Dr. Sara Gottfried: How to Optimize Female Hormone Health for Vitality & Longevity

In this episode, I discuss skin health appearance and why both are important indicators of the health status of your immune system, gut microbiome, and other organ systems. I explain why sunlight is essential for skin and hormone health and how excessive sunlight can accelerate skin aging and cause certain skin cancers. I discuss the different types of sunscreens (physical, chemical, and mineral-based) and potential health concerns of the chemicals found in some (but not all) sunscreens. I also discuss the importance of getting your skin (and not just moles) checked for pre-cancerous and cancer growths, the role of nutrition and lifestyle factors that improve skin health and appearance, and how to improve your skin by reducing local and systemic inflammation and supporting your microbiome.  I explain what works to improve your skin's youthfulness and appearance, including reducing wrinkles, sagging, and pore size. I review the data on ingesting (or topically applied) collagen, vitamin C, niacinamide, hyaluronic acid, and retinol, and what is known about the use of peptides (e.g., BPC-157, copper peptides) and red and far-red light phototherapies for improving skin health and appearance. I also discuss the causes of acne, rosacea, and psoriasis and explain nutritional, skin care, and prescription-based approaches to treating these common skin conditions. This episode ought to help everyone better understand the biology of the skin and help them make the best possible decisions for their skin health, care, and appearance according to age, goals, and current skin conditions. Access the full show notes, including referenced articles, books, people mentioned, and additional resources at hubermanlab.com. Andrew's New Book Protocols: An Operating Manual for the Human Body: https://protocolsbook.com Thank you to our sponsors AG1: https://drinkag1.com/huberman Joovv: https://joovv.com/huberman BetterHelp: https://betterhelp.com/huberman  ROKA: https://roka.com/huberman  LMNT: https://drinklmnt.com/huberman  Timestamps 00:00:00 Skin Health 00:02:59 Sponsors: Joovv, BetterHelp & ROKA  00:07:18 Skin Biology, Skin Layers 00:12:40 Sun Exposure, UV Light & Skin Cancers; Sunscreen 00:19:51 Aging, Sun Exposure, Skin Cancers, Physical Barriers 00:27:24 Sunburn & Skin Cancers 00:30:09 Sponsor: AG1 00:31:58 Vitamin D, Sun Exposure & Sunscreen 00:36:50 Organic (Chemical) Sunscreen & Inorganic (Mineral-Based) Sunscreen 00:49:20 Skin Cancers, Moles, Laser Resurfacing 00:53:59 Sponsor: LMNT 00:55:34 Sun Exposure, Melanoma & Life Expectancy 01:03:13 Tool: Youthful Skin, Collagen & Vitamin C 01:12:55 Peptides, BPC-157, Copper 01:20:58 Tool: Niacinamide (Nicotinamide), Youthful Skin, Dark Spots, Hyaluronic Acid 01:26:25 Tool: Retinol (Retin-A, Tretinoin, Retinyl Esters), Youthful Skin 01:33:07 Tool: Phototherapy, Youthful Skin, Treating Skin Conditions 01:41:10 Tool: Nutrition for Skin Health, Anti-Inflammatory Diets 01:47:54 Highly Processed Foods, Advanced Glycation End Products & Skin Health 01:52:08 Tools: Reduce Inflammation: Gut Microbiome, Sleep, Alcohol, Smoking, Stress 01:58:58 Acne, Hormones & Insulin; Tool: Low Glycemic Diet, Dairy 02:07:26 Tools: Face Cleansing & Acne; Scarring & Popping Pimples 02:13:29 Tool: Treating Rosacea, Alcohol, Skin Care, Nutrition 02:18:31 Stubborn Rosacea, Over Cleansing, Pulsed Dye Laser 02:21:04 Psoriasis Treatment, Immune System & Prescriptions 02:25:24 Zero-Cost Support, YouTube, Spotify & Apple Follow & Reviews, YouTube Feedback, Protocols Book, Social Media, Neural Network Newsletter Disclaimer

