: All calories are created equal [1:05:45];
• Daily step goals [1:06:45];
• The benefits of standing versus sitting throughout the day [1:10:45];
• How to identify the most impactful and easiest-to-implement ways to improve your health [1:12:30];
• The critical importance of emotional health [1:14:30];
• Why supplements should be considered as supportive aids rather than primary solutions in one’s strategy to improve longevity [1:18:00];
• Strategies for reducing high blood pressure [1:20:45];
• Peter’s biggest frustrations with "mainstream health advice" [1:28:00];
• Peter’s chaotic, yet cherished, morning routine [1:31:00]; and
• More.

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Joel Jamieson is a conditioning expert who developed Morpheus to give people a smarter way to build their conditioning regimen and improve their recovery. In this episode, Joel dives deep into the world of heart rate variability (HRV), explaining its scientific foundation, how it measures the balance between the sympathetic and parasympathetic nervous systems, the various methods of measurement, and how it can guide healthier lifestyle choices and improved training performance. He explores the nuances of HRV calculation, the impact of aging on HRV, and the roles of genetics, exercise, and other lifestyle factors in this process. He also covers Morpheus, the innovative training tool that won Peter over after his initial skepticism, highlighting its practicality and effectiveness in guiding training and optimizing fitness outcomes.

We discuss:

• Heart rate variability (HRV): evolution, science, and practical applications of HRV in athletic training [4:00];
• Methods of measuring HRV: EKG, wrist-based sensors, and more [11:30];
• How HRV is calculated from the data [22:30];
• The role of the autonomic nervous system (ANS) in regulating HRV [25:45];
• The decline in HRV with age, and the mitigating effects of fitness and other lifestyle factors [33:30];
• The role of genetics in HRV, the modifiability of HRV, and a comparison of VO2 max and HRV as predictors of mortality [37:00];
• How aging affects HRV and sympathetic drive, and the importance of spontaneous movement and exercise in maintaining the body's adaptability [43:30];
• How Morpheus measures HRV using RMSSD and normalizes it to a 100-point scale for easier interpretation [49:45];
• The Morpheus system: development, integration with various metrics, and personalized daily training recommendations to optimize fitness and recovery [51:30];
• The benefits of morning HRV readings for assessing daily readiness compared to overnight HRV measurements [1:03:00];
• Why Morpheus recommends using a chest strap rather than an arm band [1:10:00];
• The impact of consistent exercise, stress, alcohol, and other lifestyle factors on HRV [1:11:15];
• Optimizing zone 2 training with Morpheus [1:18:15];
• Using heart rate recovery (HRR) as an indicator of athletic conditioning and the balance between aerobic and anaerobic systems [1:22:45];
• The importance of tracking HRV trends over time rather than focusing on data from a given day [1:29:00];
• Effect of GLP-1 agonists on heart rate and HRV [1:34:45];
• Where HRV belongs in the hierarchy of health metrics [1:42:00];
• Parting thoughts [1:46:30]; and
• More.

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In this quarterly podcast summary (QPS) episode, Peter introduces a new format aimed at summarizing his biggest takeaways from the last three months of guest interviews on the podcast. Peter shares key insights from each episode, covering diverse topics such as protein and muscle building with Luc van Loon, toe strength with Courtney Conley, VO2 max with Olav Aleksander Bu, liquid biopsies for cancer with Alex Aravanis, gut health and probiotics with Colleen Cutcliffe, and road safety with Mark Rosekind. Additionally, Peter shares any personal behavioral adjustments or modifications to his patient care practices that have arisen from these engaging discussions.

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 episode #304 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• How Peter keeps track of his takeaways from each podcast episode [5:15];
• Luc van Loon episode: fat utilization, muscle protein synthesis, dietary protein, aging and inactivity, and more [8:45];
• Behavioral changes that have come about from the conversation with Luc van Loon [23:45];
• Courtney Conley episode: importance of toe strength and the impact of dedicated foot training [26:45];
• Olav Aleksander Bu episode: the importance of VO2 max for lifespan, and the practicalities of measuring and improving VO2 max [36:45];
• Behavioral changes that have come about from the conversation with Olav [56:00];
• Alex Aravanis episode: liquid biopsies for cancer detection [1:01:30];
• Colleen Cutcliffe episode: the importance of gut bacteria balance, and the potential therapeutic uses of probiotics, particularly Akkermansia [1:16:45];
• Mark Rosekind: the significant issue of road fatalities and injuries, their causes, and practical safety measures to reduce risks [1:27:00]; and
• More.

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Dena Dubal is a physician-scientist and professor of neurology at UCSF whose work focuses on mechanisms of longevity and brain resilience. In this episode, Dena delves into the intricacies of the longevity factor klotho: its formation and distribution in the body, the factors such as stress and exercise that impact its levels, and its profound impact on cognitive function and overall brain health. Dena shares insights from exciting research in animal models showing the potential of klotho in treating neurodegenerative diseases as well as its broader implications for organ health and disease prevention. She concludes with an optimistic outlook for future research in humans and the potential of klotho for the prevention and treatment of Alzheimer’s disease.

Disclosure: Peter is an investor in Jocasta Neuroscience, a company working to develop klotho as a therapy for people with Alzheimer’s disease.

We discuss:

• Dena’s fascination with aging and how she came to study klotho [3:30];
• Biological properties of klotho: production, regulation, decline with age, and factors influencing its levels [11:45];
• Potential benefits of klotho on brain health [22:00];
• The relationship between soluble klotho protein, platelet factors, and cognitive enhancement [33:45];
• The role of platelet factor 4 (PF4) and it’s interaction with GluN2B in mediating cognitive enhancement [46:45];
• Benefits of klotho observed in a mouse model of Parkinson’s disease [55:45];
• Benefits of klotho observed in a mouse model of Alzheimer’s disease [1:03:00];
• Promising results of klotho in primate models, and the importance of finding an appropriate therapeutic dose before moving to human trials [1:08:00];
• Speculating why a single klotho injection has such long-lasting effects [1:25:30];
• Potential cognitive benefits of klotho in humans, the impact of the KL-VS genetic variant on klotho levels, and the need for human trials to confirm these effects [1:27:45];
• The interaction between the KL-VS genetic variant and APOE4 and how it impacts risk of Alzheimer’s disease [1:34:45];
• The significance of klotho levels: studies linking lower levels to increased mortality and the broader implications for organ health and disease prevention [1:47:15];
• Measuring klotho levels and determining an individual’s KL-VS status [1:52:15];
• The promising potential of klotho for Alzheimer’s disease treatment, and the importance of philanthropy for funding research [1:58:00]; and
• More.

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Julia Wattacheril is a physician scientist and director of the Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) program at Columbia University Irving Medical Center. In this episode, Julia delves deep into the complex world of liver health, beginning with a foundational overview of liver physiology. She provides an in-depth look at how alcohol impacts liver function, breaking down the metabolism of ethanol and its detrimental effects. Julia then shifts the focus to understanding liver function tests and optimal enzyme levels, providing a detailed explanation of AST and ALT and elucidating why fluctuations in these levels may or may not be concerning. She provides a primer on the four major stages of liver disease, discussing risk and emphasizing the importance of early diagnosis. Julia highlights the role of liver disease in increasing the risk of cancer and cardiovascular disease and covers in detail the various strategies for diagnosing, treating, and preventing the progression of liver disease.

We discuss:

• Julia’s training, the importance of liver health, and the challenges and innovations of hepatology [3:15];
• The complex and crucial functionality of the liver, its four most essential functions, and more [8:45];
• Liver injuries: historical and evolving understanding of causal factors, and the progression to liver diseases and cancer [13:15];
• How the liver metabolizes nutrients and what happens in the presence of excess calories or alcohol [24:45];
• Methods of diagnosing liver disease and how insights guide treatment and management strategies [33:30];
• The poisonous nature of ethanol to the liver [40:30];
• Varied responses to alcohol, damaging effects of alcohol beyond the liver, and the process of advising patients on their alcohol consumption [47:15];
• Understanding liver enzymes AST and ALT—interpreting levels, lifestyle factors that affect them, and diagnostic approaches [58:30];
• Interpreting liver function tests for fatty liver disease, and the challenges of diagnosing liver pathologies, particularly in children versus adults [1:13:15];
• Comprehensive liver health assessments via imaging and various diagnostic tools to prevent overlooking potential liver pathologies [1:18:45];
• Potential impact of recreational drugs, statins, and other medications on liver function test results [1:26:45];
• Shifting nomenclature from NAFLD to MASLD to reflect accuracy in the underlying pathophysiology and understanding of liver diseases [1:30:30];
• Pathophysiology of MASLD, the need for proactive screening, and the significance of liver fat percentage as an indicator of metabolic health [1:36:30];
• The importance of screening for rare conditions alongside common metabolic diseases associated with fatty liver accumulation [1:42:45];
• Practical strategies for managing MAFLD [1:45:30];
• The impact of fructose consumption on liver health and the challenges of disentangling its effects from other factors like obesity and insulin resistance [1:52:45];
• The potential of GLP-1 agonists for the treatment of MASLD [1:57:45];
• How the four stages of liver disease have evolved [2:00:30];
• Increased cancer and heart disease risk associated with early-stage MAFLD [2:05:15];
• Emerging drugs and therapies for addressing fat accumulation and fibrosis related to MAFLD [2:12:15];
• Peter’s major takeaways [2:18:45]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter delves into the often misunderstood concept of inflammation. He first defines inflammation and differentiates between acute inflammation and chronic inflammation, the latter of which is linked to aging and a plethora of age-related diseases. Peter breaks down the intricate relationship between chronic inflammation, obesity, and metabolic health, and highlights the signs that might suggest someone may be suffering from chronic inflammation. From there, the conversation centers on actionable advice and practical steps one can take to manage and minimize chronic inflammation. He explores how diet plays a crucial role, including the potential benefits of elimination diets, and he examines the impact of lifestyle factors such as exercise, sleep, and stress management. Additionally, he discusses the relevance of food inflammatory tests and concludes by examining the potential benefits and drawbacks of drugs and supplements in managing inflammation.

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

We discuss:

• Defining inflammation (and the cultural impact of Napoleon Dynamite) [1:45];
• Acute vs chronic inflammation [8:00];
• The connection between chronic inflammation, aging, and age-related diseases [11:00];
• The impact of inflammation on metabolic health [18:30];
• Understanding and diagnosing chronic inflammation: blood tests and other approaches, and challenges with measurement [20:00];
• Factors that contribute to low-level chronic inflammation [28:00];
• Minimizing inflammation through diet [29:45];
• The important role of fiber for gut health and inflammation [33:45];
• A closer look at the impact of trans fats and saturated fats on overall health [34:45];
• Why Peter prefers dietary fiber from food sources over supplements [38:30];
• Debunking “superfoods”: emphasizing proven methods over marketing claims for reducing inflammation [39:00];
• Is there any value in over-the-counter food inflammatory tests? [42:30];
• Food elimination diets: how they work, symptoms and markers to watch, challenges and limitations [45:15];
• Identifying dietary triggers for gut-related symptoms through low-FODMAP diets like the “carnivore diet” [51:15];
• Dairy: the complex role of dairy on inflammation and individual responses [55:00];
• Wheat: the complexities and conflicting evidence around wheat's inflammatory effects [57:45];
• How exercise influences inflammation [1:02:00];
• How sleep quality and duration impacts inflammation [1:07:00];
• The potential impact of chronic psychological stressors on inflammation [1:13:00];
• The impact of oral health on inflammation and overall well-being [1:15:00];
• The role of medications in managing chronic inflammation [1:18:15];
• Supplements: evaluating the efficacy of various anti-inflammatory supplements [1:22:15];
• Parting thoughts and takeaways [1:27:00]; and
• More.

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In this special edition celebrating 300 episodes of The Drive, Peter discusses a variety of popular topics and health interventions and classifies them based on their level of evidence and relevance using the following categories: proven, promising, fuzzy, noise, and nonsense. Peter first delves into the topic of geroprotective molecules, covering rapamycin, metformin, NAD and its precursors, and resveratrol. Next, he explores the significance of metrics like VO2 max and muscle mass, as well as emerging concepts like blood flow restriction and stem cells. The conversation extends to nutrition, addressing questions surrounding long-term fasting, sugar consumption, sugar substitutes, and the contentious role of red meat in cancer. Peter not only provides his current stance on each topic—most of which have been covered in great detail in the previous 300 episodes—but also reflects on how his opinion may have evolved over the years.

We discuss:

• Defining the categories of “proven, promising, fuzzy, noise, and nonsense” [3:15];
• Rapamycin [9:30];
• Metformin [17:00];
• NAD and its precursors [24:30];
• Resveratrol [32:45];
• The importance of VO2 max, muscle mass, and muscular strength for lifespan [38:15];
• Blood flow restriction (BFR) training [44:00];
• Using stem cells to treat osteoarthritis or injury [51:30];
• Fasting as a tool for longevity (and why Peter stopped his fasting protocol) [55:45];
• The energy balance theory [1:06:30];
• The idea that sugar is poison [1:12:00];
• The idea that sugar substitutes are dangerous [1:22:15];
• The debate on red meat and cancer [1:28:45]; and
• More.

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This is a special episode of The Drive with Peter’s friend and fellow car enthusiast Dax Shepard. In this podcast, which commemorates the 30th anniversary of the death of Brazilian Formula One legend Ayrton Senna, Dax sits down with Peter to better understand what made Senna so special and why Peter remains an enormous fan. This conversation focuses on Senna’s life, the circumstances of his death, and his lasting impact and legacy on the sport of F1.

We discuss:

• Peter’s interest in motorsports began as a child [2:30];
• The drama and dangers of F1 [6:00];
• What made Senna special [13:00];
• What Senna meant to Brazilians [24:00];
• The cause of the fatal crash [28:15];
• Why Peter is obsessed with Senna [40:30];
• Being the best versus having the best record [43:30];
• Senna’s unique driving style and incredible intuition about automotive engineering [46:30];
• Back to the day of the dreadful race [53:00];
• What Peter believes caused the crash [1:02:45];
• Views on dying young, in the prime of life [1:13:00];
• Senna lives on in his foundation and in safety changes adopted by F1 [1:21:00];
• Statistics aren’t enough for fandom, and why people like who they do [1:24:15];
• The biggest difference between F1 today and F1 in the 80s [1:28:30];
• Senna’s driving superpower [1:30:30];
• The fastest drivers currently in F1 [1:38:30];
• Current F1 obsessions [1:45:00];
• How hard it is to do what the top F1 drivers do [1:50:15];
• Dax’s love of motorcycles and his AMG E63 station wagon [1:52:15];
• Awesome Senna mementos from Etsy [2:01:15];
• What makes specialists interesting, and Max’s devotion to F1 [2:10:15];
• What Senna might have done if he had not died that day [2:14:00];
• Michael Schumacher and Max Verstappen are also top F1 drivers [2:17:30];
• Interlagos in Sao Paulo Brazil is always an incredible experience [2:18:45]; and
• More.

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Luc van Loon is an internationally renowned expert in skeletal muscle metabolism. In this episode, Luc starts with an exploration of the roles of insulin and triglycerides in endurance exercise, highlighting their impact on skeletal muscle metabolism, and he offers profound insights into the significance of protein in this context. He elucidates how different protein types and forms influence muscle protein synthesis rates, exploring the nuances of protein absorption, digestibility, amino acid quality, and their implications for performance and recovery. Delving deeper, he differentiates between animal and plant protein sources, unraveling the distinctive properties of various protein types, from the differences between whey and casein to the emerging trends in collagen protein supplementation. Moreover, Luc dissects the intricate connections among physical activity, lean muscle mass, muscle protein synthesis induced by resistance training, and dietary protein.

We discuss:

• Luc’s background and insights about fuel selection during exercise [3:30];
• Fuel utilization during endurance exercise [9:30];
• Fat metabolism, intramuscular lipids, and the nutritional dynamics of endurance sports [17:15];
• The optimal window for replenishing intramuscular fat stores and glycogen post-exercise [25:15];
• Luc’s interest in protein metabolism and exploration of amino acids' dual role as building blocks and signaling molecules in driving muscle protein synthesis [32:15];
• How protein metabolism differs between sedentary individuals and those engaged in predominantly strength training or endurance training [38:45];
• The basics of how proteins are digested and absorbed, and how muscle protein synthesis is measured [50:30];
• How factors like food texture, cooking methods, and protein composition impact muscle protein synthesis, and the importance of protein distribution throughout the day [59:45];
• Differences in whey and casein proteins, and the ability of ingested protein to stimulate muscle protein synthesis [1:03:30];
• Dietary protein distribution and quantity for the maximization of muscle protein synthesis [1:09:00];
• Muscle loss with age and inactivity and the importance of resistance exercise to maintain type II muscle fibers [1:17:15];
• Differences between whey and casein proteins, and the importance of both quantity and quality of protein sources [1:28:30];
• Optimizing muscle protein synthesis: exercise, timing of protein intake, protein quality, and more [1:37:00];
• How to preserve muscle while trying to lose weight [1:46:00];
• Anabolic resistance and overcoming it with physical activity [1:55:45];
• Importance of protein intake and physical activity in hospitalized patients [2:06:30];
• Reviewing the efficacy of collagen supplements [2:13:30];
• Plant-based diets: how to ensure a balance of amino acids, and other considerations [2:20:30];
• Future research: understanding protein metabolism in the brain [2:23:45]; and
• More.

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Paul Conti is an author and practicing psychiatrist who specializes in helping people heal from trauma. In this episode, Paul returns to The Drive to delve into the intricate relationship between emotional health, healthspan, and lifespan. He first challenges common assumptions about the inevitable decline of emotional health with age, providing strategies for conducting a comprehensive audit of internal emotional health. He establishes a framework for the foundation of good emotional health: a balance between the generative drive, the assertive drive, and the pleasure drive. Paul also explores the nuanced dynamics of motivation, happiness, and satisfaction as it relates to material possessions, draws connections between physical and emotional well-being, confronts the impact of negative self-talk, and describes how making peace with our mortality can foster a sense of hope, purpose and well-being. Additionally, Paul offers many practical insights into initiating emotional health improvements and navigating the search for a suitable therapist.

We discuss:

• The importance of prioritizing emotional health as we age [2:45];
• The impact of emotional health on healthspan and how to foster a proactive approach to emotional well-being [7:00];
• The discrepancy between outward success and inner fulfillment, and the importance of a healthy “generative drive” for genuine well-being [13:00];
• A deeper dive into generative drive: impact on human behavior, resilience, purpose, and more [23:15];
• Evaluating one’s inner self: introspection, self-awareness, challenging societal norms, and returning to the basics of physical and emotional well-being [29:00];
• Self-auditing tools: introspection, curiosity, and exploring underlying reasons for unwanted behaviors [41:45];
• Breaking free from destructive cycles by understanding the continuum of self-care and addictive behaviors and remaining curious [50:15];
• Critical self talk: the malleability of one’s inner dialogue and the potential for transformative change with perseverance and self-compassion [1:00:15];
• Slowing the anger response and gaining insights into the underlying triggers to achieve lasting change and self-understanding [1:13:45];
• Foster gratitude and humility by achieving balance between the three drives—assertion, pleasure, and generative [1:20:45];
• The conflict between intellectual understanding and emotional feelings, problematic comparison frameworks, and the importance of living in the present with intentionality [1:24:15];
• How making peace with our mortality can foster a sense of hope, purpose and well-being [1:34:45];
• Advice for finding a compatible therapist [1:43:45];
• The key components of therapeutic progress [1:57:00];
• The caricatures of four common patient phenotypes, and how to get through to them [2:05:30];
• How Paul manages his own well-being and the emotional challenges that come with his line of work [2:15:15]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter delves into the crucial yet often overlooked topic of iron and iron deficiency. He explores why iron is indispensable for the body, explains the repercussions of iron deficiency, and sheds light on the prevalence of this issue and who is most susceptible. Peter outlines strategies for increasing iron levels, covering dietary iron, supplementation, and infusion options, while also discussing the suitability of each approach for different individuals. Shifting gears, Peter tackles rapid-fire questions on creatine and sodium, as well as inquiries related to his book.

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

We discuss:

• Overview of today’s topics and the importance of understanding iron levels in the body [1:45];
• The importance and ubiquity of iron in the body, and the role of the protein called ferritin [4:30];
• The processes of iron absorption, utilization, and transportation [9:30];
• Options for testing iron levels and how to interpret the results [13:45];
• What does it mean to be iron deficient, and how is it different from anemia? [17:15];
• Symptoms of iron deficiency and/or anemia [22:15];
• How prevalent is iron deficiency, and who is most susceptible? [24:30];
• The importance of consuming an adequate amount of iron daily to prevent deficiency [30:30];
• The best way to improve iron levels for someone who is deficient [34:45];
• Iron supplementation: various formulations and potential side effects [37:45];
• Intravenous iron infusion as an alternative to oral supplements -- plus restless legs syndrome and other topics [42:00];
• Iron supplementation: who should and should not consider it [44:00];
• Peter’s approach to creatine and his pre- and post-workout supplements [50:15];
• Navigating sodium intake: effect on blood pressure, who should use precaution, and other considerations [54:45];
• Peter’s thoughts about the potential of writing another book [57:15]; and
• More.

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Courtney Conley is an internationally renowned foot and gait specialist. In this episode, Courtney delves into the intricate world of foot anatomy and functionality. She explores the complexities of the foot, discussing its anatomy, common injuries, and the importance of understanding its structure in preventing issues. She covers a range of foot ailments, factors contributing to them, treatment options, and prevention strategies. She delves into the significance of loading, balance, range of motion, and posture, emphasizing the crucial role of strength in preventing both injuries and falls. Additionally, she sheds light on the interconnectedness of the kinetic chain, from the leg muscles down to the foot, and how issues within this chain can cascade downstream, leading to various injuries and pathologies. Additionally, she provides a comprehensive overview of footwear, discussing suitable options for both adults and children to promote foot health and mitigate potential problems.

In addition to this interview, Courtney also recorded a series of videos to better explain a number of the concepts discussed such as diagnostic tests that are used to determine mobility and strength and the exercises one should perform to improve the outcomes based on the diagnostics. The interview will be available to everyone while the videos from the gym will only be available to paid subscribers (found at the end of the show notes page).

We discuss:

• Why Courtney chose to specialize in the foot [3:30];
• The vital role of foot strength, function, and health in human movement and well-being [6:15];
• Anatomy of the rear foot and midfoot [10:15];
• The development of flat feet, the impact of footwear, and the benefits of going barefoot [19:45];
• Anatomy of the forefoot, common injuries, and why most injuries occur in the forefoot [23:15];
• Foot musculature and its role in maintaining foot stability and preventing deformities like bunions and hammer toes [30:15];
• The intrinsic musculature of the foot, plantar fasciitis, footwear, and more [39:00];
• Plantar fasciitis: diagnosis, causes, and treatment [51:30];
• Posterior leg muscles: strength assessment methods, role in ACL injuries, and more [59:15];
• Lateral and medial muscles: ankle stability, arch support, big toe stabilization, and exercises to strengthen and prevent injuries [1:04:15];
• Importance of strength of lower leg muscles for gait and preventing shin splints, stress injuries, and more [1:08:15];
• Tendinopathies and other common pathologies related to the anterior and lateral compartments of the foot [1:13:00];
• The importance of midfoot integrity, ankle dorsiflexion, and a discussion of gait alterations [1:19:45];
• Proximal stability and its implications for posture and movement patterns [1:27:00];
• The age-related decline in foot sensation and strength [1:32:45];
• Common toe injuries, treatment, and how to prevent further progression of the injury [1:36:30];
• Preventing falls and managing arthritis with proactive foot care and exercises [1:46:45];
• Footwear: advice for picking shoes that promote foot health [1:54:45];
• Footwear for runners [2:05:30];
• The importance of prioritizing footwear that promotes natural foot movement and strength while considering individual comfort and foot health needs [2:09:30]; and
• More.

