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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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In this episode, Peter sits down with Dr. Kathryn (Katie) Gray, a physician-scientist, high-risk obstetrician, and maternal-fetal medicine specialist at the University of Washington School of Medicine. Katie begins by explaining the remarkable physiologic changes that occur during pregnancy and how the cardiovascular, metabolic, and hormonal systems adapt to support both mother and developing fetus. From there, the conversation turns to some of the most important complications that can arise. Katie explains how gestational diabetes is screened for and treated, and what a diagnosis may mean for the long-term health of both mother and child. She then walks through the biology of preeclampsia, including who is at risk and how the condition is managed. She also discusses HELLP syndrome and postpartum depression. Peter and Katie explore the realities of labor and delivery, including breech presentation, the role of midwives, and the trade-offs between vaginal and cesarean delivery. The conversation also covers stillbirth and the growing role of cell-free DNA in prenatal genetic screening. Other topics include prenatal nutrition and folate, breastfeeding, and exercise during pregnancy. Throughout the episode, Peter and Katie return to a larger question: What can pregnancy reveal about a woman's long-term health? They discuss how complications during pregnancy can provide important clues about future health risks. Finally, Katie highlights some of the major questions that remain unanswered in maternal health and why greater investment in research is needed to improve outcomes for mothers and their children.

Disclaimer: The views expressed on this podcast are solely those of Dr. Kathryn Gray and do not represent the University of Washington or any of its affiliated units. Dr. Gray speaks solely in a personal capacity, and nothing here should be construed as an official position or endorsement from the University of Washington.

We discuss:

• What drew Katie to obstetrics and gynecology, and fundamental questions in the field that remain unanswered [3:15];
• Pregnancy as a cardiovascular and metabolic stress test; the first symptoms and early changes [6:30];
• Early hormonal changes, prenatal nutrition, and neural tube defects [16:00];
• Fetal development and the physiology of gestational diabetes [23:45];
• Diagnosing and treating gestational diabetes [30:00];
• Preeclampsia: diagnosis, biology, acute risk, and how it's managed [37:00];
• HELLP syndrome, what genetic studies reveal about preeclampsia, and the antihypertensive medications used to treat it [49:00];
• What pregnancy reveals about long-term cardiometabolic health [54:45];
• Cesarean delivery, breech presentation, and stillbirth [1:01:15];
• The onset of labor, cervical dilation, and membrane rupture [1:14:15];
• Vaginal delivery and breastfeeding: benefits versus myths [1:23:15];
• Exercise during pregnancy, sleep position in the third trimester, and postpartum depression [1:27:00];
• Prenatal genetic screening: the growing role of cell-free DNA and the gap between what is technologically possible and what gets deployed in the clinic [1:33:00];
• Midwifery and the realities of childbirth [1:39:00];
• Maternal health in the United States and the need for research investment [1:48:30]; and
• More.

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