In this episode, my guest is Dr. Gabrielle Lyon, D.O., a board-certified physician who did her clinical and research training at Washington University in geriatrics and nutrition. She is also an expert in how diet and exercise impact muscle and whole-body health and longevity. Dr. Lyon is a bestselling author and public educator. We discuss how healthy skeletal muscle promotes longevity, brain health, disease prevention, ideal body composition, and the health of other organs and bodily systems. She makes specific nutritional recommendations for optimal health: what to eat, how much to eat, the timing of meals, the essential need for adequate quality protein (including animal and plant-based options), supplementation, and how our dietary requirements change with age. She explains why specific types of resistance training are essential to build and maintain muscle and overall metabolic health. She also describes how to include resistance training as part of your exercise regimen — regardless of age or sex.  She also provides specific mindset tools to encourage sustained adherence to healthy eating and exercise practices. Women and men of all ages will benefit from Dr. Lyon’s practical, evidence-based protocols to improve muscle and whole-body appearance, function, and health. Access the full show notes, including referenced articles, books, people mentioned, and additional resources at hubermanlab.com. Andrew's New Book Protocols: An Operating Manual for the Human Body: https://protocolsbook.com Thank you to our sponsors AG1: https://drinkag1.com/huberman Maui Nui Venison: https://mauinuivenison.com/huberman  Levels: https://levels.link/huberman  Helix Sleep: https://helixsleep.com/huberman InsideTracker: https://insidetracker.com/huberman  Timestamps 00:00:00 Protocols Book; Dr. Gabrielle Lyon 00:03:23 Sponsors: Maui Nui, Levels & Helix Sleep 00:07:40 Skeletal Muscle & Longevity 00:11:25 “Under-muscled”, Leucine & Muscle Health 00:15:55 Muscle Health 00:19:45 Tool: Carbohydrate Consumption & Activity, Glycogen 00:25:14 Tools: Nutrition for Healthy Skeletal Muscle, First Meal 00:31:57 Sponsor: AG1 00:33:46 Quality Protein, Animal & Plant-Based Proteins 00:37:36 Dietary Protein Recommendations, Meal Threshold 00:41:19 Muscle Health & Aging 00:46:02 Supplements & Creatine; Dietary Protein 00:50:07 Tool: Dietary Protein Recommendation; Gout & Cancer Risk 00:52:43 Effects of Dietary Protein & Exercise on Body Composition 01:03:06 Thermic Effects, Protein  01:05:02 Sponsor: InsideTracker 01:06:14 Protein & Satiety, Insulin & Glucose 01:12:04 Tool: Older Adults, Resistance Training & Dietary Protein 01:17:48 Dietary Protein, mTOR & Cancer Risk 01:21:36 Muscle Span & Aging, Sedentary Behaviors 01:24:00 Mixed Meals, Protein Quality, Fiber 01:29:21 Inactivity & Insulin Resistance, Inflammation 01:38:43 Exercise & Myokines, Brain Health & BDNF 01:44:11 Tool: Resistance Training Protocols, Hypertrophy, “High Ground” 01:52:51 High Ground Exercises; Tendon Strength; Training Duration, Blue Zones 01:58:19 Movement, Exercise & Older Adults 02:04:25 Tool: Protein Timing & Resistance Training; VO2 Max, Aging, Blood Work 02:11:13 Supplements: Creatine, Urolithin A, Whey Protein, Fish Oil, Collagen 02:20:18 Fasting, Older Adults; Tool: Meal Timing 02:25:18 Animal Proteins & Dairy; Organ Meats, Vegan; Magnesium, Zinc 02:30:59 Medications & Muscle Health 02:32:49 Obesity & GLP-1 Analogs, Ozempic, Mounjaro, Skeletal Muscle 02:40:48 Benefits of Skeletal Muscle & Aging 02:42:16 Tools: Nutrition & Resistance Training for Muscle Health 02:45:44 Mindset Tools: Standards vs. Goals; Vulnerability Points 02:52:00 Mindset Tools: Neutrality; Health & Worth 03:01:14 Zero-Cost Support, Spotify & Apple Follow & Reviews, YouTube Feedback, Social Media, Neural Network Newsletter, Protocols Book Disclaimer