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Mark Rosekind is an expert on road safety and a policy leader with more than 30 years of experience enacting strategic, practical, and effective data-based solutions that enhance driver and pedestrian safety and health in complex environments. In this episode, Mark delves into the persistent issue of accidental deaths resulting from roadway accidents, a concern for those focused on longevity given its consistent risk throughout life. From exploring statistics on car crashes to identifying the demographics most at risk and the key locations of incidents, he uncovers various risk factors including distractions like smartphone usage, the influence of alcohol and cannabis, the dangers of sleep deprivation, and speeding. Mark also provides practical advice for both drivers and pedestrians to enhance safety, while delving into the potential and challenges of emerging technologies such as autonomous vehicles. Additionally, Mark provides valuable resources for listeners, particularly parents navigating the road safety landscape with teenage drivers.

We discuss:

• Mark’s background and education, and the profound impact of transportation accidents on human lives [4:15];
• From sleep science to safety leadership: Mark’s journey in transportation innovation [14:15];
• Stats on transportation accidents and fatalities [18:00];
• Historical trends in road fatalities and the key contributors—impairment, distraction, and more [28:00];
• The demographics of drivers involved in crashes, and the life-saving potential of better driver education programs [34:30];
• The most critical areas where drivers need to be hyper-aware to protect themselves [41:00];
• The role of the National Transportation Safety Board (NTSB) in accident investigations, and the importance of data sources like event data recorders (EDRs) in accident reconstruction and investigations [47:00];
• The dangers of phone use while driving [53:45];
• How drunk driving was addressed through advocacy and legal changes [1:01:30];
• The need to address distracted driving and the psychological impact of distracted driving accidents on both victims and perpetrators[1:07:15];
• Navigating the roads and lowering your risk of accidents: weather, human error, and defensive driving [1:15:45];
• The impact of impaired driving: alcohol, cannabis, prescription drugs, and more [1:26:15];
• Mitigating the effects of vehicle speed [1:38:15];
• The promise and challenges of autonomous vehicles for road safety [1:44:15];
• Automatic emergency braking (AEB): the effectiveness and challenges of implementing AEB as a standard feature in new vehicles [1:53:00];
• Sleep deprivation: the impact of poor sleep, drowsiness, and disrupted circadian rhythm on driving [1:58:15];
• Protecting pedestrians: strategies for reducing the risk of fatal accidents with pedestrians on foot or bicycle [2:02:30];
• Empowering safe driving: essential resources and tips for parents and teenage drivers [2:14:00];
• Promoting a culture of proactive safety: parting thoughts from Mark [2:19:15]; and
• More.

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Olav Aleksander Bu is an internationally renowned sports scientist acclaimed for his coaching prowess with elite athletes spanning a diverse range of sports disciplines. In this episode, Olav delves deep into the intricacies of VO2 max and its profound impact on performance. They explore the relationship between VO2 max and ATP production, energy efficiency, and power, as well as the impact of low-intensity training on VO2 max. The conversation extends to Olav’s experiences pushing the boundaries with high-performance athletes and the data driven interventions he uses to improve performance. They also dissect the role of lactate threshold, discuss other important metrics to track, and explore the exciting possibility of utilizing a portable VO2 testing device as a practical alternative to traditional lab-based assessments.

We discuss:

• Olav’s background, expertise in exercise physiology, coaching experience, and interest in the extremes of human capability [4:15];
• The processes of energy conversion within the human body and its implications for performance [9:30];
• Improving movement efficiency, and the importance of mindfulness in training to optimize performance [20:00];
• 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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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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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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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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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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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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Walter Green is a remarkable philanthropist, mentor, author of This Is the Moment!, and founder of the impactful “Say It Now” movement. In this episode, Walter delves into the unique insights gained from his challenging upbringing, discusses embracing mortality, and highlights the mindset of “finishing strong.” He shares insights on intentionality, thinking in reverse, saying “no,” prioritizing relationships, and the essence of focusing on others. The conversation focuses on the “Say It Now” movement, which stresses the importance of expressing sentiments to loved ones well before the end of life.

We discuss:

• How Peter and Walter met through Ric Elias [2:45];
• The unique perspectives and life lessons provided by Walter’s challenging childhood [5:30];
• Walter’s harrowing experience with a sudden mental breakdown and his subsequent recovery with the help of therapy [11:15];
• A diverse professional journey ending in great success [18:15];
• The birth of a movement: celebrating friendships through public tributes and expressing gratitude to those who have shaped your life’s journey [22:30];
• Intentionality, thinking in reverse, saying “no”, and other guiding principles for Walter [30:00];
• Walter’s global journey of gratitude on his 70th birthday: visiting friends and creating memorable experiences [39:15];
• The profound impact of acknowledging and expressing gratitude for the people who contribute to our lives [46:15];
• The key elements for creating meaningful connections and cultivating deep, authentic friendships [52:15];
• The “Say It Now” movement: the inspiration behind the remarkably impactful initiative [58:30];
• What “finishing strong” means to Walter [1:07:30];
• Finding peace at the end of life through expressing gratitude and finding purpose in serving others [1:16:00];
• Resources to learn about “Say It Now” [1:26:15]; and
• More.

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Stuart McGill is a distinguished professor emeritus at the University of Waterloo and the chief scientific officer at Backfitpro Inc. where he specializes in evaluating complex cases of lower back pain from across the globe. In this episode, Stuart engages in a deep exploration of lower back pain, starting with the anatomy of the lower back, the workings of the spine, the pathophysiology of back pain, and areas of vulnerability. He challenges the concept of nonspecific back pain, emphasizing the importance of finding a causal relationship between injury and pain. Stuart highlights compelling case studies of the successful treatment of complex cases of lower back pain, reinforcing his conviction that nobody needs to suffer endlessly. He also covers the importance of strength and stability, shares his favorite exercises to prescribe to patients, and provides invaluable advice for maintaining a healthy spine.

We discuss:

• Peter’s experience with debilitating back pain [3:30];
• Anatomy of the back: spine, discs, facet joints, and common pain points [14:45];
• Lower back injuries and pain: acute vs. chronic, impact of disc damage, microfractures, and more [24:45];
• Why the majority of back injuries happen around the L4, L5, and S1 joints [31:00];
• How the spine responds to forces like bending and loading, and how it adapts do different athletic activities [36:15];
• The pathology of bulging discs [43:15];
• The pathophysiology of Peter’s back pain, injuries from excessive loading, immune response to back injuries, muscle relaxers, and more [46:00];
• The three most important exercises Stuart prescribes, how he assesses patients, and the importance of tailored exercises based on individual needs and body types [56:15];
• The significance of strength and stability in preventing injuries and preserving longevity [1:08:15];
• Stuart’s take on squats and deadlifting: potential risks, alternatives, and importance of correct movement patterns [1:19:30];
• Helping patients with psychological trauma from lower back pain by empowering them with the understanding of the mechanical aspects of their pain [1:30:00];
• Empowering patients through education and understanding of their pain through Stuart’s clinic and work through BackFitPro [1:39:00];
• When surgical interventions may be appropriate, and “virtual surgery” as an alternative [1:46:45];
• Weakness, nerve pain, and stenosis: treatments, surgical considerations, and more [1:55:30];
• Tarlov cysts: treatment and surgical considerations [2:00:15];
• The evolution of patient assessments and the limitations of MRI [2:02:15];
• Pain relief related to stiffness and muscle bulk through training [2:07:00];
• Advice for the young person on how to keep a healthy spine [2:14:15];
• Resources for individuals dealing with lower back pain [2:25:30]; and
• More.

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Andrew Huberman, professor of neurobiology at Stanford University and host of the Huberman Lab podcast, returns for another special journal club episode. Andrew introduces an observational study investigating the influence of light exposure on circadian clock regulation and its link to mental health, while Peter covers a phase III clinical trial employing immune checkpoint inhibitors for the treatment of metastatic cancer. They delve into the essential findings of their respective papers, elucidate the reasons for their enthusiasm, and tackle potential limitations and unanswered questions. Additionally, they provide valuable insights into their approaches for comprehending research studies, aiding listeners in independently navigating this process.

We discuss:

• The intricate relationship between light exposure, circadian rhythms, and mental health [3:30];
• The importance of low solar angle sunlight, and other types of light needed for optimal mental and physical health [12:00];
• Promising new lightbulb technology that simulates low solar angle sunlight [17:45];
• The significance of both darkness and the need for direct light exposure to the eyes, specifically [20:00];
• Some tips and advice regarding optimizing light exposure, blue blockers, and effects on circadian rhythm [22:15];
• Andrew presents a paper which suggests avoiding light at night and seeking light during the day is associated with better mental health [25:45];
• Examining the data: the negative impact of increasing nighttime light exposure and the positive effects of daytime light exposure [34:30];
• Statistical analysis: the importance of focusing not only on statistical significance but also clinical relevance, power analysis, error bar range, and more [45:45];
• Takeaways from the study of daytime and nighttime light exposure [49:45];
• The practicalities of minimizing light exposure and screen time at night, the use of sleep trackers, and overall challenge of modern, indoor lifestyles [55:15];
• Potential limitations of the light exposure study, reverse causality, and the complex interplay of variables in epidemiological studies [1:06:00];
• A tangent on diet soda and sugar substitutes as an example of reverse causality [1:13:15];
• Andrew and Peter’s take on the causality vs. correlation of light exposure to mental health, the damage of circadian disruption, and the interpretation of observational data [1:17:30];
• A primer on the immune system as background for the paper Peter chose [1:25:00];
• Background on cancer: causes, how it evades the immune system, and the logic behind immune checkpoint inhibitor therapy [1:35:45];
• Peter presents a paper on immune checkpoint inhibitor therapy in cancer patients [1:50:15];
• Unpacking the results of the checkpoint inhibitor trial [1:59:45];
• Other noteworthy observations, including the differing results between males and females [2:15:30];
• Adverse effects resulting from treatment with an immune checkpoint inhibitor targeting CTLA-4 [2:20:00];
• Why melanoma is especially responsive to immunotherapy, and the remarkable success story of immunotherapy for pancreatic cancer [2:25:15];
• Why immunotherapy may be the most important hope we have for treating cancer [2:35:30];
• Avoiding melanoma: the sunscreen debate, sunburn as the biggest risk factor, and more [2:38:45]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter delves into the crucial topic of exercise, starting with the importance of having a goal in training, including how and why Peter uses the goal of training for the “Centenarian Decathlon” when structuring his training plans. Peter elaborates on how to identify deficient areas within the four pillars of exercise and guides listeners on incorporating periodization training for optimal improvement and training variety. The episode explores diverse case studies, offering insights into tailored workouts for individuals of various training backgrounds, from seasoned enthusiasts to complete beginners. Additionally, Peter tackles the universal issue of emotional stress and its impact on training, as well as how exercise can help manage stress and how to determine when training should be adjusted during a high-stress period.

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

We discuss:

• Overview of exercise topics [2:15];
• Importance of training with a goal in mind, the Centenarian Decathlon, and the natural decline of fitness with age [4:00];
• The four pillars of exercise [12:15];
• Measuring peak aerobic output with VO2max, and the importance of VO2max as a predictor of longevity [16:45];
• Measuring aerobic efficiency with zone 2 [25:45];
• Measuring and tracking muscle mass and strength [27:30];
• Case study of a fit person with a neglected pillar: why adding more training volume may not the best strategy [30:30];
• Periodization training: what it is and why it is beneficial [36:15];
• Periodization case study: high cardio fitness, lacking muscle and strength [40:00];
• Periodization case study: adequate muscle, low cardio fitness [44:45];
• Case study: significant improvement needed across all exercise pillars [48:45];
• Best ways to do zone 2 exercise and how to use relative perceived exertion (RPE) to find your zone 2 level [56:30];
• How the body responds to physical and emotional stress, its impact on training, and the consequences of chronic stress [1:01:00];
• The difference between “good” stress and “bad” or chronic stress [1:10:30];
• The complex relationship between exercise and stress, and the importance of adjusting exercise goals during high-stress periods [1:13:30];
• Clues that stress may be impacting your training [1:19:15];
• The use of wearables and devices for tracking trends and making decisions related to training [1:21:00];
• Parting thoughts regarding the importance of exercise for longevity and stress management [1:32:00]; and
• More.

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Bestselling author Michael Easter returns to The Drive to discuss his new book, Scarcity Brain. In this episode, Michael explores the evolutionary backdrop that molded human beings, a setting characterized by scarce food, limited information, and few possessions. He contrasts that with the modern era, marked by abundance and comfort, and the ensuing repercussions on our physical and mental well-being. Michael introduces the concept of the “scarcity loop,” a three-part behavior cycle which helps explain modern challenges such as overeating, addiction, gambling, and materialism, and offers practical strategies to break free from its cycle. The episode culminates in a thought-provoking exploration of happiness, drawing on Michael's experiences with monks and underscoring the value of boredom, exploration, and discomfort as transformative elements that elevate awareness, presence, and the will to live.

We discuss:

• Inspiration for Michael’s latest book, Scarcity Brain [2:15];
• Evolutionary adaptations to the scarcity of food contrasted with the modern obesity crisis [4:00];
• Lessons learned about diet and nutrition from living with hunter-gatherers [9:30];
• The impact of ultra-processed foods on energy balance [20:30];
• Michael’s experience with attempting the hunter-gatherer diet at home [27:30];
• The roots of excess: factors that contribute to overeating and the varied vulnerabilities among individuals [34:00];
• The scarcity loop: how components of the scarcity loop are illustrated in gambling and addiction [39:45];
• Using knowledge of the scarcity loop to break the cycle [50:45];
• The evolutionary drive to acquire material possessions [58:15];
• The benefits of boredom and value of exploration [1:07:00];
• The consequences of an attention economy driven by negativity bias [1:16:30];
• Navigating the world of endless information and the value in “slow information” [1:23:00];
• Defining happiness, and the downward trend in reports of happiness [1:33:00];
• Purpose, austerity, self-reliance and other missing elements of happiness gleaned from the study of monks [1:38:30];
• The value in uncomfortable activities that increase your awareness, presence, and will to live [1:48:45]; and
• More.

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James Clear is the author of the New York Times bestseller Atomic Habits. His extensive research into human behavior has helped him identify key components of habit formation and develop the “Four Laws of Behavioral Change.” In this episode, James provides insights into how both good and bad habits are formed, including the influence of genetics, environment, social circles, and more. He points to changes one can make to cultivate more perseverance and discipline and describes the profound impact habits can have when tying them into one’s self-identity. Finally, James breaks down his “Four Laws of Behavioral Change” and how to use them to create new habits, undo bad habits, and make meaningful changes in one’s life.

We discuss:

• Why James became deeply interested in habits [2:00];
• Viewing habits through an evolutionary lens [6:15];
• The power of immediate feedback for behavior change, and why we tend to repeat bad habits [9:30];
• The role of genetics and innate predispositions in determining one’s work ethic and success in a given discipline [14:45];
• How finding one’s passion can cultivate perseverance and discipline [23:30];
• Advantages of creating systems and not just setting goals [29:30];
• The power of habits combined with self-identity to induce change [36:45];
• How a big environmental change or life event can bring on radical behavioral change [50:45];
• The influence of one’s social environment on their habits [54:30];
• How and why habits are formed [1:00:45];
• How to make or break a habit with the “Four Laws of Behavior Change” [1:09:45];
• Practical tips for successful behavioral change—the best strategies when starting out [1:16:30];
• Self-forgiveness and getting back on track immediately after slipping up [1:30:45];
• Law #1: Make it obvious—Strategies for identifying and creating cues to make and break habits [1:40:00];
• Law #2: Make it attractive—examples of ways to make a new behavior more attractive [1:48:00];
• Law #3: Make it easy—the 2-minute rule [1:59:00];
• Law #4: Make it satisfying—rewards and reinforcement [2:03:45];
• Advice for helping others to make behavioral changes [2:06:15]; and
• More.

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Colleen Cutcliffe is an expert in molecular biology and co-founder of Pendulum Therapeutics, a company working to develop treatments for a variety of diseases by targeting the microbiome. In this episode, Colleen delves into the complexity of the microbiome, how it is tested, and how it changes over time. She explores how probiotics, prebiotics, and postbiotics affect the gut and makes a compelling case that well-developed products have the potential not only to enhance gut health but also to positively influence overall metabolic well-being. Colleen emphasizes the significance of a high-fiber diet in sustaining a thriving gut microbiome, shares insights on minimizing microbiome damage during antibiotic use, provides tips for fostering and preserving a healthy gut, and much more.

We discuss:

• Colleen’s background and current focus [4:45];
• The basics of the microbiome [7:15];
• The study of the human microbiome [15:15];
• Categories of bacteria, and the implications on health of the rapid evolution of bacteria [19:45];
• Methods for measuring and understanding the microbiome, and key indicators of microbiome health [28:30];
• The important role of fiber for promoting gut health through the production of butyrate [38:30];
• The case for manipulating gut bacteria via fecal microbiota transplant (FMT) [45:00];
• Dynamics of the microbiome: the gut-brain connection and how antibiotics, nutrition, stress, and more impact the microbiome's diversity and function [50:15];
• Factors that influence the vaginal microbiome [55:15];
• The effect of gut microbes on obesity and challenges with fecal transplants in people [58:45];
• Beneficial strains of gut bacteria and strains commonly found in probiotics [1:01:15];
• The difference between a probiotic and prebiotic, and how CFUs are a measure of the “active ingredient” [1:09:45];
• Considerations about how probiotic strains are produced, and more on the meaning of CFU [1:14:15];
• Mitigating the effect of antibiotics on the microbiome [1:22:30];
• What do we know about the effect of artificial sweeteners on the gut microbiome? [1:30:00];
• Why Akkermansia is a keystone strain with implications for metabolic health and an individual’s response to dietary interventions [1:36:15];
• The essential steps necessary to develop a robust probiotic for optimal health support [1:45:45];
• How Akkermansia helps control blood glucose, and potential implications of Akkermansia in weight loss, diabetes management, and more [1:48:45];
• Pendulum Therapeutics’ commitment to rigorous product develop [2:06:30];
• Details about the probiotic “Glucose Control” and other probiotics developed by Pendulum Therapeutics [2:13:00];
• Further studies of Akkermansia that have been proposed or are underway [2:20:30]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter tackles essential questions about magnesium, beginning with the important roles it plays in the body and why maintaining proper levels is crucial. Peter discusses the harms of magnesium deficiency, how to determine if you're deficient, potential causes of deficiency, and how diet and supplementation can be used to increase magnesium levels. Peter unravels the confusion surrounding magnesium supplementation, discussing the optimal forms and recommended daily intake while addressing concerns about excess consumption. He also explores the potential cognitive and sleep benefits associated with magnesium supplementation. Finally, Peter concludes with a look into his recent experimentation with new exercises to serve as benchmarks to assess his progress and fitness levels as he navigates the aging process.

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

We discuss:

• The important roles of magnesium in the body [2:45];
• How to determine if you might be deficient in magnesium [10:15];
• Addressing migraines related to low magnesium [14:45];
• The prevalence of magnesium deficiency [16:30];
• Various conditions and drugs that can negatively impact magnesium levels [21:30];
• Magnesium-rich foods and factors that impact absorption of magnesium [24:30];
• Daily targets for magnesium supplementation and whether it’s possible to take too much [30:15];
• The different forms of supplemental magnesium [34:00];
• How absorption of magnesium from food compares to absorption from supplements [36:15];
• Choosing the right magnesium supplements for optimal absorption [37:15];
• The unique ability of magnesium L-threonate to increase brain magnesium concentration [40:15];
• Potential cognitive benefits of magnesium [43:00];
• Potential sleep benefits of magnesium [48:45];
• Takeaways on magnesium and a look into Peter’s personal protocol [53:15];
• Peter’s new benchmarks related to exercise and age [58:30]; and
• The potential impact of hearing loss on brain health and neurodegeneration [2:04:30]; and
• More.

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Richard Miller is a professor of pathology and the Director of the Center for Aging Research at the University of Michigan, as well as a previous guest on The Drive. In this episode, Rich provides an update on the exciting work of the Interventions Testing Program (ITP), an initiative designed to assess potential life-extending interventions in mice. Rich covers the notable successes like rapamycin, 17⍺-estradiol, and acarbose as well as notable failures like nicotinamide riboside, metformin, and resveratrol, providing valuable lessons about the intricacies of the aging process. Rich delves deep into aging biomarkers and aging rate indicators, unraveling crucial insights into the science of geroprotective molecules. Additionally, Rich discusses some surprising successes of recent molecules tested by the ITP and concludes with an optimistic look at future frontiers, including bridging the gap from mice to humans.

We discuss:

• An overview of the Interventions Testing Program (ITP) [3:45];
• How the mice used by the ITP are superior for research relative to mouse models used in most research [11:15];
• Design of ITP studies, outcomes tested, and metrics of interest [19:00];
• The process and challenges of drug formulation for mice [30:00];
• Four drugs identified by the ITP that extends the lifespan of mice [36:30];
• The success of rapamycin and what it tells us about the biology of aging [43:15];
• Other measures of healthspan evaluated by the ITP in stage 2 studies [50:45];
• Distinguishing aging rate indicators from biomarkers of aging [57:30];
• Aging rate indicators identified through the examination of slow-aging mice [59:15];
• Why proteomics are essential to understand changes in the cell [1:12:15];
• Unraveling aging rate indicators: dose-effect, duration, and future frontiers [1:21:45];
• A closer look at aging rate indicators: bridging the gap from mice to humans [1:27:00];
• What do laboratory mice die from? [1:38:45];
• Distinguishing between a drug that improves an age-sensitive outcome and a drug that improves all aspects of aging [1:42:00];
• The ITP study of 17⍺-estradiol: mechanisms of life extension and surprising sex differences [1:43:30];
• Unsuccessful drugs studied by the ITP: resveratrol, metformin, and nicotinamide riboside [1:51:30];
• Over-the-counter successes in the ITP: meclizine and astaxanthin [2:01:00];
• A senolytic drug, fisetin, fails to extend lifespan [2:07:00];
• Can targeting senescent cells slow aging? [2:13:00];
• Optimism about future findings [2:16:30]; and
• More.

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Arthur Brooks is a social scientist, professor at Harvard University, columnist for The Atlantic, and bestselling author. In this episode, Arthur returns to the podcast to discuss his new book, Build the Life You Want. He delves into the nuanced concept of happiness, differentiating between momentary feelings and overall wellbeing. He explains the importance of understanding one’s personality pattern with respect to positive and negative emotions in order to better self-manage emotions. He delves into the three key elements of happiness, offering practical strategies for enhancing those specific domains through methods such as metacognition, transcendent experiences, discipline, minimizing self-focus while directing attention outward, and more. Through personal examples, Arthur demonstrates that one can actively track well-being levels and take intentional steps to cultivate happiness and enhance overall well-being.

We discuss:

• Happiness vs. happy feelings, and how happiness and unhappiness can coexist [4:30];
• The six fundamental emotions [8:00];
• The evolution and heritability of happiness, and the four personality patterns with respect to positive and negative emotions [17:30];
• Navigating relationships: the power of complementarity over compatibility [23:30];
• The importance of self-managing your mental habits [25:30];
• Enjoyment: one of the three macronutrients of happiness [32:00];
• Satisfaction: one of the three macronutrients of happiness [43:45];
• The reverse bucket list, metacognition, and other techniques to protect yourself from your limbic system [51:00];
• Meaning: one of the three macronutrients of happiness [57:30];
• The four quarters of your life and how that relates to the meaning of your life [1:05:00];
• Putting metacognition into practice [1:09:00];
• What might explain the societal downdrift in happiness over the last few decades? [1:17:00];
• Taking charge of your happiness: discipline, transcendent experiences, and other deliberate actions for happiness [1:30:30];
• Tracking happiness: biomarkers and micronutrients behind the macronutrients of happiness [1:42:00];
• The value in minimizing the self and looking outward [1:49:45];
• How Arthur surprised himself with his ability to improve his happiness [1:54:00]; and
• More.

