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In this episode, Peter sits down with Dr. Lisa Feldman Barrett, a psychologist, neuroscientist, author, and distinguished professor at Northeastern University whose research challenges many of the conventional assumptions about emotions and how the brain works. Lisa is best known for her theory of constructed emotion, which challenges the idea that emotions such as fear, anger, and sadness are hardwired responses with universal biological signatures. She begins by explaining how unexpected findings early in her research led her to question traditional theories of emotion. She discusses why studying individual variation, rather than relying on averages, is essential to understanding the brain. Lisa then explores the idea that the brain is fundamentally a predictive system rather than a reactive one. She explains how past experiences and memories shape what we perceive, feel, and do. She also describes how the brain continuously anticipates and regulates metabolism through a process called allostasis. The conversation then turns to the effects of chronic stress, uncertainty, and childhood adversity on physical and emotional health. Lisa explains how our relationships help regulate our nervous systems and why the loss of a loved one can have such a profound physiological impact. She also discusses how deliberate practice and new experiences can reshape the brain's predictions, potentially changing how we think, feel, and respond to the world around us. Throughout the discussion, Peter and Lisa explore how this framework challenges traditional views of emotion and offers a greater sense of agency over our emotional lives.

We discuss:

• How unexpected results in graduate school changed Lisa's understanding of emotion [3:30];
• Why variation is the norm for emotion, and the danger in tracking averages instead of characterizing variation [15:30];
• Lisa's experience with Hashimoto's disease and the value of modeling individual variation [30:00];
• How Lisa's research challenges common views about emotions, and why there is no biomarker for emotions [40:00];
• The difficulty of defining emotions and the brain's role in regulating the body [49:15];
• Consciousness, interoception, and the limits of subjective experience [54:00];
• Defining emotion: fear and anger [1:00:15];
• The brain as a predictive system rather than a reactive one [1:13:15];
• Baseball as an example of the brain's predictive nature [1:31:00];
• How the human brain differs from that of other animals [1:44:00];
• The impact of stress on metabolism, and the role of the brain in maintaining allostasis [1:49:45];
• Childhood adversity, social regulation of the nervous system, and the effect of chronic stress [1:56:45];
• Understanding chronic stress: why some people respond differently, and its impact on metabolism [2:02:15];
• How practicing new predictions can change thoughts and feelings [2:10:15];
• Lisa's practice of finding awe in everyday experiences and the greater sense of agency it brings [2:13:30];
• The impact of grief on nervous system regulation and the metabolic "body budget," as well as practices that reduce sadness [2:22:15];
• The connection between memories and predictions, and Peter's closing thoughts [2:29:45]; and
• More.

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In this episode, Peter welcomes back Dr. Siddhartha Mukherjee, a physician, oncologist, researcher, and the Pulitzer Prize-winning author of The Emperor of All Maladies. Fifteen years after the book was first published, Sid released an updated edition. This conversation examines what has changed in our understanding of cancer—not only in how we treat it, but in how we think about its causes, prevention, detection, and biology. Sid explores the contributions of genetics, environmental exposures, random mutations, and inflammation to cancer risk, including the emerging role of hyperinsulinemia and metabolism. He discusses why detecting cancer early remains so difficult, particularly in pancreatic cancer, and how advances in immunotherapy, CAR T cell therapy, and targeted treatments such as KRAS inhibitors are changing the treatment landscape. The conversation then broadens beyond cancer to what Sid calls "regenerative failure"—the declining ability of tissues to repair and replenish themselves with age. Peter and Sid explore how this process may contribute to conditions such as osteoarthritis, and whether longevity should be approached less as the prevention of individual diseases and more as the preservation of regenerative capacity. Sid weighs in on the potential for chemoprevention, metabolic interventions, and AI to transform cancer prevention and treatment. Finally, they discuss what it would take to develop meaningful biomarkers of longevity that could ultimately help to extend human healthspan and lifespan.

We discuss:

• What oncology has learned in the 15 years since The Emperor of All Maladies was published [2:45];
• The contributions of genetic risk, bad luck, and inflammation to cancer [14:45];
• The role of metabolism and hyperinsulinemia in cancer [31:00];
• Osteoarthritis: the role of inflammation and regenerative stem cells [40:45];
• How cancer escapes the immune system—the subtleties of neoantigens and immune checkpoints [49:45];
• AI and the thymus as a predictor of longevity, and T cell aging and immune regeneration [57:15];
• How CAR T cell therapy works and why solid tumors are harder to treat [1:04:00];
• Targeting KRAS in pancreatic cancer [1:10:45];
• The rise of colorectal cancer in younger adults [1:19:15];
• How AI may transform drug discovery [1:23:00];
• The future of cancer prevention: chemoprevention [1:33:15];
• Challenging the current model of longevity—disease prevention versus targeting regenerative failure [1:37:45];
• The need for a biomarker of longevity—comparing geroscience to atherosclerosis [1:50:30];
• Clinical trials targeting cancer metabolism [1:56:00];
• What Sid is currently writing about and a glimpse into his writing process [1:58:00]; and
• More.

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In this "Ask Me Anything" (AMA) episode, Peter looks back on 400 episodes of The Drive with another installment of "strong convictions, loosely held," revisiting some of the positions he has taken over more than eight years of the podcast. He explains why changing one's mind in response to new evidence, conversations with experts, and clinical experience is essential for practicing medicine well. Peter begins with nutrition, describing how his views on ketogenic diets, extended fasting, and the framework of dietary restriction, time restriction, and calorie restriction have evolved. He explains why he no longer takes metformin for longevity and discusses his growing uncertainty around rapamycin despite compelling animal data. Peter also revisits his views on cancer screening, including whole-body MRI and liquid biopsies for early detection. On exercise, Peter explains how his approach to cardiorespiratory training and the 80/20 Zone 2 framework has changed, particularly for people with limited time to train. He also shares why he has moved away from heavy barbell squats and deadlifts and how he now thinks about balancing benefit and injury risk. Throughout the episode, Peter emphasizes the importance of focusing on durable principles, strong foundations, and sustainable practices rather than chasing optimizations that provide marginal gains.

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We discuss:

• Strong convictions, loosely held: changing opinions as evidence, expert conversations, and clinical experience evolve [2:00];
• Nutrition: Peter's evolving view of ketogenic diets, energy balance, and dietary dogmatism [5:30];
• Extended fasting, autophagy, lean-mass loss, and who may benefit from prolonged fasting [12:00];
• The dietary restriction, time restriction, and calorie restriction framework—and why GLP-1 agonists are tipping the balance toward calorie restriction [20:15];
• Why Peter no longer views metformin as geroprotective for metabolically healthy people [24:45];
• Rapamycin for longevity: compelling animal data, unresolved human dosing, and Peter's growing uncertainty [29:15];
• The importance of early cancer detection, declining whole-body magnetic resonance imaging (MRI) quality, and more targeted alternatives [41:30];
• Liquid biopsies for cancer screening: the NHS-Galleri trial, why early-stage rather than late-stage detection is what actually matters, and why the technology remains "fuzzy" [53:30];
• Evolving exercise goals, the limitations of the 80/20 Zone 2 framework, and programming cardio at lower training volumes [1:00:00];
• Exercise prescriptions for limited time, building a training habit, and becoming less dogmatic about forcing workouts [1:05:00];
• Moving away from heavy squats and deadlifts, alternative exercises, and deliberate risk management [1:13:00];
• Prioritizing principles, foundations, and sustainable practices over marginal optimization [1:21:30]; and
• More.

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