I'm honored to share Episode 2 of the first season of Perform with Dr. Andy Galpin. Dr. Andy Galpin is a tenured full professor at California State University, Fullerton, where he co-directs the Center for Sport Performance and leads the Biochemistry and Molecular Exercise Physiology Laboratory. Andy is both a friend and a colleague, and I'm delighted to have assisted in the creation of this podcast. I'm certain you'll both enjoy and learn from it. Season 1 features 10 episodes, airing every Wednesday for 10 weeks. Dr. Galpin will cover everything from building strength, the importance of strength for long-term health, the science of breathing, the benefits of sleep extension, genetic testing for personalized training, and nutrition for injury recovery. While we have Episode 2 of Perform with Dr. Andy Galpin here, please be sure to subscribe and follow Perform with Dr. Andy Galpin on your preferred platform. Show notes for this episode can be found at performpodcast.com. Timestamps 00:00:00 Introduction from Dr. Andrew Huberman 00:01:06 Skeletal Muscle 00:04:06 Sponsors: Absolute Rest & Momentous 00:07:20 Quantity & Quality; Organ System; Health & Performance 00:12:58 Plasticity, “Look Good, Feel Good, Play Good”; Muscle Types 00:15:46 What is Muscle?, Muscle Fibers, Tendon 00:21:37 Muscle Fiber Number, Hyperplasia, Anabolic Steroids, Age 00:24:03 Myonuclei & Adaptability 00:26:27 Muscle Fiber Types, Variable Muscle Functions 00:32:24 Fiber Type & Lifestyle Factors 00:34:54 Sponsors: David Protein & AG1 00:37:37 Age & Muscle Loss, Slow vs. Fast-Twitch Fibers; Motor Units 00:46:36 Muscle Size vs. Muscle Strength, Quantity vs. Quality 00:50:56 Investigate: Muscle Quantity, Fat-Free Mass Index (FFMI) 00:56:21 FFMI, Elite Athletes, Muscle Mass 01:00:59 Muscle Asymmetry; Too Much Muscle Possible? 01:03:49 Interpret: Muscle Mass, FFMI Calculations & Percentiles 01:09:28 Tool: Intervene - Increase Muscle Mass, 72-Hour Rule 01:15:27 Sponsors: Maui Nui & Renaissance Periodization 01:17:51 Investigate: Muscle Quality & 4 Movement Principles 01:23:34 Muscle Quality & 3 Performance Principles  01:26:42 Interpret: Muscle Speed, Age 01:32:45 Muscle Power, Vertical Jump, Broad Jump 01:36:17 Muscle Strength, Powerlifting Elite, Bench Press, Leg Press, Grip Strength 01:44:05 Increasing Strength, Improve Health & Longevity 01:46:44 Tool: Intervene - Improve Muscle Quality, 4 Training Principles, 3-to-5 Rule 01:53:56 Zero-Cost Support, YouTube, Spotify & Apple Subscribe & Reviews, Sponsors, YouTube Feedback, Social Media 01:56:10 Conclusion from Dr. Andrew Huberman Disclaimer

In this episode, my guest is Dr. Zachary Knight, Ph.D., a professor of physiology at the University of California, San Francisco (UCSF), and Howard Hughes Medical Institute (HHMI) investigator. We discuss how the brain controls our sense of hunger, satiety, and thirst. He explains how dopamine levels impact our cravings and eating behavior (amount, food choices, etc) and how we develop and can change our food preferences and adjust how much we need to eat to feel satisfied. We discuss factors that have led to the recent rise in obesity, such as interactions between our genes and the environment and the role of processed foods and food combinations. We also discuss the new class of medications developed for the treatment of obesity and diabetes, including the GLP-1 agonists semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro). We discuss how these medications work to promote weight loss, the source of their side effects, and the newer compounds soon to overcome some of those side effects, such as muscle loss. Dr. Knight provides an exceptionally clear explanation for our sense of hunger, thirst, and food cravings that translates to practical knowledge to help listeners better understand their relationship to food, food choices, and meal size to improve their diet and overall health. For show notes, including referenced articles and additional resources, please visit hubermanlab.com. Thank you to our sponsors AG1: https://drinkag1.com/huberman  BetterHelp: https://betterhelp.com/huberman Eight Sleep: https://eightsleep.com/huberman Waking Up: https://wakingup.com/huberman