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To support Tom’s mission and work, please visit: https://africanmissionhealthcare.org/donation/catena/.

In this episode, Tom Catena, a missionary physician who runs Mother of Mercy Hospital in the Nuba Mountains in Sudan, describes some of his extraordinary work as the only doctor in a remote, war-torn region of Africa. In terms of individual lives saved, you could argue that there is no other person on the front lines doing more than Tom. Additionally, we explore the manner in which the Nuba people die, which is in striking contrast to the ubiquity of chronic disease and self-harm in the West, despite the extreme poverty and unimaginable suffering experienced by the Nuba people. Lastly, we discuss the lessons to be gleaned from the Nuba people, who, despite their suffering, live so harmoniously, happily, and resiliently.

We discuss:

• Background, medical training, and early days of missionary work in Africa [5:15];
• Tom arrives at Mother of Mercy Hospital in the Nuba Mountains of Sudan, civil war breaks out, and his staff evacuates [12:30];
• Learning surgery on the job and earning the trust of the community [37:00];
• The amazing people of Nuba, and why Nuba feels like home to Tom [47:45];
• NY Times article about Tom’s work, and Tom’s new venture on the board of the Aurora Prize Foundation, raising awareness and funds for other missionaries [59:45];
• Tom’s mind-blowing ability to deal with chaos while seeing hundreds of patients per day [1:12:00];
• The most afraid Tom has ever been, and how he copes with the emotional trauma of his daily experiences [1:19:45];
• The basic tools, technologies, and medicines that Tom is lacking that could save many lives [1:30:00];
• The logistical challenge of helping Tom’s hospital, and what Tom really needs [1:35:15];
• Diseases in the adult population [1:38:30];
• Living without possessions, finding meaning, and being a missionary [1:55:45];
• Happiness, sense of purpose, and suicide: contrasting the US with Nuba [2:07:15];
• Other than donations, is there a way people can help Tom and other similar causes? [2:15:15];
• The food in Nuba [2:18:30];
• Tom’s annual bout of malaria [2:23:45];
• Patients Tom will never forget [2:26:00];
• Resources for people wanting to get involved in helping Tom’s work [2:31:00];
• Peter tells a story that defines Tom [2:32:00]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter explores various pharmacologic tools commonly utilized to improve metabolic health and treat diabetes, including SGLT-2 inhibitors, metformin, and GLP-1 agonists. He examines the available data on these drugs, assessing their comparative effectiveness and their potential in the context of lifestyle interventions. Additionally, he offers insights into whether SGLT2 inhibitors hold promise as geroprotective agents beyond their effects on glycemic control. Next, Peter analyzes the relationship between statin usage and the risk of developing insulin resistance and type 2 diabetes, investigating possible causal pathways and providing insights into strategies for risk reduction. He offers insights on monitoring adverse statin effects and evaluating the need for adjustments, ultimately weighing the trade-off between the risk to overall metabolic health against the benefits of reducing apoB levels through statin use.

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

We discuss:

• Pharmacologic tools for improving metabolic health, and the relationship between statins and insulin resistance [2:00];
• SGLT-2 inhibitors: how they work and help to manage type 2 diabetes [4:15];
• The history of SGLT2 inhibitors – from discovery to the current state [10:15];
• Comparing the various FDA-approved SGLT2 inhibitors [15:00];
• Other beneficial effects of SGLT2 inhibitors outside of glycemic control [20:15];
• Exploring SGLT2 inhibitors as potential geroprotective molecules [22:45];
• The side effects and risks associated with SGLT2 inhibitors [31:45];
• Medications, lifestyle interventions, and other considerations for treating diabetes and improving metabolic health [37:45];
• Metformin as a tool for pre-diabetics, and how metformin compares to lifestyle interventions [44:00];
• How GLP-1 agonists compare to metformin and SGLT2 inhibitors in terms of glycemic control and weight loss [49:15];
• Exploring the relationship between statin use and the risk of developing insulin resistance and type 2 diabetes [52:30];
• Possible mechanisms of statin-induced insulin resistance and diabetes, and potential mitigation strategies [1:04:30];
• How to monitor for adverse effects of statin use and assess the need for adjustments [1:11:45];
• Weighing the benefits and risks of statin use: does the diabetes risk outweigh the benefits of lowering apoB with a statin? [1:15:30];
• Parting thoughts [1:20:45]; and
• More.

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Harold (Hal) Burstein is an internationally renowned breast cancer expert. In this episode, Hal discusses a broad range of topics related to breast cancer, starting with the intricacies of breast anatomy and the endocrinological factors at play. He covers the spectrum of breast cancer, from precancerous lesions to invasive breast cancer, classifying these conditions into a helpful framework. He delves into various screening methods, including self-exams, mammograms, ultrasounds, and MRIs, and addresses the ongoing debate surrounding early screening and detection. Hal provides insights into the latest advancements in cancer treatment, offering valuable guidance for individuals to understand their unique circumstances within the three primary categories of breast cancer. Finally, Hal delves into the role of genetics in breast cancer and brings attention to the less commonly addressed issue of male breast cancer.

We discuss:

• The prevalence and mortality rate of breast cancer in women [4:15];
• The anatomy of the breast and the complex factors behind breast cancer development [6:30];
• The three main categories of breast cancer [16:45];
• Breast cancer risk: the impact of menopause, estrogen, breast density, obesity, and more [21:15];
• Finding and evaluating lumps in the breast [25:30];
• Identifying and treating precancerous lesions like ductal carcinoma in situ (DCIS) [31:00];
• Post-lumpectomy for DCIS: standard of care, future risk of cancer, and pros and cons of radiation and other preventative options [41:15];
• Lobular carcinoma in situ (LCIS): how it differs from DCIS in terms of treatment and future risk of invasive cancer [55:00];
• Breast cancer screening: mammography, ultrasound, MRI, and more [1:03:45];
• Invasive breast cancer: pathology report, surgery, and survival [1:11:00];
• The argument for aggressive screening for breast cancer [1:22:15];
• Advances in the treatment of breast cancer, adjuvant therapy, and neoadjuvant therapy [1:27:00];
• The use of hormone replacement therapy in women who are in remission from breast cancer [1:41:15];
• The role of genetics in breast cancer [1:44:45];
• The importance of multidisciplinary care delivered by cancer centers [1:53:15];
• Breast cancer in men [2:03:30];
• Parting thoughts and takeaways [2:05:45]; and
• More.

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Kari Nadeau is a physician scientist with expertise in treating food allergies. In this episode, Kari first explains the fascinating workings of the immune system, exploring how it adeptly defends against bacteria and viruses but how the same system can lead to food allergies. She proceeds to explore the complexities of food allergies, detailing their typical developmental patterns, underscoring the significance of preventative approaches like early exposure, and highlighting the potentially life-threatening nature of severe food allergies. Kari illuminates the latest advancements in immunotherapies that not only mitigate allergy severity but also hold the potential to completely cure the patient. Additionally, Kari shares her concerns about the increasing levels of air pollution, elucidating its adverse effects on health while providing valuable suggestions for reducing exposure.

We discuss:

• Kari’s motivation to study food allergies [4:00];
• Overview of the immune system and the family of immunoglobulins [9:00];
• How our immune system fights viruses, bacteria, or fungi, and some exceptions to the rule [13:00];
• Why our immune system is generally better at fighting viruses than bacterial infections [18:45];
• Differentiating a food sensitivity from a food allergy, and a discussion about celiac disease [25:30];
• How food allergies develop, why they can be lethal, and factors contributing to the uptrend in food allergies [35:45];
• The role of environmental factors in the onset of food allergies and strategies for prevention [50:15];
• How immunotherapy helps to overcome, and even cure, food allergies [1:04:15];
• Can immunotherapy work for environmental allergens like pollen? [1:24:00];
• Air pollution: impact on health and tips for reducing your risk [1:25:30];
• Resources for those wanting to learn more or find clinical trials related to food allergies [1:40:45]; and
• More.

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In this special episode of The Drive, Peter discusses a variety of topics, breaking away from the typical deep-dive format to explore a wide range of common questions submitted by listeners. Peter tackles subjects like the viability of living to 120 and beyond, addressing some of the optimistic theories regarding achievement of this remarkable feat. Peter then shares his drug and supplement regimen while emphasizing how individualized these protocols need to be. The conversation also touches on lowering apoB, the long-term use of statins, the myth of good vs. bad cholesterol, the complexities of nutrition research, the quest for the ideal diet, and Peter's strategies for hitting daily protein goals. Peter finishes with a discussion about his favorite health-tracking wearables, the role of CGM in non-diabetics, and more.

We discuss:

• Overview of topics and previous episodes of a similar format [2:45];
• The viability of living to 120 and beyond: some optimistic theories [4:45];
• The potential of mTOR inhibition as a mid-life intervention, and longevity potential for the next generation [13:30];
• A framework for thinking about geroprotective drugs and supplements in the context of a lack of aging biomarkers [17:00];
• Supplements Peter takes and how his regimen has changed in the last year [26:15];
• Pharmacologic strategies to lower ASCVD risk, the limitations of statins, nutritional interventions, and more [36:15];
• Misnomers about cholesterol [48:00];
• Why nutritional research is so challenging, some general principles of nutrition, and why Peter stopped doing prolonged fasts [50:45];
• Optimizing protein intake [59:45];
• Wearables for sleep and exercise, continuous glucose monitors (CGM), and a continuous blood pressure monitor on the horizon [1:04:45]; and
• More.

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In this "Ask Me Anything" (AMA) episode, the discussion zeroed in on the practical application of hormone replacement therapy in women. Peter walks through the signs, symptoms, and hormonal changes in women approaching – and going through – menopause. He provides an overview of the FDA-approved HRT formulations and explains how women might go about choosing the right option for themselves. Peter also describes the significant changes in testosterone levels in women over time and the options, as well as the considerations and challenges of testosterone replacement therapy (TRT) for women. Lastly, Peter highlights the necessary role of compounding pharmacies in HRT, underscores concerns regarding the quality and sterility of compounded drugs, and offers guidance on locating a trustworthy pharmacy.

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

We discuss:

• Why hormone replacement therapy is such an important topic [2:00];
• The onset of menopause: symptoms, blood tests, and when to consider HRT [6:00];
• Tests that may provide indications of perimenopause and their implications for fertility [9:15];
• Vasomotor symptoms: hormonal changes that cause hot flashes/night sweats, and HRT therapies that can help [13:45];
• The role of estrogen in menopausal HRT [17:30];
• The limited role of progesterone in HRT protocols [25:15];
• What is a “bioidentical” hormone? [28:30];
• Overview of the FDA-approved HRT formulations [31:45];
• Determining HRT dosing and considerations for perimenopausal women [37:45];
• Choosing the right HRT formulation: pros and cons [43:30];
• Examining the link between certain forms of estrogen and breast cancer [46:45];
• Changes in testosterone levels in women over time and why it matters [50:00];
• Recognizing low testosterone in women: common symptoms and diagnosis [53:45];
• Testosterone replacement therapy for women: options, considerations, and challenges [57:30];
• The long-term use of testosterone in women: examining the limited data [1:00:15];
• What is a compounding pharmacy? [1:09:30];
• Reasons to opt for a compounding pharmacy over a pharmacy that adheres to stricter regulations [1:16:00];
• The tragic incidents that heightened concerns about compounding pharmacies [1:20:45];
• Tips for finding a reputable compounding pharmacy [1:27:45]; and
• More.

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We discuss:

• Derek’s interest in weightlifting and experimentation with anabolic steroids at a young age [3:15];
• Derek’s experience acquiring steroids from underground labs and the potential long-term fertility concerns early in his bodybuilding career [12:00];
• The backstory on More Plates, More Dates and Derek’s unique ability to blend scientific knowledge with personal observation [17:00];
• Growth hormone – from extreme use-cases to the more typical – and the misconception that it’s the “elixir of life” [21:30];
• Growth hormone 101: definition, where it comes from, and the challenges of measuring it [28:45];
• Does exogenous growth hormone compromise one’s ability to make endogenous growth hormone? [40:00];
• The use of growth hormone in restoration of tissue during periods of healing [42:00];
• Growth hormone-releasing peptides to increase endogenous GH: various peptides, risks, benefits, and comparison to exogenous growth hormone [48:45];
• The role of growth hormone in building muscle and burning fat, as well as its effects on sleep and daytime lethargy [1:02:30];
• The evolution of drug use in the sport of bodybuilding [1:10:30];
• What explains the protruding abdomens on some bodybuilders and athletes? [1:20:30];
• Death of bodybuilders [1:26:00];
• The complex interplay of hormones, and the conversion of testosterone into metabolites like DHT and estrogen [1:33:45];
• Post-finasteride syndrome and how Derek successfully treated his hair loss [1:43:15];
• Testosterone replacement therapy: compelling use-cases, side effects, and optimal dosing schedules [1:57:15];
• Aromatase inhibitors to suppress estrogen, and the misconceptions around estrogen in men [2:16:00];
• Other hormones beyond testosterone for male sex hormone replacement [2:21:00];
• The history of anabolic compounds, and the differing effects of various anabolic testosterone derivatives and related drugs [2:24:30];
• Use of SARMs by bodybuilders [2:29:45];
• Anabolic steroid and testosterone regimens of professional bodybuilders and the downstream consequences [2:36:15];
• The challenge of accurate hormone testing in the presence of anabolic steroids and supplements [2:44:45];
• The use of Clomid, hCG, and enclomiphene [2:47:15];
• Concerns about fertility: comparing the use of testosterone and hCG [3:00:30];
• The use of BPC-157 peptide for healing injuries [3:12:00]; and
• More.

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Ted Schaeffer is an internationally recognized urologist who specializes in prostate cancer. In this episode, Ted delves deep into the realm of prostate health, starting with strategies for vigilance and effective management of the issues that can arise with aging, including urinary symptoms, prostatitis, pelvic pain, and prostate inflammation. Ted sheds light on the popular drug finasteride, renowned for its dual purpose in prostate shrinkage and hair loss prevention, as well as the contentious topic of post-finasteride syndrome. Ted then shifts to the topic of cancer, explaining how androgens, genetics, and non-genetic factors contribute to the pathogenesis of prostate cancer. He provides valuable insights into cancer screening, examining blood-based screening tools like PSA and the use of MRI in facilitating biopsies and their interpretation. Finally, he explores the various treatment options for prostate cancer, including surgical interventions, androgen deprivation therapy, and more.

We discuss:

• Changes to the prostate with age and problems that can develop [3:45];
• Behavioral modifications to help manage nocturnal urinary frequency and other lower urinary tract symptoms [8:30];
• Pharmacologic tools for treating nocturnal urinary frequency and lower urinary tract symptoms [16:30];
• Surgical tools for treating symptoms of the lower urinary tract [26:15];
• HoLEP surgery for reducing prostate size [32:30];
• Prostate size: correlation with cancer and considerations for small prostates with persistent symptoms [40:30];
• Prostatitis due to infection: symptoms, pathogenesis, and treatment [46:45];
• Prostatitis caused by factors besides infection [58:45];
• How to minimize risk of urosepsis in patients with Alzheimer’s disease [1:05:00];
• Prostate cancer: 5-alpha reductase inhibitors, how androgens factor into pathogenesis, and more [1:10:00];
• Post-finasteride syndrome [1:18:15];
• The relationship between testosterone and DHT and the development of prostate cancer over a man's lifetime [1:26:30];
• How genetic analysis of a tumor can indicate the aggressiveness of cancer [1:35:15];
• Pathogenesis and genetic risk factors of prostate cancer and the use of PSA to screen for cancer [1:37:45];
• Non-genetic risk factors for prostate cancer [1:45:45];
• Deep dive into PSA as a screening tool: what is PSA, definition of terms, and how to interpret results [1:56:30];
• MRI as a secondary screening tool and the prostate biopsy options [2:13:15];
• Ted’s ongoing randomized trial comparing different methods of prostate biopsy [2:24:00];
• Determining when a biopsy is necessary, interpreting results, explaining Gleason score, and more [2:27:00];
• Implications of a Gleason score of 7 or higher [2:46:45];
• Metastasis of prostate cancer to different body locations, treatment options, staging, and considerations for patients' quality of life and survival [2:53:30];
• How prostate cancer surgery has improved [3:09:30];;
• Questions to ask your neurologist if you are considering prostatectomy for cancer [3:21:45]; and
• More.

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In this episode of The Drive, Peter welcomes guests David Sabatini and Matt Kaeberlein, two world-leading experts on rapamycin and mTOR. David and Matt begin by telling the fascinating story of the discovery of rapamycin and its brief history as a pharmacological agent in humans. They then unravel the function of mTOR, a central regulator of numerous biological processes, and they discuss the pathways through which rapamycin exerts its potential benefits on lifespan. They touch upon initial studies that suggested rapamycin may have geroprotective effects and the ongoing research that continues to shed light on this unique molecule. Furthermore, they discuss the elusive details surrounding the frequency and dosing of rapamycin use in humans, and Peter emphasizes his reservations about indiscriminately prescribing rapamycin as a longevity drug for patients.

We discuss:

• David and Matt’s expertise in mTOR and rapamycin [3:00];
• The discovery of rapamycin and its first use in humans as an immunosuppressant [13:15];
• The emergence of rapamycin as a molecule with the potential to prolong lifespan [19:30];
• The groundbreaking rapamycin study on mouse lifespan extension and the open questions about the timing and frequency of dosing [26:00];
• Explaining mTOR and the biology behind rapamycin’s effects [35:30];
• Differences in how rapamycin inhibits mTOR complex 1 (MTORC1) versus mTOR complex 2 (MTORC2) [45:15];
• Reconciling the biochemical mechanism of rapamycin with its longevity benefit [49:15];
• Important discoveries about the interplay of amino acids (leucine in particular) and mTOR [54:15];
• Reconciling rapamycin-mediated mTOR inhibition with mTOR's significance in building and maintaining muscle [1:01:30];
• Unanswered questions around the tissue specificity of rapamycin [1:08:30];
• What we know about rapamycin’s ability to cross the blood-brain barrier and its potential impacts on brain health and neurodegeneration [1:13:45];
• Rapamycin may act as an immune modulator in addition to immunosuppressive effects [1:21:30];
• Might rapamycin induce changes in T cell methylation patterns, potentially reversing biological aging? [1:34:15];
• Rapamycin side effects and impacts on mental health: fascinating results of Matt’s survey on off-label rapamycin use [1:42:00];
• The impact of taking rapamycin in people who contracted COVID-19: more insights from Matt’s survey [1:51:15];
• What David would like to study with mTOR inhibitors [1:54:45];
• Joan Mannick’s studies of RTB101 and other ATP-competitive inhibitors of mTOR [2:00:30];
• The impact of mTOR inhibition on autophagy and inflammation and a discussion of biomarkers [2:10:00];
• The Dog Aging Project: what we’ve learned and what’s to come from testing rapamycin in companion dogs [2:17:30];
• Preliminary results of primate studies with rapamycin [2:24:45];
• Dosing of rapamycin [2:27:45];
• The effect of rapamycin on fertility [2:36:45];
• The outlook for future research of rapamycin and the development of rapalogs [2:39:00]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter dives deep into the critical topic of metabolic disease. He first sheds light on how poor metabolic health drives up the risk of developing other chronic diseases such as cardiovascular disease, cancer, neurodegenerative disease, and overall mortality. He explores the array of metrics and tests used to assess metabolic health, underscoring his preferred methodologies utilized with patients. Finally, Peter provides an overview of the factors one can manipulate in order to improve metabolic health.

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

We discuss:

• Importance of metabolic health and a primer on metabolic disease [1:30];
• How poor metabolic health increases one’s risk for other chronic diseases [6:00];
• How useful is body weight and BMI for estimating metabolic health? [9:45];
• Overview of various tests and metrics used to understand metabolic health [12:15];
• Traditional biomarkers and how Peter’s point of view may differ from the guidelines [15:00];
• Lactate: insights into metabolic health through fasting and resting lactate levels [17:00];
• Zone 2 output: an important functional test of metabolic health [20:00];
• Cardiopulmonary exercise testing (CPET) [25:45];
• Visceral adipose tissue (VAT): what is VAT and how does it impact health? [27:00];
• Oral glucose tolerance test (OGTT): how it works and why it is such an important metric for assessing metabolic health [32:15];
• The utility of a continuous glucose monitor (CGM) [40:45];
• Liver function and NAFLD [42:15];
• Sleep as an intervention [46:00];
• Exercise as an intervention [53:15];
• Diet and nutrition [59:00];
• How reducing stress can improve metabolic health [1:05:15]; and
• More.

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Andrew Huberman, Professor of Neurobiology at Stanford University and host of the Huberman Lab podcast joins us in a special journal club episode. Peter and Andrew each present a recent paper that sparked their interests, delving into the findings, dissecting their significance, discussing potential confounders and limitations, and exploring remaining questions. Importantly, they share their methodologies for comprehending research studies, providing valuable insights for listeners to navigate this process independently. Peter presents an epidemiological study reevaluating a noteworthy metformin result that intrigued the anti-aging community, leading to discussions on metformin's geroprotective potential (or lack thereof) and the current lack of aging biomarkers. Andrew introduces a paper examining how our beliefs about the medications we take influence their biological effects, distinguishing the "belief effect" from a placebo effect and highlighting its exciting implications for the future.

We discuss:

• The motivation behind this journal club conversation [2:45];
• Why Peter chose a paper on metformin, how metformin works, and why it generated excitement as a longevity-enhancing agent [9:00];
• Defining insulin resistance and its underlying causes [16:15];
• Metformin as a first-line treatment for type 2 diabetes, and Peter’s evolving interest in metformin as a geroprotective drug [22:00];
• Defining the term “geroprotection” [24:45];
• The 2014 study that got the anti-aging community interested in metformin [26:00];
• Peter presents the 2022 paper that repeats the analytical approach from the 2014 Bannister study [33:15];
• Greater mortality in the metformin group: how results differed between the 2022 paper and the 2014 paper [40:00];
• Understanding statistical significance, statistical power, sample size, and why epidemiology uses enormous cohorts [51:45];
• Interpreting the hazard ratios from the 2022 metformin study, and the notable takeaways from the study [56:45];
• Drugs that may extend lifespan, why Peter stopped taking metformin, and a discussion of caloric restriction [1:08:45];
• Current thoughts on the use of metformin for longevity [1:21:00];
• Could there be any longevity benefit to short periods of caloric restriction? [1:22:45];
• Peter and Andrew’s process for reading scientific papers [1:26:45];
• The biological effects of belief, and how “belief effects” differ from placebo effects [1:32:30];
• The neurobiology of nicotine: a precursor conversation before delving into the paper Andrew chose [1:39:45];
• Andrew presents a paper that demonstrates the impact of belief [1:45:30];
• Analyzing the fascinating results of the Perl paper [1:54:30];
• Exciting implications of the findings about “belief” reported by Perl and colleagues [2:03:15]; and
• More.

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This special episode is a rebroadcast of AMA #30, now made available to everyone, in which Peter and Bob Kaplan dive deep into all things related to studying studies to help one sift through the noise to find the signal. They define various types of studies, how a study progresses from idea to execution, and how to identify study strengths and limitations. They explain how clinical trials work, as well as biases and common pitfalls to watch out for. They dig into key factors that contribute to the rigor (or lack thereof) of an experiment, and they discuss how to measure effect size, differentiate relative risk from absolute risk, and what it really means when a study is statistically significant. Finally, Peter lays out his personal process when reading through scientific papers.