LMNT: https://drinklmnt.com/huberman Timestamps 00:00:00 Dr. Zachary Knight 00:02:38 Sponsors: BetterHelp, Helix Sleep & Waking Up 00:07:07 Hunger & Timescales 00:11:28 Body Fat, Leptin, Hunger 00:17:51 Leptin Resistance & Obesity 00:20:52 Hunger, Food Foraging & Feeding Behaviors, AgRP Neurons 00:30:26 Sponsor: AG1 00:32:15 Body Weight & Obesity, Genes & POMC Neurons 00:39:54 Obesity, Genetics & Environmental Factors 00:46:05 Whole Foods, Ultra-Processed Foods & Palatability 00:49:32 Increasing Whole Food Consumption, Sensory Specific Satiety & Learning 00:58:55 Calories vs. Macronutrients, Protein & Salt 01:02:23 Sponsor: LMNT 01:03:58 Challenges of Weight Loss: Hunger & Energy Expenditure 01:09:50 GLP-1 Drug Development, Semaglutide, Ozempic, Wegovy 01:19:03 GLP-1 Drugs: Muscle Loss, Appetite Reduction, Nausea 01:23:24 Pharmacologic & Physiologic Effects; GLP-1 Drugs, Additional Positive Effects 01:30:14 GLP-1-Plus Development, Tirzepatide, Mounjaro, AMG 133 01:34:49 Alpha-MSH & Pharmacology 01:40:41 Dopamine, Eating & Context 01:46:01 Dopamine & Learning, Water Content & Food 01:53:23 Salt, Water & Thirst 02:03:27 Hunger vs. Thirst 02:05:46 Dieting, Nutrition & Mindset 02:09:39 Tools: Improving Diet & Limiting Food Intake 02:14:15 Anti-Obesity Drug Development 02:17:03 Zero-Cost Support, Spotify & Apple Follow & Reviews, YouTube Feedback, Social Media, Neural Network Newsletter Disclaimer

I'm honored to share the first episode of the new podcast, Perform with Dr. Andy Galpin. Dr. Andy Galpin is a tenured full professor at California State University, Fullerton, where he co-directs the Center for Sport Performance and leads the Biochemistry and Molecular Exercise Physiology Laboratory. Andy is both a friend and a colleague, and I’m delighted to have assisted in the creation of this podcast. I'm certain you'll both enjoy and learn from it. Season 1 features 10 episodes, airing every Wednesday for 10 weeks. Dr. Galpin will cover everything from building strength, the importance of strength for long-term health, the science of breathing, the benefits of sleep extension, genetic testing for personalized training, and nutrition for injury recovery. While we have Episode 1 of Perform with Dr. Andy Galpin here, please be sure to subscribe and follow Perform with Dr. Andy Galpin on your preferred platform. Show notes for this episode can be found at performpodcast.com. Timestamps 00:00:00 Introduction from Dr. Andrew Huberman 00:01:07 Heart 00:03:55 Sponsors: Vitality Blueprint & Rhone 00:07:27 Muscle Types 00:09:54 VO2 max, Health & Mortality 00:15:49 Overall Health, Cardiorespiratory Fitness & All-Cause Mortality 00:25:23 Sponsor: AG1 00:26:54 Disease, Health & Mortality 00:30:02 Cardiac Muscle & Heart 00:38:29 Cardiac Muscle vs. Skeletal Muscle, Cardiac Advantages 00:43:53 Pacemakers & Heart Rate, Vagus Nerve 00:50:35 Why Doesn’t the Heart Get Sore? 00:54:32 Heart & Exercise, Stroke Volume, Ejection Fraction, Cardiac Output 00:59:21 Heart Rate Variability 01:02:41 Sponsors: Momentous & LMNT 01:06:54 Why Do You Breathe?: Oxygen, Carbon Dioxide & Respiratory Rate 01:13:37 Respiratory Rate & Stress 01:15:08 Tool: The “Three I’s”, Investigate: Heart Rate, Respiratory Rate, VO2 Max 01:19:53 Tool: Interpretation, Resting Heart Rate & Ranges 01:23:16 Tool: Interpretation: VO2 Max & Ranges 01:30:45 Athletes & Highest VO2 Max Scores 01:35:53 Elite Athletes & Context for VO2 Max Scores 01:41:42 Tool: Intervention, VO2 Max, Varying Exercise Intensities, SAID Principle 01:48:20 Tool: Varying Exercise Intensity; Intervals & Continuous Training; Frequency 01:58:18 Zero-Cost Support, YouTube, Spotify & Apple Subscribe & Reviews, Sponsors, YouTube Feedback, Social Media 01:59:55 Conclusion from Dr. Andrew Huberman Disclaimer

In this episode, my guest is Dr. Jonathan Haidt, Ph.D., professor of social psychology at New York University and bestselling author on how technology and culture impact the psychology and health of kids, teens, and adults. We discuss the dramatic rise of suicide, depression, and anxiety as a result of replacing a play-based childhood with smartphones, social media, and video games. He explains how a screen-filled childhood leads to challenges in psychological development that negatively impact learning, resilience, identity, cooperation, and conflict resolution — all of which are crucial skills for future adult relationships and career success. We also discuss how phones and social media impact boys and girls differently and the underlying neurobiological mechanisms of how smartphones alter basic brain plasticity and function.  Dr. Haidt explains his four recommendations for healthier smartphone use in kids, and we discuss how to restore childhood independence and play in the current generation.  This is an important topic for everyone, young or old, parents and teachers, students and families, to be aware of in order to understand the potential mental health toll of smartphone use and to apply tools to foster skill-building and reestablish healthy norms for our kids. For show notes, including referenced articles and additional resources, please visit hubermanlab.com. Thank you to our sponsors AG1: https://drinkag1.com/huberman  Helix Sleep: https://helixsleep.com/huberman AeroPress: https://aeropress.com/huberman Joovv: https://joovv.com/huberman LMNT: https://drinklmnt.com/huberman Timestamps 00:00:00 Dr. Jonathan Haidt 00:02:01 Sponsors: Helix Sleep, AeroPress & Joovv 00:06:23 Great Rewiring of Childhood: Technology, Smartphones & Social Media 00:12:48 Mental Health Trends: Boys, Girls & Smartphones 00:16:26 Smartphone Usage, Play-Based to Phone-Based Childhood 00:20:40 The Tragedy of Losing Play-Based Childhood 00:28:13 Sponsor: AG1 00:30:02 Girls vs. Boys, Interests & Trapping Kids 00:37:31 “Effectance,” Systems & Relationships, Animals 00:41:47 Boys Sexual Development, Dopamine Reinforcement & Pornography 00:49:19 Boys, Courtship, Chivalry & Technology; Gen Z Development 00:55:24 Play & Low-Stakes Mistakes, Video Games & Social Media, Conflict Resolution 00:59:48 Sponsor: LMNT 01:01:23 Social Media, Trolls, Performance 01:06:47 Dynamic Subordination, Hierarchy, Boys 01:10:15 Girls & Perfectionism, Social Media & Performance 01:14:00 Phone-Based Childhood & Brain Development, Critical Periods 01:21:15 Puberty & Sensitive Periods, Culture & Identity 01:23:55 Brain Development & Puberty; Identity; Social Media, Learning & Reward 01:33:37 Tool: 4 Recommendations for Smartphone Use in Kids 01:41:48 Changing Childhood Norms, Policies & Legislature 01:49:13 Summer Camp, Team Sports, Religion, Music 01:54:36 Boredom, Addiction & Smartphones; Tool: “Awe Walks” 02:03:14 Casino Analogy & Ceding Childhood; Social Media Content 02:09:33 Adult Behavior; Tool: Meals & Phones 02:11:45 Regaining Childhood Independence; Tool: Family Groups & Phones 02:16:09 Screens & Future Optimism, Collective Action, KOSA Bill 02:24:52 Zero-Cost Support, Spotify & Apple Reviews, YouTube Feedback, Social Media, Neural Network Newsletter Disclaimer

Recently I had the pleasure of hosting a live event in Brisbane, Australia. This event was part of a lecture series called The Brain Body Contract. My favorite part of the evening was the question and answer period, where I had the opportunity to answer questions from the attendees of each event. Included here is the Q&A from our event at the Brisbane Convention & Exhibition Centre. Sign up to get notified about future events: https://www.hubermanlab.com/events Thank you to our sponsors AG1: https://drinkag1.com/huberman Eight Sleep: https://eightsleep.com/huberman Resources Mentioned Huberman Lab Non-Sleep Deep Rest Protocols Huberman Lab Guest Series with Dr. Matt Walker Huberman Lab Guest Series with Dr. Paul Conti Huberman Lab