We discuss:

• The ever-changing landscape of scientific literature [2:30];
• The process for a study to progress from idea to design to execution [5:00];
• Various types of studies and how they differ [8:00];
• The different phases of clinical trials [19:45];
• Observational studies and the potential for bias [27:00];
• Experimental studies: randomization, blinding, and other factors that make or break a study [44:30];
• Power, p-values, and statistical significance [56:45];
• Measuring effect size: relative risk vs. absolute risk, hazard ratios, and “number needed to treat” [1:08:15];
• How to interpret confidence intervals [1:18:00];
• Why a study might be stopped before its completion [1:24:00];
• Why only a fraction of studies are ever published and how to combat publication bias [1:32:00];
• Frequency of training for Olympic weightlifting [1:22:15];
• How post-activation potentiation (and the opposite) can improve power training and speed training [1:24:30];
• The Strongman competition: more breadth of movement, strength, and stamina [1:32:00];
• Why certain journals are more respected than others [1:41:00];
• Peter’s process when reading a scientific paper [1:44:15]; and
• More.

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Wendy Chung is a board-certified clinical and molecular geneticist with more than 25 years of experience in human genetic disease research. In this episode, Wendy delves deep into the world of genetics by first exploring the historical landscape of genetics prior to decoding the human genome, contrasting it with what we know today thanks to whole genome and exome sequencing. She provides an overview of genetic testing by differentiating between various genetic tests such as direct-to-consumer, clinical, whole genome sequencing, and more. Additionally, Wendy unravels the genetic underpinnings of conditions such as PKU, breast cancer, obesity, autism, and cardiovascular disease. Finally, Wendy goes in depth on the current state and exciting potential of gene therapy while also contemplating the economic implications and ethical nature of gene editing.

We discuss:

• Wendy’s interest in genetics and work as a physician-scientist [2:45];
• The genetics of phenylketonuria (PKU), a rare inherited disorder [5:15];
• The evolution of genetic research: from DNA structure to whole genome sequencing [18:30];
• Insights and surprises that came out of the Human Genome Project [28:30];
• Overview of various types of genetic tests: direct-to-consumer, clinical, whole genome sequencing, and more [34:00];
• Whole genome sequencing [39:30];
• Germline mutations and the implications for older parents [45:15];
• Whole exome sequencing and the importance of read depth [50:30];
• Genetic testing for breast cancer [54:00];
• What information does direct-to-consumer testing provide (from companies like 23andMe and Ancestry.com)? [1:01:30];
• The GUARDIAN study and newborn genetic screening [1:06:30];
• Treating genetic disease with gene therapy [1:18:00];
• How gene therapy works, and the tragic story of Jesse Gelsinger [1:22:00];
• Use cases for gene therapy, gene addition vs. gene editing, CRISPR, and more [1:28:00];
• Two distinct gene editing strategies for addressing Tay-Sachs and fragile X syndrome [1:37:00];
• Exploring obesity as a polygenic disease: heritability, epigenetics, and more [1:41:15];
• The genetics of autism [1:48:45];
• The genetics of cardiovascular disease [2:01:45];
• The financial costs and economic considerations of gene therapy [2:06:15];
• The ethics of gene editing [2:12:00];
• The future of clinical genetics [2:21:00]; and
• More.

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Keith Flaherty is the director of clinical research at the Massachusetts General Hospital Cancer Center and a previous guest on The Drive. In this episode, Keith first delves into the statistics on cancer's prevalence as we age, underscoring the significance of finding effective treatments and early detection methodologies. He touches on the history of cancer therapeutics and illuminates the notable enhancements in cancer therapy within the last decade that are setting the stage for a promising future. He goes into detail on the potential of immunotherapy and therapies that can combat cancer’s evasive tactics while explaining some of the existing challenges around specificity, cost, and scalability. Additionally, Keith highlights the significant leap in early detection methodologies, namely liquid biopsies, which have the potential not only to determine if a cancer is present in an early stage, but also identify the possible tissue of origin.

We discuss:

• Keith’s interest and expertise in cancer [3:15];
• Cancer deaths by decade of life, and how cancer compares to other top causes of death [7:00];
• The relationship between hormones and cancer [12:00];
• The link between obesity and cancer [18:45];
• Current state of treatments for metastatic cancer and reasons for the lack of progress over the decades [22:30];
• The interplay between the immune system and cancer cells [32:00];
• Different ways cancer can suppress the immune response, and how immunotherapy can combat cancer’s evasive tactics [39:30];
• Elimination of a substantial portion of cancers through immune cell engineering faces challenges of specificity, cost, and scalability [52:15];
• Why TIL therapy isn’t always effective, and the necessity for multimodal therapy to address various aspects of the cancer microenvironment [1:01:00];
• Potential developments in cancer therapy over the next five years: T-cell activation, metabolic interventions, targeting tumor microenvironments, and more [1:06:30];
• The challenge of treating metastatic cancer underscores the importance of early detection to improve survivability [1:19:15];
• Liquid biopsies for early detection of cancer and determining the possible tissue of origin [1:24:45];
• Commercially available cancer screening tests [1:33:45];
• How to address the disparity in cancer care, and the exciting pace of progress for cancer detection and treatment [1:40:15]; and
• More.

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In this "Ask Me Anything" (AMA) episode, Peter delves into the realm of genetics, unraveling its connection to disease and emphasizing the value of understanding one's genetic risks. He elucidates essential background knowledge on genetics before delving into the myriad reasons why individuals might consider genetic testing. Peter differentiates scenarios where genetic testing provides genuine insights from those where it may not be as useful. From there, Peter explores a comprehensive comparison of commercial direct-to-consumer genetic tests, providing insights on interpreting results and identifying the standout options for gaining insights into personal health.

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

We discuss:

• Defining the term “genetics” and why it’s important [2:15];
• What is DNA, and how does it impact our biology and traits? [5:45];
• How are genetics passed down from parent to child? [8:45];
• How much do genes vary across individuals? [13:00];
• Which traits are determined by genetics versus experience or environmental factors? [17:00];
• Reasons for genetic testing [22:30];
• What exactly is being measured by a genetic test? [29:15];
• Testing for monogenic disorders [35:15];
• Understanding polygenic risk [39:30];
• Is genetic testing more important for someone who doesn’t know their family history? [40:45];
• What does it mean to be positive for a particular variant? [43:00];
• What does it mean to be negative for a particular variant? [45:45];
• How does someone get genetic testing through their healthcare provider, and how are these tests performed? [48:15];
• The financial cost of various genetic tests [54:30];
• Could having a risk allele for a disease result in an increase in one’s insurance premium? [57:15];
• Other risks associated with genetic testing [59:00];
• How do commercial, direct-to-consumer genetic tests compare to the information one might receive from clinical genetic testing? [1:01:45];
• Are certain direct-to-consumer tests better than others? [1:03:45];
• How long until whole genome sequencing becomes genuinely useful? [1:16:00];
• How useful are personalized dietary recommendations based on genetics? [1:18:15];
• Final thoughts and advice regarding genetic testing [1:20:00]; and
• More.

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Oliver Burkeman is the author of The New York Times best-seller Four Thousand Weeks: Time Management for Mortals. In this episode, Oliver delves into the pervasive idea that time can be mastered, exploring whether maximizing productivity is an attainable goal or a perpetual trap. He discusses the allure of attempting to control time—and, therefore, the future—and shares his personal journey of experimenting with diverse time management techniques that failed to deliver the emotional satisfaction he sought. Ultimately, they explore the mismatch between being a finite human and existing in a world of infinite possibilities and how all of these concepts intertwine with finding a sense of purpose and meaning. Additionally, Oliver shares insights from his book on productivity, using our time wisely, and embracing our finitude to live a more fulfilling life.

We discuss:

• Oliver’s experience that led him to write the book Four Thousand Weeks [3:15];
• Human’s relationship with time and the struggle with the finite nature of time [7:15];
• How productivity can be a trap [11:00];
• The fallacy that being more efficient will open up more time and bring a feeling of control [16:45];
• The paradoxical nature of trying too hard to be present in the current moment [22:45];
• The value of relationships in meaningful experiences and fulfillment, and how time gets its value from being shared [26:45];
• The importance of time synchronicity [36:00];
• Identifying your biggest priorities and the paradox of wanting to do more than you have time for [41:00];
• Oliver’s moment of clarity in 2014 [47:15];
• The role of a sense of purpose in fulfillment [50:15];
• Reconciling the finite nature of time and letting go of trying to master your time [59:00];
• Why we tend to have a future-focused attitude and how to combat that with atelic activities [1:05:45];
• The power of shifting your perspective about time and your experiences [1:12:45];
• How to operationalize the three principles for the dilemma of finite time [1:20:15];
• Harnessing the power of patience in the face of a problem or experience [1:28:00];
• The value of incrementalism for being productive [1:34:15];
• Embracing your finitude with curiosity [1:38:00];
• Acting on an idea in the moment rather than letting the idea be the obstacle [1:41:15]; and
• More.

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Adam Cohen is an orthopedic surgeon with expertise in sports medicine. In this episode, Adam breaks down the anatomy of the lower extremities: the hip, knee, ankle, and foot. He explains in detail the common injuries, sources of pain, and what leads to the development of arthritis. He lays out the non-surgical and surgical treatment options as well as the factors that determine whether surgery is appropriate. The discussion includes various procedures like hip replacement, knee replacement, ACL reconstruction, repair of meniscus tears, and more. Additionally, Adam sheds light on the utility of biological therapies like stem cells and platelet-rich plasma (PRP) and how they compare to more traditional approaches.

We discuss:

• Anatomy of the hip, hip dysplasia in infants, and the development of arthritis [3:00];
• Diagnosing hip pain in people under 50, stress fractures in the femoral neck, and more [11:15];
• Common hip injuries, gender differences, and problems that occur when the hip isn’t formed normally [19:30];
• Advancements in hip replacement surgery [25:15];
• Common hip problems in people over age 60 [27:30];
• The importance of muscular strength around the hips for injury prevention [30:30];
• Hip fractures due to osteopenia and osteoporosis [36:00];
• The utility of biological therapies like stem cells and platelet-rich plasma (PRP) [40:30];
• Cortisone as a treatment to delay the need for surgical intervention [53:30];
• Anatomy of the knee [56:30];
• Are activities like running that amplify forces bad for the knee? [59:45];
• Risk of future knee issues and arthritis following an ACL tear or other substantial knee injury [1:04:30];
• How the ACL injury happens and how it is repaired [1:08:30];
• Arthritis of the knee [1:19:00];
• Meniscus tears: how they happen and when surgery is appropriate [1:21:30];
• Total knee replacement: when it’s appropriate and how the recovery process compares to hip replacement [1:30:30];
• Learning from elite athletes, heart rate recovery, V02 max, and other metrics [1:58:45];
• Surgical vs. non-surgical approaches to various knee injuries [1:40:45];
• Achilles tendon: tendinitis, rupture of the Achilles tendon, and prevention strategies [1:44:15];
• Anatomy of the ankle and foot [1:49:00];
• Common injuries to the ankle and foot [1:51:15];
• Tips for finding a good orthopedic surgeon [2:01:45]; and
• More.

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Michael “Micky” Collins is an internationally renowned expert in sports-related concussions and a consultant for multiple professional sports organizations. In this episode, Mickey first explains the definition and diagnosis of a concussion, as well as the diverse signs and symptoms associated with different types of concussions. He discusses the risk factors that contribute to increased susceptibility and/or severity of concussions in certain individuals, emphasizes the significance of prompt treatment, and uses case studies to illustrate the latest in treatment protocols and recovery process. Additionally, Mickey provides insight into the evolving field of concussion treatments, including the exploration of hyperbaric oxygen and synthetic ketones. He gives advice to parents of kids who play sports and discusses the promising prospects in the realm of concussion management.

We discuss:

• Micky’s interest in concussion and how he started the first concussion clinic [3:15];
• Concussion: definition, pathophysiology, and risk factors making someone more susceptible [9:45];
• Symptoms of concussion, predictors of severity, and the importance of early and effective treatment [20:00];
• The six types of concussion, the effectiveness of treatment, and factors that impact recovery [25:45];
• The importance of seeing a specialist and the prognosis for recovery [30:00];
• Case study of a racecar driver who suffered a vestibular concussion [32:15];
• Why vestibular concussions are particularly problematic [42:45];
• A treatment plan for the racecar driver, possible use of medications, and how to address the root cause [45:45];
• Exploring alternative treatments: hyperbaric oxygen, synthetic ketones, and more [52:00];
• The natural history of a concussion if untreated and the effect, if any, of concussion on subsequent risk of brain disease [57:15];
• Chronic traumatic encephalopathy (CTE) [1:01:45];
• Advice for parents of kids who play sports: when and where to seek treatment for a possible concussion [1:04:45];
• Is there any evidence that the APOE4 genotype increases susceptibility to concussion or TBI? [1:10:15];
• The increased risk of concussions in older adults and a case study of a 90-year-old patient who suffered a head injury in a fall [1:11:15];
• Funding for concussion research and fellowship programs to train concussion specialists [1:15:30]; and
• More.

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In this "Ask Me Anything" (AMA) episode, Peter goes into depth on the topic of brain health, starting with how Alzheimer's disease is diagnosed, the significance of blood-based biomarkers in diagnosis, and what the various APOE gene variants mean in terms of a person's risk of developing Alzheimer's disease. Next, Peter discusses the various strategies for preventing Alzheimer's disease and neurodegeneration. He touches briefly on exercise as a potent tool, but focuses more on lesser-known factors that could impact brain health, such as nutrition supplementation, lipid management, brain games, sauna, oral health, hearing loss, and more.

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

We discuss:

• Topics: exercise, kidneys, and brain health [1:30];
• Rucking: advice for beginners, proper load, packs, and shoes [4:30];
• Rucking for women, bone health, using a treadmill, zone 2, and more [11:45];
• Building vs. maintaining: when and how to transition from the goal of building muscle and strength to focusing on maintenance [16:00];
• Should you lift weights before or after a cardio session? [24:00];
• Heart rate recovery: defining heart rate recovery and how it relates to cardiovascular fitness [28:45];
• How to measure heart rate recovery, and what is considered a "good" heart rate recovery [33:15];
• How kidney health and function typically measured [42:30];
• Differentiating between creatine and creatinine [48:15];
• The cystatin C blood test as a practical way to assess kidney health [52:45];
• How kidney function impacts lifespan and the five stages of kidney disease [59:15];
• Slowing the decline of kidney function [1:08:15];
• The main drivers of kidney disease [1:11:15];
• The importance of managing homocysteine levels for brain health [1:14:00];
• The relationship between alcohol consumption and brain health [1:21:30]; and
• More.

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In this special episode filmed live in front of readers of Outlive, Peter answers questions revolving around his concept of the centenarian decathlon. He starts by defining the “marginal decade” and how that shapes his training for the events and activities that make up his personal centenarian decathlon. Peter explains how he coaches patients through the challenges of customizing their own list and building out a training plan, including how to set fitness goals early in life in preparation for the marginal decade. From there, he dives into training within the four pillars (zone 2, VO2 max, stability, and strength), including the minimum effective dose, how to split your time, his personal protocols, and other considerations. Additionally, he touches on bone mineral density, female-specific considerations, working through injuries, and the profound impact training can have on the overall quality of life.

We discuss:

• The best interventions for longevity [2:15];
• The marginal decade and the centenarian decathlon [4:45];
• Peter’s personal list of events for his “centenarian decathlon” and how he helps patients create their own list [8:00];
• Determining your fitness goals early in life in preparation for the marginal decade, metrics to track, and more [15:00];
• How does playing sports like tennis, basketball, or golf fit into training for the centenarian decathlon? [24:15];
• Training within the four pillars: minimum effect dose, how to split your time, and other considerations [27:45];
• Advice for the older person and why it’s never too late to start [33:45];
• Bone mineral density and other female-specific concerns and considerations [36:15];
• Training advice for those with minimal access to a gym or equipment [39:30];
• Injuries: prevention and working through existing conditions [41:00];
• Cardiorespiratory training: how to split time between zone 2 and VO2 max training, and different modalities for a true zone 2 workout [44:15];
• VO2 max training: modalities, Peter’s protocol, and how to monitor progress [54:45];
• The profound impact training can have on the overall quality of life [58:15]; and
• More.

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In this episode, radiologist/engineer, Raj Attariwala, explains how he was able to apply his engineering background to create a unique MRI scanner that is capable of constructing whole-body images with a resolution that is unmatched in the industry. Peter and Raj discuss the implications of such a robust, radiation-free imaging tool on the early detection of cancer. They dive deep into cancer screening and define terms such as sensitivity and specificity that are necessary to really understand this complex space. They then describe the biggest risks involved in this type of screening (false positives) and how Raj’s unique technology and process might drive down this risk substantially. But before that, they discuss all the common imaging technology from X-ray, to CT scan, to PET scans, to ultrasound, to MRI, and more. They touch on the history of each, how they work, the usefulness and limitations of each of them, as well as the varying risks involved such as radiation exposure. If you are interested in cancer screening and/or you’ve ever wondered how any radiology tool works, this episode is for you.

We discuss:

• Raj’s road from engineering to radiology [2:45];
• How X-ray works, the risk of radiation exposure, and the varying amounts of radiation associated with the different imaging technologies [13:00];
• Computed tomography scans (CT scans): The history of CT, how it works, and why we use contrast [22:45];
• Ultrasound: Benefits and limitations, and a special use for the heart [36:00];
• Detecting breast cancer with mammography: When is works, when you need more testing, and defining ‘sensitivity’ and ‘specificity’ [46:15];
• Magnetic resonance imaging (MRI): How it works, defining terms, and looking at the most common types of MRI [59:00];
• Brain aneurysms: Using MRI to find them and save lives [1:18:45];
• Raj’s unique MRI technology [1:25:15];
• The risk of false positives in cancer detection, and how Raj’s MRI can reduce the number of false positives (i.e., increase specificity) [1:38:45];
• The unique software Raj created to pair with his MRI machine [1:46:15];
• Comparing the radiation exposure of a whole-body PET-CT to Raj’s equipment (DWIBS-MRI) [1:48:45];
• How diffusion-weighted magnetic resonance imaging (DW-MRI) has revolutionized cancer screening [1:50:15];
• Why a DW-MRI is still not a perfect test [1:54:15];
• The potential for advancing MRI technology: Where does Raj think it could improve in the next 5-10 years? [1:58:00];/li>
• Are there any commercially available scanners that can match the resolution of Raj’s images? [2:01:00];
• Machine learning: When and where might machine learning/AI impact the field of radiology? [2:03:45]; and
• More.

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Mohit Khera is a world-renowned urologist with expertise in sexual medicine and testosterone therapy. In this episode, Mohit provides a comprehensive overview of male sexual health. He begins with an in-depth exploration of erectile dysfunction, shedding light on its prevalence across different age groups, diagnostic methods, and its intriguing connection to cardiovascular disease. He then ventures into Peyronie's disease, penile fractures, penile enlargement treatments, prolonged erections, premature ejaculation, and anorgasmia. Shifting gears, Mohit delves into the intricate workings of testosterone, DHT, and estrogen, emphasizing their physiological significance and interplay. He explains blood tests for diagnosing low testosterone, the correlation between symptoms and blood levels in cases of low testosterone, and the pros and cons of different methodologies for increasing testosterone. He concludes with a thought-provoking conversation about the role of testosterone in patients with prostate cancer and addresses concerns surrounding DHT, finasteride, and post-finasteride syndrome.

We discuss:

• Mohit’s career path and interest in sexual medicine and infertility [3:00];
• The anatomy of the male genitalia [5:45];
• The prevalence of sexual dysfunction, its impact on quality of life, and the importance of seeking help [7:15];
• Erectile dysfunction (ED): definition, diagnosis, pathophysiology, and more [11:00];
• The history of medications to treat ED and the mechanisms of how they work [15:30];
• Relationship between aging and erectile dysfunction and Mohit's approach to treating patients and prescribing medications [20:00];
• The impact of lifestyle on sexual health and the association between ED and cardiovascular disease [29:30];
• Causes and treatments for Peyronie’s Disease, penile fracture, and more [37:30];
• The value of ultrasound for ED diagnosis and management strategies [47:45];
• Various treatment options for ED: injections, penile prosthesis, and more [50:15];
• Priapism (prolonged erection): what is happening and when to seek treatment [57:15];
• Shockwave therapy as a treatment for ED [1:02:45];
• Stem cell therapy for ED [1:08:15];
• Platelet-rich plasma (PRP) injections as a treatment for ED [1:12:00];
• Premature ejaculation (PE): prevalence, pathophysiology, and treatment [1:14:45];
• Anorgasmia: causes and treatment [1:22:00];
• The interplay of sex hormones, the impact of aging, symptoms of low testosterone, and considerations for testosterone replacement therapy (TRT) [1:26:45];
• Methods for increasing endogenous testosterone [1:38:45];
• Testosterone replacement therapy: various forms of exogenous testosterone, weighing risk vs. reward, and more [1:52:30];
• The physiology and purpose of testosterone and DHT, why some men feel fine even with “low” testosterone, personalized approaches to treating low testosterone, and more [2:02:30];
• Post-finasteride syndrome [2:09:00];
• The role of testosterone in prostate cancer and addressing the notion that TRT could increase risk [2:16:15];
• The effects of testosterone as an adjunct to therapy for estrogen-sensitive breast cancer in women [2:27:15];
• Resources for those looking for healthcare providers [2:28:45]; and
• More.

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Sharon Parish is a Professor of Medicine in Clinical Medicine and Clinical Psychiatry at Weill Cornell Medical College and a prominent sexual medicine specialist who has been practicing for 30 years. In this episode, Sharon tackles the topic of women's sexual health, including the conditions associated with decreased sexual function and desire and available treatment options. She explores the influence of sexual health on overall well-being while also examining the potential effects of childbirth, birth control, metabolic health, and more on sexual function and desire. Through case studies, Sharon teases apart the differences between desire and arousal, explains the various factors that affect them, and walks through hypothetical treatment plans for the case study patients. In addition, she delves into the subject of menopause, addressing its impact on sexual health as well as the misguided fears around hormone replacement therapy. Stay tuned for next week's launch of our complementary podcast on men's sexual health.

We discuss:

• Sharon's interest in sexual medicine and the current state of the field [3:00];
• How hormones change in women over time and how that impacts sexual function [8:15];
• Changes after childbirth and its impact on sexual function [11:00];
• The role of metabolic health and systemic vascular health in sexual health [20:15];
• Conditions associated with decreased sexual function and the importance of sexual health for overall wellbeing [26:15];
• Sexual dysfunction case study #1: A 41-year-old mother of two, the sexual response cycle, and the difference between arousal and desire [38:45];
• Medications that may reduce sexual desire [49:45];
• The effect of birth control pills on sexual desire [56:30];
• The importance of testosterone in women for sexual function and desire, and why the FDA hasn't approved exogenous testosterone as a therapeutic [1:01:15];
• Challenges faced by physicians who are open to prescribing off-label testosterone for women, and Sharon's approach in managing this aspect with her patients [1:14:30];
• A hypothetical treatment plan for the patient in case study #1 [1:26:45];
• The role of DHEA (a precursor to testosterone) in female sexual health [1:32:15];
• Case study #2: A 30-year-old woman with anorgasmia (inability to orgasm) [1:38:30];
• Resources for helping women and their partners to enhance the pleasure experienced during sex, overcome anxiety, and increase desire [1:51:30];
• Two drugs for premenopausal women with low desire [1:59:30];
• Why treatments are potentially underutilized for both desire and genitourinary syndrome of menopause [2:13:15];
• Case study #3: A menopausal woman with symptoms [2:19:00];
• Addressing the misguided fears around hormone replacement therapy and cancer [2:24:15];
• Symptoms and treatment of genitourinary syndrome of menopause [2:32:45];
• Age 65 and beyond, and resources for finding a provider [2:37:30]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter delves into the critical subject of blood pressure, which is one of the three primary causes of atherosclerosis, along with high apoB and smoking. He begins by unraveling the nature of high blood pressure, its prevalence, and why it often goes undiagnosed. Peter describes in detail the proper way to accurately measure blood pressure and what determines a diagnosis. Next, Peter discusses the actionable steps one can take in response to high blood pressure, shedding light on the extent to which factors like weight loss, exercise, and nutrition can make an impact. He also explores the pharmacological options available and offers valuable insights on how to approach them.

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

We discuss:

• Blood pressure and other risk factors for cardiovascular disease [2:30];
• Defining blood pressure and the purpose and meaning of a blood pressure measurement [5:45];
• The implications of high blood pressure and the importance of maintaining an optimal level [10:30];
• The importance of accurate measurements of blood pressure and how Peter approaches the care of patients at the very top range of “normal” [21:45];
• The prevalence of high blood pressure—a hidden epidemic? [24:30];
• The consequences of high blood pressure on cardiovascular health, brain health, kidneys, and more [27:45];
• Low blood pressure: symptoms and consequences [35:30];
• How to properly measure blood pressure [37:45];
• Daily variance in blood pressure and the transient changes in blood pressure during exercise [48:00];
• Primary hypertension vs. secondary hypertension: what to look for [51:45];
• Lifestyle factors impacting blood pressure: weight loss, exercise, and sodium [57:45];
• Impact of insulin resistance and type 2 diabetes on blood pressure [1:04:45];
• How sleep impacts blood pressure [1:06:45];
• Pharmacologic options for managing blood pressure [1:08:00]; and
• More.

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Tommy Wood is an Assistant Professor of Pediatrics at the University of Washington, where he studies brain injury and how lifestyle choices and environmental factors contribute to brain health, cognitive function, and chronic disease. In this episode, Tommy delves into the complexities of age-related cognitive decline and explores interventions to counteract it. Drawing from his experience working with Formula 1 drivers, he highlights the connection between cognitive function and the right type of demands and training leading to improvement. Next, he explores the various theories on the different types of pathology in dementia and neurodegeneration. He makes the case that a large fraction of dementia is preventable through lifestyle choices and nutrient status, and provides an in-depth overview of interventions and supplements that support cognitive function. Finally, he provides a comprehensive overview of head injuries, including concussions and traumatic brain injuries (TBIs), discussing symptoms, how to mitigate damage following an incident, and long-term management.

We discuss:

• Tommy’s professional work, unique skill sets, and interests [3:00];
• Age-related decline in cognitive function and memory [5:45];
• Improving brain function with the right level and type of demand [20:15];
• Formula 1 as a model for how to perform under high cognitive demand and how to increase multitasking capacity [31:30];
• Advice for the person reaching middle life looking to mitigate cognitive decline [37:45];
• Tasks and activities that support and improve cognitive function [45:30];
• Neuropathology of Alzheimer’s disease: exploring the role of amyloid and tau proteins [49:30];
• Why Tommy believes dementia research funding should be focused on environmental and lifestyle-based risk factors [1:05:15];
• Benefits of lowering homocysteine and boosting omega-3’s, and evidence-based supplements that support cognitive function [1:09:00];
• A unifying theory of dementia [1:20:45];
• How muscular strength can help with both the prevention and survivability of dementia [1:24:15];
• Head injuries: comparing concussions against traumatic brain injuries (TBIs), mitigating the damage after an incident, and the long-term management of head injuries [1:29:15];
• Is hyperbaric oxygen treatment helpful after a TBI? [1:45:45];
• Supplements that aid recovery from a TBI: creatine, DHA, and choline [1:49:30];
• Demands faced by F1 drivers, and testing interventions to improve their performance [1:57:30]; and
• More.

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In this special episode of The Drive, Peter provides a comprehensive overview of the various endocrine systems: the thyroid system, the adrenal system, and the sex hormone system (for both men and women). He walks through the basic biology and the feedback cycles that regulate the production of these hormones and discusses the various options for the treatment of hormone deficiencies. In addition, Peter delves into hormone replacement therapy (HRT), providing nuanced insights into its appropriate usage and the clinical approach he adopts when working with patients.

Peter supplements these explanations with whiteboard illustrations. For a more complete understanding, we highly recommend watching these videos over just listening. The videos can be found on our YouTube channel or on the show notes page.

We discuss:

• The thyroid system [2:15];
• The adrenal system [15:45];
• The female sex hormone system [27:00];
• The male sex hormone system [40:00]; and
• More.

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John Kastelein is a renowned expert in lipoprotein metabolism and atherosclerotic cardiovascular disease (ASCVD) research. In this discussion, John delves deep into familial hypercholesterolemia (FH), a genetic disorder characterized by high levels of LDL cholesterol in the blood that increases the risk of developing heart disease. He covers its definition, genetic underpinnings, and clinical identification. He then explores the therapeutic options available for the prevention and treatment of cardiovascular disease, including the captivating history of CETP inhibitors. He explains the past shortcomings of previous CETP inhibitors before underscoring the compelling potential of the latest iterations, not only for cardiovascular disease but also for conditions like Alzheimer's disease and type 2 diabetes. Moreover, he unveils the intricate role of APOE, shedding light on why the APOE4 isoform codes for a protein that significantly increases the risk of Alzheimer's disease and cardiovascular disease. Concluding the discussion, John shares a profound sense of optimism, envisioning the possibility of targeted therapeutic interventions for high-risk patients in the near future.

We discuss:

• Familial hypercholesterolemia (FH): a genetic condition [4:30];
• Differentiating between phenotype and genotype when it comes to FH [9:45];
• The pathophysiology related to mutations of FH [15:30];
• Clinical presentations, physical manifestations, and diagnosis of FH [22:00];
• Why a small fraction of people with FH do not develop premature ASCVD [34:15];
• Treatment and prevention for those with FH [39:45];
• Addressing the assertion by some that elevated LDL is not casual in cardiovascular disease [52:45];
• The history of CETP inhibitors, and the role of the CETP protein [55:45];
• The thrifty gene hypothesis and why genes underlying FH may have been preserved [1:09:00];
• The compelling potential of the latest CETP inhibitor (obicetrapib) [1:13:00];
• Promising results from phase 3 trials exploring obicetrapib [1:27:45];
• Why the APOE4 allele increases the risk of Alzheimer’s disease, and the connection to blood lipids [1:41:30];
• The role of APOE in cardiovascular disease [1:51:45];
• Takeaways and looking ahead [1:57:00]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter delves deep into the data surrounding different forms of cold therapy, including cold water immersion, cryotherapy, and cold showers, aiming to unveil the potential benefits and drawbacks associated with cold therapy. He dissects the studies examining the effects of cold therapy on delayed onset muscle soreness (DOMS), activation of brown adipose tissue, and its potential impact on mood and as a therapeutic approach for depression. Furthermore, Peter discusses the potential negative impact cold therapy may have on muscular hypertrophy and offers his perspective on the extent to which the data support the notion of cold therapy providing longevity benefits. Finally, he also discusses the existing consensus, or lack thereof, regarding the optimal structure of an effective cold therapy protocol.

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

We discuss:

• Overview of discussion on cold therapy (and a Formula 1 tangent) [1:45];
• The most common cold exposure therapies [5:45];
• Potential benefits of cold water immersion: a look at the data [9:30];
• Comparing the effects of cold water immersion with whole-body cryotherapy [18:30];
• The potential impact of cold exposure on mood and as a treatment for depression [20:45];
• How do cold showers compare to cold water immersion? [28:15];
• Cold exposure and the activation of brown adipose tissue (BAT) [34:15];
• Things that clearly impact brain health: smoking, alcohol, sleep, head injuries, blood pressure, and more [34:15];
• Exercising in cold temperatures: impact on exercise performance [38:30];
• Potential downsides of cold therapy and its impact on hypertrophy, strength, and recovery [44:45];
• Are the blunting effects of cold on hypertrophy due to the effects on inflammation? [50:45];
• Does cold exposure offer any potential geroprotective benefits? [53:15];
• Cold therapy protocols for delayed onset muscle soreness (DOMS) [56:30];
• Summarizing the data and takeaways from Peter [1:01:00]; and
• More.

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JoAnn Manson is a world-renowned endocrinologist, epidemiologist, and Principal Investigator for the Women’s Health Initiative (WHI). In this episode, she dives deep into the WHI to explain the study design, primary outcome, confounding factors, and nuanced benefits and risks of hormone replacement therapy (HRT). JoAnn reflects on how a misinterpretation of the results, combined with sensationalized headlines regarding an elevated risk of breast cancer, led to a significant shift in the perception and utilization of HRT. From there, they take a closer look at the breast cancer data to separate fact from fiction. Additionally, JoAnn gives her take on how one should weigh the risks and benefits of HRT and concludes with a discussion on how physicians can move towards better HRT practices.

We discuss:

• The Women’s Health Initiative: the original goal of the study, hormone formulations used, and potential confounders [4:15];
• Study design of the Women’s Health Initiative, primary outcome, and more [16:00];
• JoAnn’s personal hypothesis about the ability of hormone replacement therapy to reduce heart disease risk prior to the WHI [26:45];
• The relationship between estrogen and breast cancer [30:45];
• Why the WHI study was stopped early, and the dramatic change in the perception and use of HRT due to the alleged increase in breast cancer risk [37:30];
• What Peter finds most troubling about the mainstream view of HRT and a more nuanced look at the benefits and risks of HRT [45:15];
• HRT and bone health [56:00];
• The importance of timing when it comes to HRT, the best use cases, and advice on finding a clinician [59:30];
• A discussion on the potential impact of HRT on mortality and a thought experiment on a long-duration use of HRT [1:03:15];
• Moving toward better HRT practices, and the need for more studies [1:10:00]; and
• More.

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Rhonda Patrick, Ph.D., is a scientist with expertise in the areas of aging, cancer, and nutrition who translates complex scientific topics into actionable insights on her podcast, Found My Fitness. In this episode, Rhonda provides her latest thinking as it relates to Alzheimer's disease including the possibility of a vascular hypothesis as well as the factors that can impact disease risk such as type 2 diabetes, blood pressure, omega supplementation, exercise, sauna, and more. She also touches on cancer risk including the relationship between cancer and exercise as well as the link between alcohol consumption and cancer. Additionally, Rhonda explains her new focus on exercise and protein consumption as well as how her perspective has shifted as it pertains to fasting and time-restricted feeding.

We discuss:

• Alzheimer’s disease: Rhonda’s evolved thinking on neurodegenerative diseases [2:30];
• The breakdown of the blood-brain barrier in neurodegenerative disease [8:45];
• An explanation for the observation that type 2 diabetes increases risk of Alzheimer’s disease [15:45];
• The role of omega-3 fatty acids (EPA and DHA) in brain health and prevention of neurodegeneration [19:45];
• Comparing the preventable nature of type 2 diabetes, atherosclerosis, cancer, and dementia [32:15];
• Blood pressure: an important modifiable lifestyle factor that can affect Alzheimer's disease risk [35:15];
• Rhonda’s outlook on “precision medicine” as it pertains to one’s genetic predispositions [38:45];
• Possible mechanisms by which exercise reduces the risk of Alzheimer’s disease [45:45];
• Building your aerobic pyramid: neurobiological effects of exercise, benefits of lactate peaks, and more [53:45];
• Maximizing mitochondrial biogenesis: alternative training approaches and strategies [58:45];
• Possible brain benefits of sauna, and Rhonda’s personal protocol [1:09:30];
• The relationship between cardiorespiratory fitness and dementia risk [1:15:30];
• How exercise may reduce the risk of cancer [1:20:30];
• The overarching impact of exercise on health, and the importance of focusing the factors that matter most [1:33:15];
• Impact of alcohol consumption on breast cancer risk and overall health [1:37:15];
• Exercise as an intervention for poor sleep habits [1:42:30];
• The longevity benefits of consuming adequate protein and strength training to preserve muscle mass and strength [1:46:30];
• How to get enough of the right kind of protein in your diet [2:05:15];
• Fasting: weighing the risk vs. reward [2:12:15];
• How Rhonda’s views have shifted on diet and exercise [2:15:30];
• How to follow Rhonda’s work and more about the benefits of lactate for the brain [2:21:00]; and
• More.

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In this episode, Robert Sapolsky, Ph.D., discusses the widespread impact of stress on our physical and emotional health as well as the mechanisms by which it can precipitate chronic illness, dementia, depression, and more. He also provides insight into the factors that contribute to the stress response (and our ability to handle it) such as social rank, personality, environment, and genetics. Lastly, we discuss how our behavior is altered in the face of stress and how that not only has a pervasive effect on a personal level, but also on society as a whole in how we interact with each other.

We discuss:

• Background, interest in stress, and Robert’s time in Kenya studying baboons [2:45];
• Physiology of a stress response, and why it’s ingrained in our DNA [9:45];
• Individual variation in the response to stress, and how everyone has a different optimal level [19:45];
• How social rank and personality differences affect our stress response [26:30];
• What’s happening in the brain when faced with stressful situations? [35:00];
• What makes the human brain different than all other species? [44:15];
• Imprinting stress to your kids epigenetically [48:00];
• The role of stress on memory and the consequences of hypercortisolemia [53:00];
• The impact of subjective socioeconomic status and social media on stress levels and health [57:45];
• Tips for managing stress in the modern world [1:13:15];
• What Robert learned about himself studying the social behavior of baboons [1:25:30];
• The multilayered factors behind every human behavior, the context of “good and bad”, and exploring the human capacity of the wild extremes of violence and altruism from moment to moment [1:30:15];
• PMS: How two women with identical hormone levels can have completely different emotional experiences [1:34:45];
• How much of a role do genes play in depression and other emotional states? [1:38:00];
• Why is cortisol elevated under sleep deprivation? [1:46:00];
• The impact of stress on cancer [1:50:30];
• The impact of stress on atherosclerosis, dementia, addiction, and depression [1:57:00];
• Impulsiveness, impaired judgment, and lack of empathy in times of stress [2:01:45];
• What advice would Robert give his 25-year-old self? [2:08:45]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter goes into depth on the topic of brain health, starting with how Alzheimer's disease is diagnosed, the significance of blood-based biomarkers in diagnosis, and what the various APOE gene variants mean in terms of a person's risk of developing Alzheimer's disease. Next, Peter discusses the various strategies for preventing Alzheimer's disease and neurodegeneration. He touches briefly on exercise as a potent tool, but focuses more on lesser-known factors that could impact brain health, such as nutrition supplementation, lipid management, brain games, sauna, oral health, hearing loss, and more.

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

We discuss:

• Diagnosing Alzheimer's disease [2:45];
• Biomarkers for Alzheimer’s disease, the C2N test, and other tools for diagnosis [7:30];
• Genetic component of Alzheimer’s disease: genes that confer risk [12:45];
• Understanding your APOE status and why it’s important to know [17:15];
• The prevalence of Alzheimer’s disease and other forms of dementia, and who is at higher risk [21:15];
• Can the risk of Alzheimer’s disease be decreased with behavioral changes? [24:15];
• Overview of modifiable behaviors that potentially play a role in risk reduction of neurodegeneration [30:15];
• Things that clearly impact brain health: smoking, alcohol, sleep, head injuries, blood pressure, and more [34:15];
• How nutrition impacts brain health: common diets, metabolic health, energy balance, and more [46:15];
• Comparing common diets: data showing the association between the incidence of Alzheimer’s disease and specific diets [59:45];
• Supplements: EPA and DHA, vitamin D, and B vitamins [1:13:00];
• Supplements: theracurmin, cocoa flavonols, and magnesium L-threonate [1:25:15];
• Impact of exercise on brain health, minimum effective dose, and the most important types of exercise [1:33:00];
• Challenging the mind with brain games—does it impact neurodegeneration? [1:43:00];
• The data on sauna and brain health [1:49:45];
• Oral health and its association with brain health [1:52:45];
• How reducing lipids can improve brain health and prevent neurodegeneration [1:55:30];
• The potential impact of hearing loss on brain health and neurodegeneration [2:04:30]; and
• More.

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Andy Galpin is a Professor of Kinesiology at California State University at Fullerton, where he studies muscle adaptation and applies his research to work with professional athletes. In this episode, Andy returns to the podcast and continues the conversation about training for longevity. He examines the training practices of powerlifters, Olympic weightlifters, Strongmen/women, CrossFit athletes, and sprinters in order to extract insights that can be applied to the individual wanting to optimize for longevity. Andy goes into detail about exercise load and repetition, training volume, the importance of learning proper movement patterns, the advantage of working to technical failure instead of the number of reps, and much more. Andy ties the discussion together by providing a hypothetical training plan for an individual wanting to optimize for longevity and offers advice for avoiding injury.

We discuss:

• Review of the function and organization of skeletal muscle [3:15];
• Review of muscle fiber types [9:30];
• Hypertrophy: changes in muscle fibers and the underlying mechanisms that make a muscle grow [19:30];
• Defining sarcoplasmic hypertrophy and how it relates to the number of reps in a set [30:15];
• Training for maximum strength: what we can learn from powerlifters and a hypothetical training plan [32:45];
• Ideal reps, volume, and load for the powerlifter [44:45];
• What should powerlifters do on their off days? [56:45];
• Are there consequences of powerlifting on long-term health? [1:02:00];
• Defining Olympic weightlifting: a test of power [1:04:30];
• Training principles of Olympic weightlifting [1:07:45];
• Tracking power output when training [1:17:15];
• Frequency of training for Olympic weightlifting [1:22:15];
• How post-activation potentiation (and the opposite) can improve power training and speed training [1:24:30];
• The Strongman competition: more breadth of movement, strength, and stamina [1:32:00];
• Training principles of Strongmen and advice for someone new to the Strongman competition [1:36:45];
• CrossFit: a combination of weightlifting movements, endurance, and circuit training [1:50:15];
• Learning from elite athletes, heart rate recovery, V02 max, and other metrics [1:58:45];
• Optimizing towards being a well-rounded athlete as opposed to a specialist [2:09:45];
• What we can learn from the sprinters about speed, acceleration, peak velocity, and technique [2:17:45];
• A training plan for the “centenarian athlete” [2:24:30];
• Debunking some training and exercise myths [2:33:00];
• The “do nots” of training and tips for avoiding injury [2:34:15]; and
• More.

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Andrew Huberman is a Professor of Neurobiology at Stanford University and host of the Huberman Lab podcast. In this episode, Andrew begins with a fascinating discussion about the brain, including the role of the prefrontal cortex in adjusting your ruleset to match your setting, the neural circuitry underlying the ability of stress to limit creativity and problem-solving, the effect of belief on physiology and performance, and more. He speaks about vision being our “superpower” and compares this to animals that rely more on other senses. Next, he opens up about his personal journey, the struggles and losses he has overcome, the value of therapy, and the many great people who helped him along the way. He speaks to his love of biology and discovery and the importance of staying true to your passion rather than being driven purely by ambition. Lastly, the conversation includes a look to the future of Andrew's scientific work and podcast as well as his unique approach to communicating science and tackling the issue of scientific illiteracy.

We discuss:

• Exercise under blood flow restriction, lactate utilization, and transient changes in the brain function in response to adrenaline and stress [3:30];
• The role of the prefrontal cortex in governing rulesets [9:15];
• New discoveries about the circuitry between the prefrontal cortex, insula, and amygdala, and the insights gleaned about brain function in different emotional states [15:30];
• Comparing human vision and other senses to animals [26:00];
• A deep dive into vision: evolutionary adaptations, facial recognition, color, and more [39:45];
• Sense of smell, pheromones, and why evolution developed better vision over smell [46:30];
• The relationship between visual input and time perception [55:30];
• Mindset effects: the effect of belief on physiology and performance [1:00:45];
• Accessing higher levels of creativity with broadening rulesets and the limiting nature of stress and fear on creativity [1:05:30];
• Stress and fear increase autonomic arousal, limit access to rulesets, and inhibit performance [1:12:15];
• Andrew’s upbringing, early childhood, and tough adolescent years [1:15:00];
• Andrew’s time in a residential treatment program and how he benefited from therapy [1:20:15];
• The beginning of positive changes in Andrew’s young life [1:28:30];
• Andrew’s decision to turn his life around [1:37:00];
• A new passion for science and exercise helps Andrew [1:42:00];
• The difference between a postdoc and a PhD [1:54:15];
• Staying in touch with the love of biology and not getting pulled into ambition [1:59:15];
• Andrew starts his own lab, and continues work to overcome his demons [2:07:00];
• The loss of three mentors leads to deep soul searching [2:12:00];
• What motivated Andrew to begin his podcast [2:18:00];
• Looking to the future of Andrew’s scientific work, podcast, and more [2:22:45];
• Andrew’s unique approach to communicating science and the issue of scientific illiteracy [2:30:00]; and
• More.

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Order OUTLIVE

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After more than six years of research, planning, and writing, Peter’s book, Outlive: The Science and Art of Longevity, is officially available as of March 28th. In this episode, Peter sits down with co-author Bill Gifford to provide a behind-the-scenes look into the writing process, including the motivation for making it happen, how the book evolved over the course of the writing process, and why certain topics were chosen (and omitted). Additionally, they discuss how the book is structured and touch on a few of the book’s main themes to give potential readers an idea of what they can expect.

We discuss:

• The meaning of the book’s title and subtitle [3:00];
• Finding the right art for the book cover [9:00];
• Who is Bill Gifford, and how did he get involved in the book? [16:15];
• How Peter’s writing evolved over the six years it took to write this book [25:00];
• The structure of the book and what people can expect to learn [29:00];
• How the writing of the book and the podcast interviews have shaped Peter’s thinking and approach to translating science [32:45];
• Making the book stand the test of time despite the constant evolution of science and medicine [36:00];
• Objective, strategy, and tactics [39:30];
• Exciting possible progressions in science and medicine over the next decade [42:15];
• What is holding back “medicine 3.0” from being the norm? [46:00];
• How the book compares to the podcast in terms of technicality and readability for the layman [49:00];
• Motivation to write the book and insights into challenges around the writing process [57:15];
• Peter’s decision to be the reader for the audiobook [1:10:30];
• The many painstaking last-minute changes and edits that brought the book together and made it better [1:19:00];
• Peter and Bill’s favorite parts of the book [1:27:30];
• The incredible team of people supporting the book [1:31:30]; and
• More.

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Ethan Weiss is a preventative cardiologist at UCSF, an entrepreneur-in-residence at Third Rock Ventures, where he is working on a project related to cardiometabolic disease, and a previous guest on The Drive. In this episode, Ethan compares and contrasts the diagnostic imaging tools, CAC (coronary artery calcium score) and CTA (CT angiography), used to image plaque—including the latest in CTA software—and how these tools inform our understanding of ASCVD risk and guide clinical decision-making. Ethan discusses the types of plaque that cause events and the data that make a case for optimal medical therapy over stenting outside of particular cases. He explains why high blood pressure is problematic and walks through the data from clinical trials testing aggressive treatment. He talks about the best way to actually measure blood pressure, why we shouldn’t simply accept that blood pressure rises with age, and how he uses different pharmaceutical agents to treat hypertension. Additionally, Ethan explains our current, but limited, understanding of the role of metabolic health in ASCVD. He discusses the impact of fat storage capacity and the location of fat storage and explains how and why there is still a residual risk, even in people who have seemingly normal lipids, don't smoke, and have normal blood pressure.