Guest Series with Dr. Andy Galpin Dr. Becky Kennedy: Protocols for Excellent Parenting & Improving Relationships of All Kinds Perform with Dr. Andy Galpin Timestamps 00:00 Introduction 00:31 Sponsors: AG1 & Eight Sleep 03:48 Nicotine Discussion 07:42 ADHD Management: Tools & Medications 12:43 Sleep Deprivation & Recovery 18:54 Understanding & Addressing Burnout 22:12 Daily Nutrition & Eating Habits 24:40 Understanding Food & Neural Pathways 26:21 The Benefits of Elimination Diets 27:21 Intermittent Fasting & Personal Diet Choices 28:23 Top Health & Fitness Recommendations 30:50 The Value of Non-Sleep Deep Rest (NSDR) 33:08 Testosterone Replacement Therapy Insights 38:02 Breathing Techniques for Stress & Focus 41:46 Morning Sunlight & Circadian Rhythms 43:18 Parenting Tips for a Healthy Start 49:03 Final Thoughts & Gratitude Disclaimer

In this episode, my guest is Dr. Mary Claire Haver, M.D., a board-certified OB/GYN and an expert on women’s health and menopause. We discuss the biology and symptoms of perimenopause and menopause and their effects on body composition, cardiometabolic health, mental health, and longevity. She explains the lifestyle factors, including nutrition, resistance training, sleep, and supplements, that can better prepare women for and improve symptoms of both perimenopause and menopause. We also discuss hormone replacement therapy (HRT) and whether HRT impacts the incidence of breast cancer or can affect cardiovascular health. We also discuss contraception, cellulite, polycystic ovary syndrome (PCOS), and how to reduce the risk of osteoporosis. This episode is rich in actionable information related to what is known about menopause and perimenopause and the stages before, allowing women of all ages to best navigate these life stages. For show notes, including referenced articles and additional resources, please visit hubermanlab.com. Thank you to our sponsors AG1: https://drinkag1.com/huberman  AeroPress: https://aeropress.com/huberman  Eight Sleep: https://eightsleep.com/huberman  BetterHelp: https://betterhelp.com/huberman  InsideTracker: https://insidetracker.com/huberman  Timestamps 00:00:00 Dr. Mary Claire Haver 00:02:04 Sponsors: AeroPress, Eight Sleep & BetterHelp 00:06:26 Menopause, Age of Onset 00:09:50 Perimenopause, Hormones & “Zone of Chaos” 00:14:42 Perimenopause, Estrogen & Mental Health 00:20:04 Perimenopause Symptoms; Tool: Lifestyle Factors & Ovarian Health 00:25:26 Early Menopause, Premature Ovarian Failure; Estrogen Therapy 00:29:42 Sponsor: AG1 00:31:31 Contraception, Transdermal, IUDs; Menopause Onset, Freezing Eggs 00:38:18 Women’s Health: Misconceptions & Research 00:45:01 Tool: Diet, Preparing for Peri-/Menopause; Visceral Fat 00:48:31 Tools: Body Composition, Muscle & Menopause, Protein Intake 00:51:42 Menopause: Genetics, Symptoms; Tools: Waist-to-Hip Ratio; Gut Microbiome 00:58:22 Galveston vs. Mediterranean Diet, Fasting, Tool: Building Muscle 01:05:18 Sponsor: InsideTracker 01:06:29 Hot Flashes; Estrogen Hormone Replacement Therapy (HRT), Breast Cancer Risk & Cognition 01:15:36 Estrogen HRT, Cardiovascular Disease, Blood Clotting; “Meno-posse” 01:24:00 Estrogen & Testosterone: Starting HRT & Ranges 01:30:36 Other Hormones, Thyroid & DHEA; Local Treatment, Urinary Symptoms 01:37:57 OB/GYN Medical Education & Menopause 01:41:30 Supplements, Fiber, Tools: Osteoporosis “Prevention Pack” 01:46:53 Collagen, Cellulite, Bone Density 01:51:42 HRT, Vertigo, Tinnitus, Dry Eye; Conditions Precluding HRT  01:55:27 Polycystic Ovary Syndrome (PCOS) & Treatment; GLP-1, Addictive Behaviors 02:01:55 Post-menopause & HRT, Sustained HRT Usage 02:04:58 Mental Health, Perimenopause vs. Menopause; Sleep Disruptions, Alcohol 02:09:09 Male Support; Rekindle Libido 02:12:46 HRT Rash Side-Effect; Acupuncture; Visceral Fat 02:16:24 Zero-Cost Support, Spotify & Apple Reviews, YouTube Feedback, Sponsors, Social Media, Neural Network Newsletter Disclaimer