We discuss:

• Ethan’s entrepreneurial work in the cardiometabolic disease space [4:30];
• Calcium scans (CAC scores) and CT angiography (CTA), and how it informs us about ASCVD risk [6:00];
• Peter’s historical CAC scores, CTA results, and how one can be misled [10:45];
• How Peter’s CTA results prompted him to lower his apoB [14:45];
• Calcium scans vs. CT angiogram (CTA) [21:15];
• How Ethan makes clinical decisions based on CTA results and plaque burden, and the importance of starting treatment early to prevent ASCVD [28:15];
• Improved methods of CTA to grade plaque lesions and how it’s shaped medical decisions such as stenting [33:45];
• Why Ethan favors optimal medical therapy over stenting outside of particular situations [41:45];
• The need for FFR CTA, and the potential for medical therapy to eliminate ASCVD [54:00];
• The fat attenuation index (FAI) and other ways to measure inflammation in a plaque [57:30];
• Statins and exercise may increase the risk of calcification, but what does this mean for risk? [59:45];
• The root cause of statin hesitation despite evidence that statins are a profoundly important intervention [1:05:30];
• Importance of keeping blood pressure in check, defining what’s normal, and whether we should just accept higher blood pressure with age [1:10:45];
• Blood pressure variability, how to best measure it, and data suggesting the enormous impact of keeping blood pressure down [1:21:00];
• Drugs for treating high blood pressure recommended by the ALLHAT trial [1:35:15];
• What the SPRINT trial says about the aggressive treatment of hypertension, and the risks of such treatment [1:38:15];
• Confirmatory results in the STEP trial for blood pressure, and how Ethan uses the various pharmacological agents to lower blood pressure in patients [1:43:15];
• The role metabolic health in ASCVD: what we do and don’t know [1:51:00];
• The impact of fat storage capacity and the location of fat storage on metabolic health and coronary artery disease [1:56:15]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter focuses the discussion on two topics getting a lot of attention recently. He first dives deep into GLP-1 agonists, most notably semaglutide and tirzepatide, which originally came to market as diabetes drugs but are now being studied and prescribed for weight loss. He walks through the data and compares the effectiveness of the two drugs, the side effects, and perhaps more importantly, his reservations around wide use of these drugs and who he would consider to be a candidate for them. Next, Peter discusses how metformin, another drug originally brought to market for diabetes management, gained popularity as a potential longevity drug even for non-diabetics. Peter gives his take on this possibility and reviews data from a more recent study investigating the question of whether metformin should be used for general “geroprotection.”

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

We discuss:

• The hype around semaglutide, tirzepatide, and other GLP-1 agonists for weight loss [2:30];
• Overview of GLP-1 agonists and why these drugs are getting so much attention [6:15];
• Defining the term “geroprotective” [13:30];
• Semaglutide: background, brand names, indications, and more [15:15];
• Tirzepatide: background, brand names, indications, and more [19:15];
• How semaglutide and tirzepatide compare in their efficacy in terms of weight loss and other metabolic health metrics [23:45];
• Data showing sustained weight loss and improved metabolic metrics with after more than a year of using semaglutide and tirzepatide [29:00];
• What happens to body weight when a patient discontinues the medication? [34:45];
• Noteworthy side effects of GLP-1 agonists and similar classes of drugs [40:45];
• Increased resting heart rate and other concerning trends in patients using GLP-1 agonists [45:15];
• Changes in body composition (body fat and lean muscle) in patients on GLP-1 agonists [50:45];
• Possible reasons for the loss of lean muscle mass and tips for protecting lean mass [59:00];
• GLP-1 agonists and thyroid cancer [1:01:30];
• Who might be a candidate for GLP-1 agonists? [1:03:45];
• The large financial cost of this class of drugs [1:08:30];
• Metformin as a geroprotective drug: origin of the idea that metformin could be a longevity agent even for non-diabetic patients [1:11:30];
• A 2022 study on metformin sheds more light on the question of whether metformin should be used for “geroprotection” in non-diabetics [1:21:00];
• Peter’s current approach with metformin for his patients [1:25:15]; and
• More.

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Lewis Howes is a New York Times best-selling author, entrepreneur, speaker, and host of the popular podcast, The School of Greatness. In this episode, Lewis opens up about the various hardships and traumatic events he experienced starting at a very young age and reveals the valuable lessons he learned as he worked through those traumas to improve his emotional health. He talks about how his past hardships likely contributed to his success in business and athletics, only to leave him feeling unsatisfied and unfulfilled. Next, he discusses how many aspects of his life were suffering, the inflection point that drove Lewis to seek help, and the long but beautiful healing journey that followed. Lewis makes the case that adversity, and even trauma, can be beneficial if one finds meaning in tribulations and has the courage to face one’s fears and insecurities. Finally, Lewis shares the many modalities of therapy that helped him along the way and gives advice for those wanting to find inner peace and live a fulfilling, rich, abundant, joyful life.

We discuss:

• Lewis’s upbringing and the impact of his older brother going to prison [2:45];
• Finding lessons in tragedy and adversity [10:45];
• Lasting trauma from being sexually abused at age 5 [13:15];
• Inflection point that drove Lewis to seek help, and a beautiful experience at a therapeutic workshop [16:45];
• A powerful workshop on emotional intelligence jump started Lewis’s healing journey [27:30];
• How being authentic can strengthen bonds with family and bring inner peace [39:30];
• Comparing adversity with trauma and finding meaning in struggle [45:15];
• Association between adverse childhood events and diseases in adulthood [56:15];
• How addressing his issues with intimate relationships helped Lewis overcome physical pain related to his past trauma [59:15];
• Healing is a journey that takes time and requires courage to face your fears and insecurities [1:08:45];
• How Lewis thinks about mortality and uses it as motivation to pursue his dreams [1:13:00];
• How anyone can benefit from therapy or coaching, and Lewis’s advice for finding inner peace [1:22:45];
• Lewis’s newest book, The Greatness Mindset [1:29:15]; and
• More.

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Siddhartha Mukherjee is an oncologist, Pulitzer Prize-winning author, and previous guest on The Drive. In this episode, Sid discusses many of the subjects of his latest book, The Song of the Cell, including the incredible discovery of the cell and how it transformed medicine. He explains the evolutionary drive to go from single-cell to multicellular life and unpacks the four different types of cell-based therapies and the problems they are attempting to solve. He also provides the latest in gene therapy, such as CRISPR, and the ethical questions around human gene editing. Additionally, he touches on a number of fascinating topics, such as the challenges of medical science, the human brain, learning styles, his writing process, mental health, and more.

We discuss:

• How the cell brings the genome to life, and how Sid’s recent book fits into his prior work to tell a story [2:30];
• How the germ theory of disease and an understanding of the cell fueled a big leap in medicine [9:45];
• What is the evolutionary drive for multicellular life? [17:15];
• Four types of cell therapies and the challenges of gene therapy [26:00];
• CAR T-cell therapy: promising gene therapy for cancer [36:30];
• The possibility of using gene therapy to treat germline mutations like sickle cell disease [41:45];
• The incredible revolution of gene editing with CRISPR [45:15];
• Ethical questions around human gene editing [52:30];
• The complex role of genetics in mental illness [1:01:30];
• Two types of problems in science: the “eye in the sandstorm” problem and the “sand in the eye” problem [1:06:15];
• Understanding neural networks: an example of the “sand in the eye” problem being solved [1:08:45];
• Importance of learning by doing: comparing the learning styles of a doctoral student to a medical student [1:16:30];
• Sid’s unique and brilliant style of writing [1:20:45];
• Falling as the leading cause of accidental death: a liability of multicellular existence [1:25:00];
• Sid’s struggle with depression and his desire to change the stigma around mental illness [1:29:15]; and
• More.

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Anthony Hipolito is a sheriff’s deputy in Hays County, Texas with over 24 years of experience in law enforcement. In this episode, Anthony discusses his work to spread awareness about illicit fentanyl use and the drastic increase in accidental overdoses, especially in young people. Anthony explains the deadly nature of fentanyl, including how many counterfeit drugs are now being laced with deadly doses of fentanyl. He breaks down how fentanyl is being brought to the US and how younger and younger kids are being targeted. Additionally, Anthony discusses his goal of spreading awareness to our communities and provides important advice for what parents can do.

We discuss:

• Anthony’s life of service in law enforcement [5:30];
• Fentanyl: medical use, recreational use, and the recent rise in prevalence [8:30];
• The story of a teenager dying from an accidental overdose of fentanyl [16:30];
• The scope of deaths being caused by accidental overdoses (the majority of which are from fentanyl) [23:00];
• How young kids are being targeted, and how fentanyl makes it across our borders and gets distributed [28:30];
• What happens to a person when they overdose [35:30];
• Whether laws around drug possession are helping or hurting, and the need to focus on helping people that feel the need to take these counterfeit drugs [37:00];
• How fentanyl is being added to all kinds of drugs that you wouldn’t expect [42:45];
• What can we do as parents? [47:15];
• Narcan: a treatment for opioid overdoses [50:15];
• Importance of awareness, having conversations with kids early in life, and other key takeaways for parents [56:30]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter reviews the last 12+ years of his DEXA scan results revealing the changes to his body composition, lean muscle mass, visceral adipose tissue, and more. He explains how his body composition and blood biomarkers were impacted by the various dietary approaches (ketosis, fasting, high protein, etc.) and training protocols (primarily endurance, primarily strength training, etc.) he has undertaken over the years. Furthermore, Peter explains his planned approach moving forward following his most recent DEXA scan in late 2022.

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

We discuss:

• DEXA scans and other methods for tracking body composition [2:30];
• Importance of tracking data over time to see trends [10:15];
• DEXA scans in 2011: swimming, lifting, and a carb-restricted diet [12:45];
• DEXA scans 2012-2014 during Peter’s time on a strict ketogenic diet [18:30];
• Blood biomarkers for evaluating metabolic health [25:15];
• DEXA scan in 2020 after several years of regularly engaging in time-restricted feeding and prolonged fasting protocols [28:45];
• DEXA scan in 2021: shifting focus to adding muscle, high-protein diet, and more strength training [40:00];
• DEXA scan in early 2022: eating additional calories and adding blood flow restriction (BFR) to his workouts [44:45];
• DEXA scan in late 2022: a dramatic change following shoulder surgery, and the impact of stress [48:30];
• Peter’s approach moving forward following his most recent DEXA scan [59:15];
• A rundown of the various nutritional methods of energy restriction [1:06:15];
• Current thoughts on fasting and key takeaways [1:09:45]; and
• More.

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Ric Elias, the founder of Red Ventures and previous guest on The Drive, returns to discuss his evolving insights on time, relationships, parenting, and how to make the most of the gift of life. In this episode, he reflects on the changes he’s made since his near-death experience during the crash landing of Flight 1549 on the Hudson River in 2009. Ric reveals many keys to living a rich life, such as aiming for continuous growth, approaching life with true intentionality, and valuing our time in accordance with that. He talks about relationships as the core of a rich life and provides insights on parenting and how we should think about our relationship with our kids as they grow older. Finally, Ric discusses the importance of staying true to yourself, the value in struggle, and finding meaning in helping others.

We discuss:

• Reflecting on the tumultuous last few years and how his experience on Flight 1549 helped him [2:30];
• Parenting: a game of tug of war that you must ultimately lose [5:00];
• Importance of friendship and Ric’s motivation for his recent “Friends summit” [8:00];
• The impact of looking forward and focusing on growth on finishing life well [13:00];
• How our relationships with our children evolve as they grow, and a new perspective on purpose [21:15];
• Living with complete intention for a rich life, valuing your time, and other life lessons inspired by Ric’s near-death experience on Flight 1549 [31:15];
• How society’s relationship with work has changed, the pros and cons of remote and hybrid working environments, and an update on his company “Red Ventures” [37:45];
• Ric’s dedication to philanthropy [44:45];
• The Golden Door Scholars program aiming to help undocumented students with education and a future career [50:30];
• Ric’s journey in health and longevity [59:15];
• Letting go of guilt and loving yourself [1:02:30];
• The relationship between happiness and wealth [1:06:45];
• Playing the “infinite game,” staying true to oneself, and ignoring the negative [1:09:15];
• Speculating on the meaning of success, the drivers of greatness, and the value of struggle [1:16:00]; and
• More.

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Dan Rader is a Professor at the Perelman School of Medicine at the University of Pennsylvania, where he conducts translational research on lipoprotein metabolism and atherosclerosis with a particular focus on the function of high-density lipoproteins (HDLs). In this episode, Dan goes in-depth on HDL biology, including the genesis of HDL, its metabolism, function, and how this relates to atherosclerotic cardiovascular disease (ASCVD). He explains why having high HDL-C levels does not directly translate to a low risk of cardiovascular disease and reveals research pointing to a better way to measure the functionality of HDL and predict disease risk. He also goes into detail on the role of HDL in reverse cholesterol transport and the benefits this has for reducing ASCVD. Additionally, Dan discusses the latest thinking around the association between HDL cholesterol and neurodegenerative diseases and ends the conversation with a discussion of how the latest research on HDL provides a promising outlook for ongoing trials and future therapeutic interventions.

We discuss:

• The lipidology of apoB and apoA [4:00];
• A primer on the high-density lipoprotein (HDL): genesis, structure, and more [9:30];
• How the lipoprotein system differs in humans compared to other mammals [20:00];
• Clarifying the terminology around HDL and apoA [25:30];
• HDL metabolism [31:45];
• CETP inhibitors for raising HDL-C: does it reduce CVD risk? [34:45];
• Why it’s so important to have hard outcome trials in the field of cardiovascular medicine [42:30];
• SR-B1: an HDL receptor important for cholesterol efflux [48:00];
• The association between HDL levels and atherosclerosis: are they causally linked? [53:15];
• How insulin resistance is impacting HDL, and how HDL-C provides insights into triglyceride metabolism [58:00];
• Disappointing results from the studies of niacin—a drug that raises HDL-C and lowers apoB [1:08:15];
• HDL lipidation, dilapidation, and reverse cholesterol transport [1:12:00];
• Measuring the cholesterol efflux capacity of HDL: a better predictor of ASCVD risk than HDL-C? [1:22:00];
• A promising new intervention that may promote cholesterol efflux and reverse cholesterol transport [1:32:45];
• The association between HDL cholesterol and neurodegenerative diseases [1:34:00];
• Challenges ahead, a promising outlook, and the next frontier in lipidology [1:44:45]; and
• More.

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Andy Galpin is a Professor of Kinesiology at California State University at Fullerton, where he studies muscle adaptation and applies his research to work with professional athletes. In this episode, Andy sets the foundation for the conversation by discussing the anatomy, microanatomy, and physiology of the muscle, including explaining what it actually means to undergo hypertrophy of the muscle. He then explains the difference between power, strength, speed, and hypertrophy and how those differences relate to what's happening at the cellular level and the functional unit level. Additionally, he discusses energy sources for muscles, the importance of protein for muscle synthesis, the various types of muscle fibers, and the factors that determine one’s makeup of muscle fibers. Finally, Andy wraps the conversation with how he would design a program for an untrained person committed to adding muscle and functional strength for longevity.

We discuss:

• Andy’s path to expertise in exercise [3:30];
• Contrasting strength, power, and force production and how they inform us about training for longevity [9:30];
• Muscle energetics: Fuels that provide energy to muscles, and the importance of protein [17:45];
• The structure and microanatomy of muscle, muscle fibers, and more [29:30];
• Energy demands of skeletal muscle compared to other tissues in the body [39:45];
• How a muscle contraction works and why it requires ATP [48:00];
• Muscle fibers: modulation between fiber types with movement and changes in fibers with training and aging [53:15];
• Andy’s study of twins demonstrating the difference in muscle fibers between a trained and untrained individual [1:02:30];
• Microanatomy of fast-twitch and slow-twitch muscle fibers [1:11:15];
• Factors that determine one’s makeup of muscle fibers and how adaptable they are with training [1:22:15];
• Hypertrophy and what happens at the cellular level when a muscle grows [1:30:00];
• How athletes quickly cut water weight and the rehydration process [1:37:30];
• Different types of athletes [1:47:30];
• Training advice for a hypothetical client who’s untrained and wants to add muscle and functional strength for longevity [1:49:45];
• Changes in muscle and muscular function that occur with aging [1:53:45];
• Training plan for the hypothetical client [1:59:30];
• What drives muscle hypertrophy? [2:12:15];
• How to properly incorporate isometric exercises into a workout [2:19:00];
• Additional training tips: movement patterns, how to finish a workout, and more [2:25:45];
• Ways to incorporate high heart rate exercise into a workout plan [2:28:45]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter answers questions related to the leading cause of death in both men and women—atherosclerotic cardiovascular disease (ASCVD). He highlights the most important risk factors for ASCVD, such as apoB, LDL, hyperinsulinemia, and Lp(a), and explains the mechanism by which they confer risk and how these factors are interrelated. Peter also dives deep into the data around apoB to try to answer the question of how much residual risk is conferred for ASCVD through metabolic dysfunction once you correct for apoB. He also looks at the data around lifetime risk reduction of ASCVD in the context of low apoB.

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

We discuss:

• A racecar analogy for understanding atherosclerotic cardiovascular disease [2:00];
• Defining and differentiating apoB and LDL-C [10:00];
• The interrelated nature of insulin levels, apoB, triglycerides, and ASCVD parameters [13:00];
• Another way that hyperinsulinemia plays a role in endothelial dysfunction [18:00];
• Why Peter uses the oral glucose tolerance test (OGTT) with all patients [20:15];
• Is there any evidence that hyperinsulinemia is an independent contributor to ASCVD? [23:00];
• Thinking through risk in the context of high-fat diets resulting in improved metabolic metrics but with an elevation of apoB/LDL-C [27:30];
• Thinking through risk in the context of low apoB but higher than normal triglyceride levels [32:15];
• The importance of lowering apoB for reducing ASCVD risk [38:15];
• Data on men and women with familial hypercholesterolemia that demonstrates the direct impact of high apoB and LDL-C on ASCVD risk [47:45];
• Importance of starting prevention early, calcium scores, and explaining causality [52:30];
• Defining Lp(a), its impact on ASCVD risk, and what you should know if you have high Lp(a) [56:30];
• Lp(a) and ethnic differences in risk [1:00:30];
• Why someone with elevated Lp(a) should consider being more aggressive with apoB lowering strategies [1:05:00];
• Addressing the common feeling of hesitancy to taking a pharmacologic approach to lower ASCVD risk [1:07:15];
• Peter’s take on the 2022 Formula 1 season and thoughts on 2023 [1:15:15]; and
• More.

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Bill Perkins is one of the world’s most successful hedge fund managers and entrepreneurs, and the author of the bestseller, Die With Zero. In this episode, Bill unpacks the Die With Zero philosophy which challenges conventional thinking related to the balance between health, wealth, and time—the three variables important for fulfillment. Bill makes the case that we should strive for maximum net fulfillment rather than net worth (or even health). He argues that we need to optimize our life to have memorable experiences before it’s too late and that most people are over-saving and under-living. Bill also explains how one can apply the principles in Die With Zero to break out of “autopilot” and optimize their life to achieve maximum net fulfillment.

We discuss:

• Bill’s upbringing, background, and first job on Wall Street [3:15];
• A missed experience and feeling of regret that shaped Bill’s thinking [14:15];
• Thinking in terms of time, and the relationship between money, time, and health [17:00];
• Solving for net fulfillment and allocating your time based on the seasons of life [27:15];
• How Bill thinks about risk, opportunity costs, and the difference between fear and risk tolerance [35:30];
• Optimizing for fulfillment, finding purpose outside of work, and more [41:45];
• Thinking about the order of experiences you want to have based on seasons of life [50:00];
• Bill’s unique perspective on philanthropy and a more impactful way to give money away [54:45];
• Applying the principles in ‘Die With Zero’ to maximize fulfillment [1:04:00];
• How to break out of living life on autopilot [1:14:30];
• When should your net worth peak? [1:18:00];
• Taking calculated risks [1:21:30];
• Bill shares a lesson from his incredible birthday [1:25:15];
• How Bill’s philosophy has evolved since writing Die With Zero [1:34:00]; and
• More.

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James Clear is the author of the New York Times bestseller Atomic Habits. His extensive research into human behavior has helped him identify key components of habit formation and develop the “Four Laws of Behavioral Change.” In this episode, James provides insights into how both good and bad habits are formed, including the influence of genetics, environment, social circles, and more. He points to changes one can make to cultivate more perseverance and discipline and describes the profound impact habits can have when tying them into one’s self-identity. Finally, James breaks down his “Four Laws of Behavioral Change” and how to use them to create new habits, undo bad habits, and make meaningful changes in one’s life.

We discuss:

• Why James became deeply interested in habits [1:45];
• Viewing habits through an evolutionary lens [6:00];
• The power of immediate feedback for behavior change, and why we tend to repeat bad habits [9:15];
• The role of genetics and innate predispositions in determining one’s work ethic and success in a given discipline [14:30];
• How finding one’s passion can cultivate perseverance and discipline [23:15];
• Advantages of creating systems and not just setting goals [29:15];
• The power of habits combined with self-identity to induce change [36:30];
• How a big environmental change or life event can bring on radical behavioral change [50:30];
• The influence of one’s social environment on their habits [54:15];
• How and why habits are formed [1:00:30];
• How to make or break a habit with the “Four Laws of Behavior Change” [1:09:30];
• Practical tips for successful behavioral change—the best strategies when starting out [1:16:15];
• Self-forgiveness and getting back on track immediately after slipping up [1:30:30];
• Law #1: Make it obvious—Strategies for identifying and creating cues to make and break habits [1:39:45];
• Law #2: Make it attractive—examples of ways to make a new behavior more attractive [1:47:45];
• Law #3: Make it easy—the 2-minute rule [1:58:45];
• Law #4: Make it satisfying—rewards and reinforcement [2:03:30];
• Advice for helping others to make behavioral changes [2:06:00]; and
• More.

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Layne Norton holds a Ph.D. in nutritional sciences and is a physique coach, natural bodybuilder and powerlifter, and two-time previous podcast guest. In this episode, Layne discusses his training as a powerlifter and shares training principles that non-powerlifters can apply to improve muscle strength and mass. Layne goes in-depth on creatine supplementation, including the benefits for lean mass and strength, and addresses the common arguments against its regular usage. Additionally, Layne touches on many areas of nutrition, including how his opinions have changed on certain topics. Layne also touches on the subjects of protein, fiber, and fat in the diet, as well as the different tools and dietary approaches for energy restriction.

We discuss:

• The sport of powerlifting and Layne’s approach during competitions [2:30];
• Training for strength: advice for beginners and non-powerlifters [13:15];
• Low-rep training, compound movements, and more tips for the average person [23:15];
• How strength training supports longevity and quality of life: bone density, balance, and more [28:15];
• Peak capacity for strength as a person ages and variations in men and women [33:00];
• Effects of testosterone (endogenous and exogenous) on muscle gain in the short- and long-term [36:45];
• How Layne is prepping for his upcoming IPF World Masters Powerlifting competition [44:00];
• Creatine supplementation [54:30];
• How important is rep speed and time under tension? [1:05:30];
• Validity of super slow rep protocols, and the overall importance of doing any exercise [1:12:45];
• Navigating social media: advice for judging the quality of information from “experts” online [1:23:00];
• Layne’s views on low-carb diets, the tribal nature of nutrition, and the importance of being able to change opinions [1:34:45];
• Where Layne has changed his views: LDL cholesterol, branched-chain amino acid supplementation, intermittent fasting, and more [1:42:00];
• The carnivore diet, elimination diets, and fruits and vegetables [1:55:15];
• Fiber: Layne’s approach to fiber intake, sources of fiber, benefits, and more [2:00:15];
• Confusion around omega-6 polyunsaturated fatty acids and the Minnesota Coronary Experiment [2:05:00];
• Layne’s views on fats in the diet [2:13:00];
• Flexible dieting, calorie tracking, and the benefits of tracking what you eat to understand your baseline [2:18:00];
• The nutritional demands of preparing for a bodybuilding show [2:30:45];
• The psychological effects of aging and changes to one’s identity [2:42:00]; and
• More.

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Chris Hemsworth, best known for his role as Thor in the Marvel movies, joins Peter to discuss his recent work in the docuseries called Limitless. In the docuseries, Chris undertook extreme challenges to explore his physical and emotional limits and gain insights into longevity. In this episode, Chris discusses these many challenges—from fasting to arctic swims to 100-foot rope climbs—as well as the insights that he gained from each. Peter, who also played a role in the docuseries, guides Chris through the science of longevity, including what Chris’s APOE-ε4 genotype means for his risk of Alzheimer’s disease. Additionally, Chris describes how his outlook on health, happiness, work-life balance, and more have changed from his experience on Limitless.