In this episode, my guest is Dr. Diego Bohórquez, PhD, professor of medicine and neurobiology at Duke University and a pioneering researcher into how we use our ‘gut sense.’ He describes how your gut communicates to your brain and the rest of your body through hormones and neural connections to shape your thoughts, emotions, and behaviors. He explains how your gut senses a range of features such as temperature, pH, the macro- and micronutrients in our foods, and much more and signals that information to the brain to affect our food preferences, aversions, and cravings. Dr. Bohórquez describes his early life in the Amazon jungle and how exposure to traditional agriculture inspired his unique expertise combining nutrition, gastrointestinal physiology, and neuroscience. We discuss how the gut and brain integrate sensory cues, leading to our intuitive “gut sense” about food, people, and situations. This episode provides a scientific perspective into your gut sense to help you make better food choices and, indeed, to support better decision-making in all of life. For show notes, including referenced articles and additional resources, please visit hubermanlab.com. Thank you to our sponsors AG1: https://drinkag1.com/huberman Joovv: https://joovv.com/huberman LMNT: https://drinklmnt.com/huberman Helix Sleep: https://helixsleep.com/huberman InsideTracker: https://insidetracker.com/huberman Timestamps 00:00:00 Dr. Diego Bohórquez 00:02:37 Sponsors: Joovv, LMNT & Helix Sleep; YouTube, Spotify & Apple Subscribe 00:06:49 Gut-Brain Axis 00:11:35 Gut Sensing, Hormones 00:15:26 Green Fluorescent Protein; Neuropod Cells & Environment Sensing 00:26:57 Brain & Gut Connection, Experimental Tools & Rabies Virus 00:35:28 Sponsor: AG1 00:37:00 Neuropod Cells & Nutrient Sensing 00:43:55 Gastric Bypass Surgery, Cravings & Food Choice 00:51:14 Optogenetics; Sugar Preference & Neuropod Cells 01:00:29 Gut-Brain Disorders, Irritable Bowel Syndrome 01:03:03 Sponsor: InsideTracker 01:04:04 Gut & Behavior; Gastric Bypass, Cravings & Alcohol 01:07:38 GLP-1, Ozempic, Neuropod Cells 01:11:46 Food Preference & Gut-Brain Axis, Protein 01:21:35 Protein & Sugar, Agriculture & ‘Three Sisters’ 01:25:16 Childhood, Military School; Academics, Nutrition & Nervous System 01:36:15 Plant Wisdom, Agriculture, Indigenous People 01:41:48 Evolution of Food Choices; Learning from Plants 01:48:15 Plant-Based Medicines; Amazonia, Guayusa Ritual & Chonta Palm 01:56:58 Yerba Mate, Chocolate, Guayusa 02:00:22 Brain, Gut & Sensory Integration; Variability 02:06:01 Electrical Patterns in Gut & Brain, “Hangry” 02:12:43 Gut Intuition, Food & Bonding; Subconscious & Superstition 02:22:00 Vagus Nerve & Learning, Humming 02:26:46 Digestive System & Memory; Body Sensing 02:32:51 Listening to the Body, Meditation 02:40:12 Zero-Cost Support, Spotify & Apple Reviews, YouTube Feedback, Sponsors, Social Media, Neural Network Newsletter Disclaimer

In this episode, my guest is Dr. Gary Steinberg, MD, PhD, a neurosurgeon and a professor of neurosciences, neurosurgery, and neurology at Stanford University School of Medicine. We discuss brain health and brain injuries, including concussion, traumatic brain injury (TBI), stroke, aneurysm, and transient ischemic attacks (TIA). We discuss key and lesser-known risk factors for brain health and explain how certain treatments and medications can improve brain health and cognitive function. We also cover novel mechanisms to improve recovery after concussions and brain injury, including the use of stem cells, temperature (mild hypothermia), and vagus nerve stimulation. Dr. Steinberg also describes new advances in neurosurgery and minimally invasive brain augmentation. This episode ought to be of interest to anyone seeking actionable tools to improve their brain health and for those seeking to improve recovery after