We discuss:

• Limitless: how Chris got involved and his overall experience filming the docuseries [3:00];
• “Fasting” ‒ ep. 3 of Limitless in which Chris attempts a 4-day fast [8:15];
• “Shock” ‒ ep. 2 of Limitless in which Chris swims in the Arctic Ocean [12:15];
• Cold exposure: the potential physical and mental benefits [19:30];
• “Strength” ‒ ep. 4 of Limitless in which Chris explores how muscle can improve longevity [21:15];
• The APOE-ε4 genotype and Alzheimer’s disease risk [31:30];
• How Chris uses sauna [39:45];
• “Acceptance” - ep. 6 of Limitless in which Chris explores the meaning of life by contemplating death [42:15];
• Chris’s new perspective on work-life balance [52:00];
• “Stress-Proof” - ep. 1 of Limitless in which Chris learns about the impact of stress and how to manage it [54:30];
• Chris reflects on his intrinsic motivation driven by both fear and purpose [58:00];
• Chris reflects on his career arc and how his presence as an actor has evolved [1:01:15];
• How Chris’s outlook has changed since filming Limitless [1:05:00]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter answers a number of questions on optimizing sleep. He describes his pre-bedtime routine, how he utilizes a sauna, and his current regimen of medicines and supplements for improving sleep time and quality. He goes in depth on each of the molecules that have shown promise in boosting sleep, including their mechanisms of action as well as any noteworthy contraindications. Peter also discusses sleep wearables, including both the positives and potential negatives of using such trackers, and much more.

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 on our website at the AMA #42 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Peter’s current pre-bedtime routine [3:30];
• Sauna: Peter’s routine, sleep benefits, and tradeoffs [10:45];
• Importance of keeping an open mind as new information arrives [16:15];
• Importance of reducing stimulation leading up to bedtime [19:30];
• Medications that can enhance sleep: mechanisms of action, contraindications, risks, and Peter’s regimen [20:30];
• Why medications can enhance sleep, but should not replace good sleep habits [34:45];
• Sleep supplements: mechanisms of action, contraindications, and Peter’s regimen [37:30];
• Temperature during sleep, cooling devices, mattresses, and more [53:00];
• A tip to help avoid straining your back in the morning [59:15];
• Contrasting polysomnography with wearable sleep trackers [1:00:45];
• Sleep tracking wearables: interpreting metrics, and the pros and cons of trackers [1:04:30];
• Final takeaways on sleep [1:16:30]; and
• More.

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Alton Barron is an orthopedic surgeon specializing in the shoulder, elbow, and hand. In this episode, Alton breaks down the anatomy of the upper extremities and discusses the most common injuries associated with this area of the body. He explains in detail how he examines the shoulder, elbow, and hand to find the source of the pain and lays out the non-surgical and surgical treatment options as well as the factors that determine whether surgery is appropriate. Additionally, Alton describes the surgical procedures that, when done appropriately, can lead to tremendous reduction of pain and improvement in function.

We discuss:

• Alton’s path to orthopedic surgery [3:45];
• Evolution of orthopedics and recent advances [8:45];
• Anatomy of the upper extremities [13:30];
• Rotator cuff injuries, shoulder joint dislocation, and more [21:15];
• Peter’s shoulder problems [31:30];
• The structure of the biceps and common injuries [35:30];
• Labrum tears in the shoulder and natural loss of cartilage with usage and time [38:15];
• Shoulder evaluation with MRI vs. physical exam, diagnosing pain, and when to have surgery [41:30];
• How anatomical variation can predispose one to injury and how screening may help [50:30];
• Pain generators in the shoulder, and the important nuance of the physical exam [56:00];
• Frozen shoulder [1:05:15];
• Shoulder pain that originates in the neck [1:11:15];
• Surgical treatments for a labral tear, and factors that determine whether surgery is appropriate [1:16:00];
• Repairing the rotator cuff [1:29:15];
• Are platelet-rich plasma (PRP) injections or stem cells beneficial for healing tears? [1:38:15];
• Repair of an AC joint separation [1:45:15];
• Total shoulder replacement [1:55:45];
• The elbow: anatomy, pain points, common injuries, treatments, and more [2:05:30];
• How Tommy John surgery revolutionized Major League Baseball [2:17:15];
• History of hand surgery and the most significant advancements [2:22:15];
• The hand: anatomy, common injuries, and surgeries of the hand and wrist [2:29:30];
• Carpal tunnel syndrome [2:40:00];
• Other common injuries of the hand and forearm [2:47:15];
• Grip strength [2:55:15];
• Arthritis in the hands [2:59:30];
• Trigger finger [3:07:45];
• Nerve pain, numbness, and weakness in the upper limbs [3:14:00];
• The Musician Treatment Foundation [3:22:00];
• Gratitude and rucking [3:34:15]; and
• More.

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Gerald Shulman is a Professor of Medicine, Cellular & Molecular Physiology, and the Director of the Diabetes Research Center at Yale. His pioneering work on the use of advanced technologies to analyze metabolic flux within cells has greatly contributed to the understanding of insulin resistance and type 2 diabetes. In this episode, Gerald clarifies what insulin resistance means as it relates to the muscle and the liver, and the evolutionary reason for its existence. He goes into depth on mechanisms that lead to and resolve insulin resistance, like the role of diet, exercise, and pharmacological agents. As a bonus, Gerald concludes with insights into Metformin’s mechanism of action and its suitability as a longevity agent.

We discuss:

• Gerald’s background and interest in metabolism and insulin resistance (2:30);
• Insulin resistance as a root cause of chronic disease (6:30);
• How Gerald uses NMR to see inside cells (10:00);
• Defining and diagnosing insulin resistance and type 2 diabetes (17:15);
• The role of lipids in insulin resistance (29:15);
• Confirmation of glucose transport as the root problem in lipid-induced insulin resistance (38:15);
• The role of exercise in protecting against insulin resistance and fatty liver (48:00);
• Insulin resistance in the liver (1:05:00);
• The evolutionary explanation for insulin resistance—an important tool for surviving starvation (1:15:15);
• The critical role of gluconeogenesis, and how it’s regulated by insulin (1:20:30);
• Inflammation and body fat as contributing factors to insulin resistance (1:30:15);
• Treatment approaches for fatty liver and insulin resistance, and an exciting new pharmacological approach (1:39:15);
• Metformin’s mechanism of action and its suitability as a longevity agent (1:56:15); and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter answers a wide variety of questions, starting with a discussion on the evolution of medicine and the hopeful transition to “Medicine 3.0.” Peter recounts his unique career path and explains how he assesses risk and utilizes frameworks for decision-making. He also describes how he prioritizes his health while navigating the stresses of life, and he reviews the most exciting developments in the aging and longevity space. He finishes with some rapid-fire questions on cold plunging, strategies for lowering apoB levels, designing an exercise program for beginners, and more.

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 on our website at the AMA #41 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• The evolution of medicine and the transition to “Medicine 3.0” [3:00];
• Peter’s unorthodox career arc and what led him to this point [11:45];
• What does Peter consider to be his superpowers? [22:15];
• How Peter thinks about risk and explains it to his patients when making medical decisions [26:45];
• The advantage of using frameworks for decision-making [37:00];
• What advice would Peter give his 30-year old self? [42:15];
• Why longevity is such a hard problem to solve [42:30];
• The most impactful developments in the field of longevity and aging in the last 5 to 10 years [46:15];
• What is Peter most excited to see develop in the health and longevity space in the next few years? [51:30];
• Prioritizing healthy habits while navigating the stresses of life and time constraints [53:45];
• How Peter navigates periods of high stress [58:00];
• What fitness watch did Peter recently purchase? [1:03:45];
• Potential benefits of cold plunging [1:05:15];
• Advice for someone beginning an exercise program [1:07:30];
• Strategies and tactics to lower apoB levels [1:09:00];
• Interesting studies and books Peter has recently read [1:11:30]; and
• More.

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Erin Michos is an internationally-known leader in preventive cardiology and women’s cardiovascular health. In this episode, Erin discusses current trends in cardiovascular disease (CVD) through the lens of female biology and the observation that major adverse cardiac events in both sexes are on the rise. She walks through risk factors including LDL-cholesterol, apoB, and Lp(a) and makes the case for the importance of early preventative measures. She explains various interventions for reducing risk including a discussion of statins, GLP-1 agonists, PCSK9-inhibitors, and drugs that lower Lp(a). She goes in-depth on female-specific factors that contribute to CVD risk such as pregnancy, grand multiparity (having five or more children), oral contraceptives, menopause, and polycystic ovary syndrome (PCOS). Additionally, she explains her approach with patients as it relates to the use of hormone replacement therapy and provides advice for people wanting to lower risk both through lifestyle changes and medications.

We discuss:

• Erin’s background in preventive cardiology and women’s health [2:30];
• Recent trends in cardiovascular disease in women, mortality data, and how it compares to cancer [5:15];
• Why early preventative measures are critical for cardiovascular disease risk [13:15];
• ApoB as a causal agent of CVD, and why high apoB levels are not being aggressively treated in most cases [19:45];
• The rising trend of metabolic syndrome and other factors contributing to the regression in progress of reducing cardiac events [27:00];
• GLP-1 agonists—Promising drugs for treating diabetes and obesity [33:30];
• Female-specific risk factors for ASCVD (pre- and post-menopause) [37:15];
• Polycystic ovary syndrome (PCOS): prevalence, etiology, and impact on metabolic health, lipids and fertility [47:00];
• The effect of grand multiparity (having 5+ children) on cardiovascular disease risk for women [52:30];
• The impact of oral contraceptives on cardiovascular disease risk [55:00];
• The effect of pregnancy on lipids and other metabolic parameters [58:45];
• The undertreatment of women with familial hypercholesterolemia (FH) and how it increases lifetime risk of ASCVD [1:02:00];
• How concerns around statins have contributed to undertreatment, and whether women should stop statins during pregnancy [1:09:45];
• How Erin approaches the prescription of statins to patients [1:16:00];
• PCSK9 inhibitors and other non-statin drugs [1:21:15];
• Advice for the low- and high-risk individual [1:28:30];
• The impact of nutrition, stress, and lifestyle on lipids and CVD risk [1:31:00];
• Lp(a) as a risk enhancer for cardiovascular disease [1:41:15];
• The effect of menopause on cardiovascular disease risk [1:50:30];
• How Erin approaches decisions regarding hormone replacement therapy (HRT) for her patients [1:55:30];
• The urgent need for more data on women’s health [2:03:30];
• Erin’s goal of running a marathon in every state [2:09:45]; and
• More.

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In this special episode of The Drive, we have pulled together a variety of clips from previous podcasts about cardiovascular disease to help listeners understand this topic more deeply, as well as to identify previous episodes which may be of interest. In this episode, Peter highlights the importance of understanding cardiovascular disease and why early intervention is critical. He also provides a primer on lipoproteins and explains the fallacy of the terms “good cholesterol” and “bad cholesterol.” Allan Sniderman discusses the metrics measured in routine blood work – along with the limitations of those standard panels – before explaining why apoB is a superior metric for determining risk. Additionally, Tom Dayspring explains the causal role of apoB in atherosclerotic cardiovascular disease (ASCVD) and the therapeutic goals for apoB concentration, and Peter explains how early and aggressive lowering of apoB could change the landscape of cardiovascular disease prevention.

We discuss:

• The importance of understanding atherosclerosis early in life [2:25]
• Defining ASCVD, its causes, and the role of cholesterol [8:00];
• Why early prevention of atherosclerosis is critical [13:45];
• Preventing atherosclerosis—two fatal flaws with the “10-Year Risk” approach [16:00];
• Intro to lipids and lipoproteins: why there is no “bad” or “good” cholesterol [23:00];
• Limitations of standard blood panels [35:45];
• How Mendelian randomization is bolstering the case for apoB as the superior metric for risk prediction [39:30];
• Therapeutic goals for apoB concentration [58:15];
• How early and aggressive lowering of apoB could change the course of ASCVD [1:10:45]; and
• More.

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Holly Baxter is an accredited practicing dietician (APD), competitive bodybuilder, fitness and nutrition educator, and coach. In this episode, Holly discusses her experience as an athlete and competitive bodybuilder. She also opens up about her struggles with mental health, her long battle with an eating disorder, and the important steps she’s taken in her road to recovery. From there, she explains how she would design a nutrition and training program for a hypothetical female client wanting to improve her physique through the addition of lean muscle and loss of body fat. She explains reasonable expectations for gaining muscle and the value of a “reverse diet” for maintaining weight loss, and she shares her favorite exercises. She also talks through some female-specific training considerations such as programming, reps, volume, hormone replacement therapy, and more.

We discuss:

• Holly’s background and passion for sports and nutrition [2:00];
• Holly’s struggle with depression and an eating disorder [4:30];
• Reflecting on her eating disorder, body image, and a wake up call [18:15];
• Road to recovery: therapy, meditation, self-compassion, and a breakthrough [27:45];
• The effect of competitive bodybuilding on women [39:00];
• Holly’s competition prep and how she guides her clients wanting to improve their physique [46:45];
• Training principles for muscle hypertrophy [57:00];
• Training advice for an inexperienced person wanting to build muscle [1:01:30];
• Training program for a hypothetical woman wanting to add lean muscle and lose body fat [1:04:15];
• Lower body lifts: Holly’s approach to leg workouts with clients [1:14:00];
• Upper body exercises: Holly’s approach with her clients [1:24:45];
• Importance of nutrition and protein during the muscle building phase [1:34:00];
• Changes to nutrition and training during a fat loss phase [1:40:30];
• A “reverse diet” after a cutting phase to help prevent weight gain [1:49:45];
• Female-specific training considerations: programming, reps, volume, sex hormones, and more [1:53:15];
• Holly’s future in bodybuilding and helping struggling women [2:05:45];
• Looking forward: Holly’s focus on longevity, bone mineral density, and wellness [2:08:15]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter discusses the importance of understanding body composition and explains how to interpret the most important metrics revealed by a DEXA scan, such as lean muscle tissue mass, visceral adiposity tissue mass, bone mineral density, and more. He discusses common concerning trends in these metrics as well as strategies to address them. He goes through DEXA scan results of both male and female patient case studies and explains the prescribed intervention for each patient. Additionally, Peter answers numerous questions about dietary protein including how much we need, when we need it, and how intake should be divided throughout the day to optimize muscle protein synthesis. Finally, Peter provides his updated point of view on time-restricted feeding and fasting and how his personal approach and recommendations for patients has evolved.

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 on our website at the AMA #40 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Interpreting DEXA scans: important metrics, radiation levels, and more [2:15];
• DEXA metrics: Bone mineral density (BMD) [12:00];
• DEXA metrics: Visceral adipose tissue (VAT) [14:30];
• DEXA metrics on lean tissue: appendicular lean mass index (ALMI) and fat-free mass index (FFMI) [20:45];
• Concerning trends in BMD, VAT, & muscle mass revealed through DEXA scans [24:15];
• Muscle and lean tissue loss with age and how to overcome anabolic resistance [29:15];
• Female patient case studies: DEXA scan results and prescribed interventions [35:00];
• Male patient case studies: DEXA scan results and prescribed interventions [42:45];
• Protein consumption: recommended daily intake, Peter’s personal approach, timing around workouts, and more [48:15];
• What to look for with protein supplements [53:15];
• Protein intake: optimal timing and how it should be divided throughout the day [55:30];
• Time-restricted feeding (TRF): Peter’s updated perspective [57:45];
• Three strategies for reducing energy intake in over-nourished patients [1:03:15];
• Prolonged fasting: potential benefits and tradeoffs [1:07:15];
• A protein-supplemented version of time-restricted feeding (TRF) [1:09:30];
• Theories about time-restricted feeding (TRF) and its positive influence on sleep and circadian rhythm [1:12:00]; and
• More.

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Arthur Brooks is a social scientist, professor at Harvard University, a columnist for The Atlantic, and the bestselling author of From Strength to Strength. In this episode, Arthur explains how intelligence changes as we get older, and how to take advantage of this to maximize our happiness and success. He distills truths about the meaning of happiness and its three main components: enjoyment, satisfaction, and purpose. He goes into detail about many of the keys to a happy life, including the importance of cultivating virtuous relationships. On the flip side, Arthur warns of the dangers of social comparison, “success addition,” and the four worldly idols—money, fame, power, and pleasure—that drive many of us. Additionally, Arthur provides examples of exercises that can guide one in the right direction, overcome fear, and cultivate habits that can lead to a happier life.

We discuss:

• Insights from Arthur’s career as a professional French horn player [2:15];
• A radical shift away from music to a Ph.D. in quantitative policy [12:00];
• Personal experience with shifting intelligence: fluid vs. crystallized intelligence [16:45];
• An epiphany from a chance encounter on an airplane that shaped Arthur’s thinking [22:00];
• The three main “macronutrients” of happiness [25:00];
• Exploring the “purpose” component of happiness [29:00];
• The importance of having a partner and true friendships [32:00];
• The makeup of a true friendship, and why men tend to struggle with making real friends [36:45];
• The “satisfaction” component of happiness and the importance of “wants management” [42:15];
• The tyranny of social comparison [47:45];
• Insights into happiness through Chinese art, and the concept of a “reverse bucket list” [51:45];
• An exercise demonstrating the importance of relationships with others and the need to work on them [55:30];
• The four main idols that drive us: money, fame, power, and pleasure [1:01:15];
• Success addiction, workaholism, and their detriment to happiness [1:04:00];
• A radical approach to overcome fear—the antithesis to love and happiness [1:14:00];
• Ancient Hindu advice for the perfect life [1:26:30];
• The end result of getting caught in the 4 idols [1:31:45];
• The complexity of happiness [1:33:30]; and
• More.

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Michael Easter is the author of the bestseller, The Comfort Crisis. He’s also a journalist, Professor of Journalism at UNLV, and a leading voice on how humans can integrate modern science and evolutionary wisdom for improved health, meaning, and performance in life and at work. In this episode, Michael first talks about his upbringing, including his parents' struggle with alcoholism, his father leaving when he was young, and how these things impacted Michael's own struggle with alcoholism. He explains what led to his realization that we are in a “crisis of comfort” and how the removal of many of life’s discomforts through advancements in modern society may actually be a leading contributor to many of our most urgent physical and mental health issues. He explains the benefits of challenging oneself and the immense positive carryover which can come from doing things we find difficult. He describes the consequences of technology like smartphones, which have effectively eliminated boredom—a discomfort that comes with many benefits. He tells the story of a profound experience at an elk hunt that changed Michael’s thoughts around life and death, how happiness can thrive in places without all of the modern comforts of the West, and why we’re hardwired for stress and what to do about it. They conclude with a conversation around rucking, an activity with many physical and mental benefits.

We discuss:

• The value in doing something difficult [2:30];
• Michael’s upbringing with a single parent and alcoholism [5:45];
• Michael’s battle with alcoholism and his experience with quitting drinking [10:00];
• Origin of the idea that we are in a crisis of comfort [20:30];
• The death of boredom in modern society [28:45];
• The benefits of boredom [36:00];
• The value of disconnecting and being in nature [39:15];
• Changing the dynamic of how we think about food and the story of Peter’s daughter’s first hunt [43:45];
• How a profound experience at an elk hunt changed Michael’s thoughts about life and death [49:15];
• How happiness can thrive in places without all of the modern comforts of the West [57:15];
• Why we’re hardwired for stress, and the responsibility that comes with our level of comfort [1:05:30];
• How perspective on the timescale of our lives in relation to history can impart positive changes [1:14:00];
• The benefit of challenging oneself and the positive carryover it can have [1:19:45];
• The many benefits of rucking [1:28:45];
• Tips for rucking: ideal load, type of pack, and other considerations [1:38:00];
• Parting thoughts on the downside of comfort and benefits of difficult things [1:43:00]; and
• More.

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Don Layman is a Professor of Food Science and Human Nutrition at the University of Illinois Urbana-Champaign. He has spent the past 40 years investigating the role of dietary protein in muscle protein synthesis. In this episode, Don describes how his decades of research have shaped his thinking around protein, muscle, anabolic factors, metabolism, and more. He explains the recommended dietary allowance (RDA) for protein: what it is, how it came about, and how it should serve only as a guide for the minimum protein necessary for survival rather than as an optimal level of protein intake. He provides an overview of the essential amino acids, explains the nuances of animal versus plant protein, and provides insights for determining protein quality, absorption rates, and how to best track your intake. He discusses the ideal timing of protein intake in relation to resistance exercise, how protein should be distributed among meals, and how limitations in protein utilization per sitting can impact those practicing time-restricted eating. Additionally, Don shares results from his clinical trials, including how a high-protein diet fared in terms of fat loss, and explains the differences in protein utilization between adolescents and adults and how the problem of reduced efficiency of protein utilization in older adults can be overcome.

We discuss:

• Don’s background: from growing up on a farm to studying nutritional biochemistry [2:30];
• Don’s philosophy on nutrition, muscle, and metabolism [6:30];
• The controversial relationship between saturated fat and atherosclerosis [18:15];
• The basics of protein and amino acids [25:45];
• Origin and limitations of the current recommended dietary allowance (RDA) for protein intake [32:15];
• Protein sources: determining quality, absorption rates, and how to track intake [41:15];
• Leucine, lysine, and methionine: three important essential amino acids [48:00];
• The vital role of ruminant animals in the production of quality protein [53:15];
• The differing needs and impacts of dietary protein for a 16-year old compared to a 65-year old [59:30];
• Consequences of protein deficiency in childhood [1:06:30];
• Muscle protein synthesis: ideal timing, small meals vs. big meals, and more [1:12:45];
• Protein needs of children [1:19:45];
• How important is timing protein intake around training? [1:24:15];
• The role of leucine in fatty acid oxidation by muscle [1:28:15];
• High protein diets for fat loss: Results from Don’s clinical trials [1:31:30];
• Influence of industry funding on nutrition studies [1:43:45];
• Don’s thoughts on plant-based and synthetic “meats” [1:48:45];
• Problems with epidemiological studies of dietary protein [1:56:30];
• More.

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In this “Ask Me Anything” (AMA) episode, Peter describes what it means to exercise with the goal of longevity in mind, including his personal goals, exercise framework, and how he is optimizing for what he refers to as the “Centenarian Decathlon.” He explains the various types of cardiovascular training and how to partition your time between intensity levels (i.e., zone 2 training vs. zone 5 training) to optimize cardiorespiratory benefit. Additionally, Peter dives deep into questions around VO2 max, such as why it’s critical for longevity, how to improve it, and the value in starting VO2 max optimization early in life.

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 on our website at the AMA #39 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Exercise topics to be discussed [1:45];
• Peter’s exercise goals, and the Centenarian Decathlon [4:00];
• Peter’s exercise framework, and how he tracks his MET hours [8:30];
• How to partition your time between low and high intensity exercise to optimize results [13:15];
• Zone 2 exercise: ideal training methods and how to determine your zone 2 level [23:15];
• Rucking as a versatile mode of exercise [31:45];
• Zone 5 exercise: modalities of training, time per week, and other considerations [34:30];
• The importance of knowing your VO2 max, and methods for estimating it [38:15];
• Training methods for improving VO2 max, and realistic targets for improvement [46:00];
• Relationship of VO2max with age and the required fitness levels for daily life activities and exercise [52:30];
• The training necessary to maintain an elite VO2 max throughout life [58:45];
• The value in starting early: the compounding nature of fitness [1:01:45]; and
• More.

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Dr. Matt Kaeberlein is a globally recognized expert on the biology of aging and recurring on The Drive. In this episode, Matt explains his research findings on nutrition as it relates to aging and longevity, including the results from his recent review article in Science. From there, he and Peter dive deep into the literature on calorie restriction (CR), explaining the nuance, benefits for lifespan and healthspan, and potential downsides of CR. He discusses the epigenetic changes that occur with age and potential benefits and downsides of epigenetic reprogramming, often viewed as a panacea for reversing aging. Matt also explains the impact of dietary protein on aging, including the interesting dichotomy around how protein, a critical macronutrient, and rapamycin, a geroprotective molecule, have opposite effects on mTOR. Additionally, he talks about low-protein vs. high-protein diets and their effects on muscle mass and mortality, as well as the impact of IGF-1 signaling and growth hormone on lifespan.

We discuss:

• Challenges with understanding the effects of nutrition and studying interventions for aging [3:30];
• How Peter’s and Matt’s convictions on nutrition and thoughts optimal health have evolved [8:15];
• Calorie restriction for improving lifespan in animal models [16:15];
• Utility of epigenetic clocks and possibility of epigenetic reprogramming [22:00];
• Mutations and changes to the epigenome with aging [31:45];
• Epigenetic reprogramming: potential benefits and downsides and whether it can work in every organ/tissue [35:15];
• First potential applications of anti-aging therapies and tips for aging well [43:00];
• Impact of calorie restriction on the immune system, muscle mass, and strength [47:00];
• Insights from famous calorie restriction studies in rhesus macaques [55:00];
• An evolutionary perspective of the human diet [1:03:45];
• Antiaging diets: Separating fact from fiction—Matt’s 2021 review in Science [1:12:30];
• Mouse models of time-restricted feeding in the context of calorie restriction [1:19:30];
• Nutritional interventions that consistently impact lifespan in mice, and concerns around efficacy in humans [1:27:00];
• Differing impact of calorie restriction when started later in life [1:31:00];
• Lifespan extension with rapamycin in older mice [1:37:15];
• Relationship between protein intake and aging, and mouse studies showing protein restriction can extend lifespan [1:43:30];
• Impact of protein intake on mTOR, and why inhibition of mTOR doesn’t cause muscle loss [1:50:45];
• Low-protein vs. high-protein diets and their effects on muscle mass, mortality, and more [1:55:30];
• The impact of IGF-1 signaling and growth hormone on lifespan [2:06:30];
• Parting thoughts on the contribution of nutrition to healthspan and lifespan [2:19:45];
• More.

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In this special episode of The Drive, we have pulled together a variety of clips from previous podcasts with sleep expert Dr. Matthew Walker to help listeners understand this topic more deeply, as well as to identify which previous episodes featuring Matt may be of interest. In this episode, Matt gives an overview of why we sleep, the stages of sleep, and sleep chronotypes, and he provides tips to those looking to improve their total sleep and sleep efficiency. Additionally, Matt discusses the pros and cons of napping, and gives his current thinking on the effects of blue light and caffeine on sleep. Finally, Matt explains the dangers of sleeping pills and reveals what he believes are the most useful alternatives for someone struggling with sleep, such as those with insomnia.

We discuss:

• Evolutionary reasons to sleep [2:15];
• Stages of sleep, sleep cycles, and brainwaves [10:00];
• Understanding sleep chronotypes and how knowing yours could help you [25:45];
• Defining sleep efficiency and how to improve it [36:15];
• Correcting insomnia: a counterintuitive approach [38:45];
• Pros and cons of napping, and insights from the sleep habits of hunter-gatherer tribes [41:30];
• Sleep hygiene, wind-down routine, and tips for better sleep [50:15];
• The optimal room temperature and body temperature for the best sleep [59:30];
• Blue light: how Matt shifted his thinking [1:08:30];
• Caffeine: how Matt has adjusted his hypothesis [1:14:45];
• The dangers of sleeping pills, useful alternatives, and cognitive behavioral therapy for insomnia [1:19:45];
• More.

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Celia Morgan is a Professor of Psychopharmacology at the University of Exeter who has authored numerous publications on the potential therapeutic uses of ketamine in mental healthcare. In this episode, Celia dives deep into the neurobiology of ketamine, how it affects users, and how it differs from other, more classical psychedelics (LSD, MDMA, PCP, and psilocybin). She explains the potential promise of ketamine as a treatment for recalcitrant depression and addiction, and she details the results from her clinical trials in these areas. She discusses the importance of using ketamine in combination with psychotherapy to maximize its benefits, the potential risks associated with ketamine use, and advice for those interested in the therapeutic use of ketamine.

We discuss:

• Celia’s training and interest in ketamine [2:15];
• The history of ketamine, medical uses, and use as a party drug [3:30];
• Neurobiology and pharmacology of ketamine [8:15];
• Ketamine regulation and abuse, and how it compares with psychedelics and other molecules [18:15];
• Ketamine as a therapeutic for depression [30:45];
• The brain under the influence of ketamine and theoretical mechanisms for its anti-depressive effects [48:00];
• Risks and concerns with overusing ketamine, and what an intermittent or maintenance dose might look for a patient [57:15];
• Treating addiction with ketamine: Celia’s studies of alcohol dependance [1:04:00];
• Advice for people considering the therapeutic use of ketamine [1:19:45];
• More.

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Shireen Rizvi is a Professor of Clinical Psychology and Psychiatry at Rutgers University, where she is also the Director of the Dialectical Behavior Therapy Clinic. This episode focuses specifically on dialectical behavior therapy (DBT), a skills-based technique which was originally developed to treat borderline personality disorder (BPD) and has since been adapted to treat depression and other mental health conditions, as well as to help people who have difficulty with emotional regulation and self-destructive behaviors. Shireen explains the origins of DBT and how its creator, Dr. Marsha Linehan, came to find a need for something beyond cognitive behavioral therapy (CBT) when attempting to treat patients with suicidal behavior. From there, Shireen dives into how DBT works to resolve the apparent contradiction between self-acceptance and change to bring about positive changes in emotional regulation, interpersonal effectiveness, mindfulness, distress tolerance, and more. She also provides examples for how one can apply specific skills taught with DBT such as accessing the “wise mind,” applying radical acceptance, using the “DEAR MAN” technique, and utilizing an emotion regulation skill called “opposite action.” Finally, she explains how the tenets of DBT offer benefits to anyone, and she provides insights and resources for people wanting to further explore DBT.

We discuss:

• The basics of dialectical behavior therapy (DBT) and how it differs from cognitive behavioral therapy (CBT) [3:00];
• Treating depression with CBT: history, effectiveness, and how it laid the groundwork for DBT [8:15];
• Marsha Linehan’s inspiration for developing DBT [16:00];
• Explaining borderline personality disorder (and associated conditions) through the lens of DBT [20:00];
• How work with suicidal patients led to the development of DBT—a dialectic between change and acceptance [35:30];
• Details of DBT: defining the term “dialectical” and how to access the “wise mind” [44:30];
• Practicing mindfulness and radical acceptance in the context of DBT [51:00];
• Applying “radical acceptance” to tragic scenarios [1:02:00];
• The five domains of skills taught in DBT [1:07:15];
• Why Marsha chose borderline personality disorder as her focus when developing DBT [1:13:30];
• Is there any benefit in doing DBT for someone without a pathological condition? [1:15:45];
• The DEAR MAN skill of DBT [1:20:00];
• Adapting DBT skills for adolescents and families [1:31:00];
• Identifying vulnerability factors, increasing distress tolerance, and the impact of physical pain [1:33:45];
• The DBT chain analysis: assessing problem behaviors and identifying vulnerability factors [1:44:30];
• Why the regulation of emotions can be so challenging [1:50:30];
• The importance of mindfulness skills in DBT [1:53:30];
• Opposite action: an emotion regulation skill [1:57:00];
• Advice for those wanting to explore DBT [2:03:15];
• Finding a well-trained DBT therapist [2:08:15];
• More.

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In this “Ask Me Anything” (AMA) episode, Peter dives deep into the question of whether there is such a thing as “too much exercise.” He explores the theoretical “J-curve” relationship between exercise and longevity, whereby mortality risk declines with increasing activity levels only to see an uptick above a certain exercise volume threshold. While Peter maintains that exercise is perhaps the single most important tool we have to live longer and live better, he explains the challenges involved in identifying an optimal dose. He takes a hard look at studies—many of which have contradictory results—to highlight major limitations in methodology and how readers could be misled. Additionally, he discusses the rare, but real, risks associated with extreme levels of physical activity and concludes by weighing the benefits against the risks of exercise.

If you’re not a subscriber and 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 on our website at the AMA #38 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• How exercise reduces risk for all-cause mortality [2:40];
• Defining the metric called “MET” and how it’s useful for evaluating different exercises [8:00];
• The challenge in determining the optimal exercise doses and the limitations of methods used to study the effect of exercise [13:45];  
• Using VO2 max as a proxy for fitness to better predict mortality risk [19:30];
• Reviewing data which support the theory of a “J-curve” relationship between exercise and longevity [25:00];
• Importance of understanding p-values and statistical significance [33:45];
• Deconstructing the studies that show a J-curve: major limitations and how one could be misled [37:00];
• Peter’s takeaways on the theoretical “J-curve” relationship between exercise and longevity [51:30];
• Risk of sudden cardiac death from vigorous physical exertion [54:00];
• Atrial fibrillation associated with extreme levels of exercise [1:00:15];
• Parting thoughts: benefits of exercise far outweigh the risks [1:04:15]; and
• More.

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Mike Joyner is a physician-researcher and one of the world’s leading experts on human performance and exercise physiology. In this episode, Mike discusses how to combat age-related declines in health and fitness levels by using various modes of exercise to improve lifespan and healthspan. Mike explains the impact of exercise on the autonomic nervous system, blood pressure, heart rate, heart rate variability, heart rate recovery, and max heart rate. He dives deep into VO2 max, including how it’s measured, what is driving it, and how to improve it. Mike provides training insights for the average person, including training volume and exercise intensity as well as simple metrics to track. Furthermore, he gives his take on the theoretical “J-curve” relationship between exercise and longevity, as well as whether possible health dangers may be associated with excessive exercise.

We discuss:

• Mike’s training as an anesthesiologist and interest in exercise physiology [2:30];
• How exercise increases longevity [7:00];
• The impressive data on the benefits of exercise [9:45];
• The Centenarian Olympics and other ways to mitigate age-related decline in strength and stability [15:00];
• The violent dropoff in strength and activity with age and how exercise preserves fitness in old age [19:00];
• Benefits of exercise on mortality and fracture risk, and the interplay of nutrition and exercise [22:00];
• How exercise benefits the autonomic nervous system and why this plays an important role in our health [26:30];
• VO2 max, heart rate recovery, heart rate variability, and other metrics of fitness positively impacted by exercise [28:30];
• Reduction in all-cause mortality with increased fitness levels and VO2 max [32:45];
• Does the relationship between exercise and longevity follow a J-curve? [40:00];
• Mitigating age-related decline in fitness by elevating your VO2 max at a young age [46:15];
• Breaking down the variables that drive VO2 max [54:30];
• Learning from elite athletes: Training regimens, aerobic efficiency, and other impressive metrics [1:00:15];
• Health benefits of light exercise for the average person [1:09:00];
• Simple training metrics to track, and Mike’s current exercise regimen [1:11:15];
• How to boost your VO2 max, and the importance of form and tempo with interval training [1:18:15];
• Training advice for the average person [1:25:15];
• Why professional athletes have longer careers than they’ve had in the past [1:27:30];
• Use of performance-enhancing drugs in professional sports [1:29:45];
• Can the miracle of exercise be put in a pill? [1:36:00];
• Mike’s current research and questions he’s most interested in answering [1:39:00];
• Use of convalescent plasma to treat COVID-19 [1:41:15];
• Parting thoughts on the current state of fitness and exercise in society [1:47:15];
• More.

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Josh Rabinowitz is a Professor of Chemistry and Integrative Genomics at Princeton University, where his research focuses on developing a quantitative, comprehensive understanding of cellular metabolism through the study of metabolites and their fluxes. In this episode, Josh focuses the discussion on three main topics: metabolomics, NAD (and its precursors), and cancer metabolism. The metabolomics discussion starts with a broad definition of metabolism, metabolites, and fluxomics before diving deep into glucose metabolism, lactate as a fuel, movement of lactate, and the regulation of these substrates. He then gives a detailed explanation of the electron transport chain and Krebs cycle and their implications with respect to both drugs and nutrition while also explaining how NAD is central to the process of energy generation. He then discusses the age-related decline in NAD and what current literature says about efforts to increase NAD through intravenous or oral supplementation with the precursors NMN and NR, including whether doing so provides any advantage to lifespan or healthspan. Finally, Josh ends the conversation talking about cancer metabolism and how one particular intersection between cancer metabolism and immunotherapy might provide a hopeful outlook on the future of cancer treatment.

We discuss:

• Josh’s background and unique path to becoming a research scientist at Princeton [3:30];
• What sparked Josh’s early interest in metabolism [11:15];
• Metabolomics 101: defining metabolites and how they are regulated [16:30];
• Fluxomics: metabolism as a system in action [26:00];
• The Randle Hypothesis: glucose and fatty acids compete as substrates for oxidation [33:30];
• The important role of lactate as an alternate fuel [36:30];
• Fasting lactate levels as a potential early indicator of metabolic dysfunction [48:00];
• The beauty of the Krebs cycle and the role of NAD in energy production [53:15];
• How the drug metformin acts on complex I of the electron transport chain [1:05:00];
• The difference between NADH and NADPH [1:08:45];
• NAD levels with age, and the efficacy of supplementing with intravenous NAD [1:10:45];
• The usefulness of restoring NAD levels and efficacy of oral supplementation with NAD precursors NR and NMN [1:22:15];
• Exploring the hypothesis that boosting NAD levels is beneficial [1:32:30];
• Cancer metabolism and the intersection with immunotherapy [1:39:00];
• Making cancer a chronic disease: exploiting the metabolic quirks of cancer, augmenting the immune system, and more [1:46:15];
• The challenge of treating pancreatic cancer [1:50:30];
• Epithelial cancers that might respond to metabolic approaches to therapy [1:56:30];
• Josh’s hopeful outlook on the future of cancer treatment [1:59:00];
• Nutritional approaches to cancer attenuation [2:00:15];
• What makes Princeton University special [2:06:15];
• More.

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Mike Gershon is a Professor of Pathology and Cell Biology at Columbia University and has been at the forefront of studying neural control of the gut for the past 60 years. In this episode, Mike gives a tour de force on the pathways of gut-brain communication but first sets the stage with an overview of gastrointestinal tract development and anatomy. He then explains how the gut communicates with the brain and vice versa, from early observations in physiology and anatomy up to our present understanding of what makes the GI tract so unique and complex relative to other organs. He talks about how the gut responds to meals of different food qualities and how that affects satiety signaling to the brain. Additionally, he explains how antidepressants and other drugs impact digestion through effects on serotonin signaling, and he discusses the effects of antibiotics, and what’s really going on with “leaky gut.” Finally, Mike offers his thoughts on the utility—or lack thereof—of gut microbiome diagnostic tests, and wraps up the discussion by considering how diet, probiotics, and prebiotics impact the microbiome and GI tract.

We discuss:

• The basics of the gastrointestinal (GI) system [3:45];
• The very early development of the GI system [9:30];
• The unique properties of the blood supply and portal system in the GI tract [12:45];
• An overview of gut anatomy and innervation [16:30];
• Turnover of the epithelial lining and why cancer rarely develops in the small intestine [26:45];
• Nutrient and water absorption in the small and large intestine [30:30];
• Ways in which the gut and brain communicate [34:30];
• The gut's role in the regulation of appetite [43:30];
• The impact of gastric bypass surgery on satiety signals [51:15];
• How varicella-zoster virus (VZV) can infect neurons in the gut and create issues later in life [54:30];
• The relationship between autism and gastrointestinal illness [1:02:45];
• The important role of serotonin in the gut, and the impact of SSRIs on serotonin in the gut [1:09:45];
• Defining “leaky gut” and its most common causes [1:16:45];
• The gut microbiome [1:30:45];
• Fecal transplants: use cases, limitations, and how they illustrate the importance of gut microbes [1:40:45];
• Gut microbiome diagnostic tests: why they aren’t useful outside of special cases such as cancer detection [1:50:30];
• Nutritional approaches to a maintain optimal flora in the gut [1:55:00];
• Prebiotics and probiotics, and getting your GI system back on track after a course of antibiotics [2:02:30];
• More.

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In this “Ask Me Anything” (AMA) episode, Peter dives deep into the topic of bone health and explains why this is an important topic for everyone, from children to the elderly. He begins with an overview of bone mineral density, how it's measured, how it changes over the course of life, and the variability between sexes largely due to changes in estrogen levels. From there he provides insights into ways that one can improve bone health, from exercise to nutrition supplements to drugs. Additionally, Peter discusses what happens when one may be forced to be sedentary (e.g., bedrest) and how you can work to minimize the damage during these periods.

If you’re not a subscriber and 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 on our website at the AMA #37 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

We discuss:

• Overview of bone health topics to be discussed [1:45];
• Bones 101: bone function, structure, and more [5:15];
• Bone mineral density (BMD), minerals in bone, role of osteoblasts and osteoclasts, and more [8:30];
• The consequences of poor bone health [13:30];
• The devastating nature of hip fractures: morbidity and mortality data [17:00];
• Where fractures tend to occur in the body [23:00];
• Defining osteopenia and osteoporosis [24:30];
• Measuring BMD with DEXA and how to interpret scores [27:00];
• Variability in BMD between sexes [34:15];
• When should people have their first bone mineral density scan? [36:45];
• How BMD changes throughout the life and how it differs between men and women [39:00];
• How changes in estrogen levels (e.g., menopause) impact bone health [44:00];
• Why HRT is not considered a standard of care for postmenopausal bone loss [47:30];
• Factors determining who may be at higher risk of poor bone health [50:30];
• Common drugs that can negatively impact BMD [54:15];
• How children can optimize bone health and lay the foundation for the future [57:45];
• Types of physical activity that can positively impact bone health [1:02:30];
• How weight loss can negatively impact bone health and how exercise can counteract those effects [1:10:45];
• Nutrition and supplements for bone health [1:14:15];
• Pharmaceutical drugs prescribed for those with low BMD [1:17:15];
• Impact of extreme sedentary periods (e.g., bedrest) and how to minimize their damage to bone [1:22:00]; and
• More.

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Max Diehn is a Professor of Radiation Oncology at Stanford and a clinical radiation oncologist specializing in lung cancer. Max’s research focuses on developing novel methods for detecting circulating tumor DNA in the blood of cancer patients and on elucidating the molecular pathways and genes associated with cancer. His interests also include uncovering biomarkers that can predict patient survival, responses to therapy, and disease recurrence. In this packed episode, Max discusses the history of blood-based cancer screening and the importance of understanding the predictive value of tests—sensitivity, specificity, negative predictive value, positive predictive value – and how these metrics play into cancer screening. Max then goes in depth on the topic of liquid biopsies, including the history, current landscape, and possible future of liquid biopsies as a cancer detection tool. He discusses how these non-invasive blood tests can detect DNA/RNA from tumor cells released into the blood as well as the different methods one can use to predict if a cancer is present. He gets granular on the topic of cell-free DNA/RNA signature, methylation patterns, and the importance of knowing mutation information, and he ends with a discussion on the exciting future of liquid biopsies and how we can possibly get to the panacea of cancer screening.

We discuss:

• Max’s training that planted the seeds for development of liquid biopsies [4:30];
• Max’s decision to specialize in radiation oncology [11:45];
• A culture at Stanford that values research and physician scientists [17:00];
• The motivation to develop liquid biopsies [19:15];
• History of blood-based cancer screening and understanding the predictive value of tests [25:30];
• Current state of lung cancer and the need for better screening [32:45];
• Low-dose CT scans: an important tool for managing lung cancer but with limitations [42:00];
• Using liquid biopsies to identify circulating tumor cells [47:00];
• Liquid biopsy research moves from circulating tumor cells to cell-free DNA [1:03:00];
• Zeroing-in on circulating tumor DNA in cell-free DNA [1:10:48];
• Cell-free RNA and Max’s vision for cancer detection from a blood sample [1:22:00];
• Methylation patterns and other informative signatures found in DNA [1:24:30];
• Mutation-based methods of liquid biopsies [1:26:30];
• Understanding the sensitivity and specificity of a diagnostic test [1:30:30];
• Existing clinical liquid biopsy tests and their limitations [1:37:30];
• The future of liquid biopsies [1:44:00];
• How we get to the panacea of cancer screening [1:52:00];
• More.

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In this episode, Ric Elias, founder of Red Ventures, opens up about the fateful day he knew for certain that he was going to die as a passenger on US Airways Flight 1549. Ric dives deep into how that day impacted his life, greatly changed his perspective, and improved his relationship with his family and the broader community. We also talk about his incredible role as CEO of an enormous company, his remarkable work in philanthropy, and all the wisdom he has acquired in his extraordinary life.

We discuss: 

• Ric’s life leading up to the day of the plane crash [2:15];
• The plane crash—What it’s like knowing you’re about to die, feelings of regret and sadness [8:00];
• The improbable plane landing in the Hudson River [15:45];
• Emotions after the safe landing (and a story he’s never told before) [22:15];
• A powerful story about Captain Sully [26:15];
• Earning his second chance at life, and playing the “infinite game” [35:15];
• Why time is the ultimate currency, and how (and why) to say “no” [43:00];
• Raising kids in an achievement culture, Ric’s definition of life success, and what Ric wants to instill in his kids [49:45];
• What Ric believes is actually worth getting upset about, and the organizations that are taking steps to help people [1:05:45];
• The core principles of Red Ventures (Ric’s company) [1:16:00];
• Ric’s tips for developing business acumen and negotiation skills [1:26:15];
• What qualities does Ric look for in people he wants to work with? [1:29:15];
• What is the next big problem that Ric wants to solve? [1:32:15];
• What is the most challenging part of your business today? [1:34:15];
• If Ric could go back and talk to himself in the morning before getting on that plane, what would he say? [1:36:00]; and
• More.

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Stephan Guyenet is a neuroscientist focused on the neuroscience of obesity and energy homeostasis.  He is the author of the book, The Hungry Brain and founder/director of Red Pen Reviews. In this episode, Stephan explains how obesity has changed phenotypically over the course of human history as well as what might explain the dramatic increase in prevalence of obesity in the last few decades. He talks in depth about the role of genetics, the brain, and hormones like leptin play in the regulation of fat mass. He dives deep into two common theories of obesity—the carbohydrate-insulin model and the energy balance model and provides his take on which theory has stronger evidence. Additionally, he provides insights on how we’re hard-wired to think about food and the consequences of modern foods designed for maximal pleasure. Finally, he goes through the factors that affect body weight, set points, and provides takeaways for people wanting to take advantage of what we know about the brain’s role in regulating our body weight.

We discuss:

• Stephan’s neuroscience background and his focus on the nuances of obesity [2:15];
• How obesity has changed for humans throughout history [8:00];
• The association between obesity and adverse health outcomes, the “obesity paradox,” and confounders when relating BMI to longevity [14:00];
• The sharp increase in obesity across demographics [23:30];
• The hypothalamus and its role in obesity [30:00]; 
• The role of the hormone leptin in obesity [40:00];
• The genetic component of obesity [46:30];
• Understanding the tendency of humans to store fat through an evolutionary lens [57:00];  
• The hedonic aspect of food, and how the brain reacts to modern, highly-rewarding foods [1:03:30];
• How we are hard-wired to think about food [1:14:30];
• A review of the “Carnivore diet” [1:21:45];
• The energy balance model, carbohydrate-insulin model, and unifying the theories around adiposity [1:34:15];
• Body weight set points: a hypothetical comparison of two individuals [1:41:45];
• Takeaways for people who want to lose weight and keep it off [1:48:30];
• Evidence that favors the energy balance model of weight gain [1:56:00];
• The synergistic effect of fat and carbohydrates and observations that a low-fat diet or a low-carb diet can cause weight loss [2:04:30];
• Red Pen Reviews [2:11:00];
• More.