a brain injury such as concussion, stroke, aneurysm, or TBI. For show notes, including referenced articles and additional resources, please visit hubermanlab.com. Thank you to our sponsors AG1: https://drinkag1.com/huberman Eight Sleep: https://eightsleep.com/huberman ROKA: https://roka.com/huberman AeroPress: https://aeropress.com/huberman LMNT: https://drinklmnt.com/huberman Timestamps 00:00:00 Dr. Gary Steinberg 00:01:44 Sponsors: Eight Sleep, ROKA & AeroPress; Subscribe on YouTube, Spotify & Apple 00:06:16 Stroke, Hemorrhage & Blood Clot 00:10:25 Blood Clots & Risk Factors, Medications, Smoking, Cholesterol 00:16:19 Heart & Brain Health; Neurosurgery & Brain Function 00:23:27 Current Technology & Neurosurgery, Minimally Invasive Techniques 00:28:13 Transient Ischemic Attacks (TIA); Spinal Cord Strokes 00:33:23 Stroke Risk: Alcohol, Cocaine & Other Drugs 00:38:24 Sponsor: AG1 00:39:55 Traumatic Brain Injury (TBI), Concussion: Sports, Testing & Recovery 00:46:45 Statins; TBI & Aspirin; Caffeine & Stroke Risk 00:48:31 Exploratory MRI: Benefits & Risks 00:51:53 Blood Pressure, Lifestyle Factors; Tool: Feeling Faint, Hydration; Sleep 00:59:52 Sponsor: LMNT 01:01:27 Chiropractic Neck Adjustment & Arterial Obstruction; Inversion Tables 01:05:16 Kids, Tackle Football, Soccer, Boxing; Mild Concussion 01:10:49 Nerve Regeneration, Stem Cells, Stroke Recovery 01:17:36 Stem Cells, Immune System, Activity 01:21:27 Injury & Recovery, Restraint Therapy 01:23:46 Neuroprotection After Injury; Mild Hypothermia 01:34:59 Platelet-Rich Plasma (PRP), Stem Cell Therapy 01:42:27 Scientific Advancements & Clinical Translation, FDA & Industry 01:47:40 Vagal Stimulation 01:53:17 Zero-Cost Support, Spotify & Apple Reviews, YouTube Feedback, Social Media, Neural Network Newsletter Disclaimer

My guest this episode is Dr. Peter Attia, M.D., who trained at Stanford University School of Medicine, Johns Hopkins Hospital and the National Institutes of Health (NIH). Dr. Attia is host of The Drive podcast and is a world expert on behavioral approaches, nutritional interventions, supplementation and pharmacological techniques to improve lifespan, healthspan and athletic performance. We discuss how best to evaluate your health status using routine blood work, body scans and regular tests of physical strength and endurance. Dr. Attia explains what he uses with his patients to “back-cast” their health goals as a way to design their exercise and nutritional programs. We also discuss hormone modulation and replacement therapy for both men and women. We explain how cholesterol and related factors contribute to cardiovascular disease risk and how to monitor and mitigate that risk. Dr. Attia details various supplementation, nutrition, exercise and prescription approaches useful to people in every decade of life to improve vitality, reduce their risk of disease and increase the number of years sustaining peak cognitive and physical health.  For the full show notes, visit hubermanlab.com. Thank you to our sponsors AG1 (Athletic Greens): https://athleticgreens.com/huberman LMNT: https://drinklmnt.com/huberman Supplements from Momentous https://www.livemomentous.com/huberman Timestamps (00:00:00) Assessing Health Status & Improving Vitality  (00:03:07) Sponsors: AG1, LMNT (00:07:29) Lifespan: Bloodwork & Biomarkers Testing, The “4 Horseman of Disease”  (00:11:51) Healthspan: Functional Testing, Cognitive & Emotional States  (00:13:59) Blood Testing: Best Frequency  (00:16:01) DEXA Scan: Lean Mass & Fat, Bone Mineral Density & Osteoporosis  (00:22:33) Bone Mineral Density & Age-Related Decline, Strength Training, Corticosteroids  (00:29:24) Osteopenia & Osteoporosis Diagnosis, Strength Training (00:29:52) Sponsor: AG1 (00:32:16) Back-casting: Defining Your “Marginal Decade”  (00:38:31) All-Cause Mortality: Smoking, Strength, VO2 max  (00:44:43) Attia’s Rule of Supplementation, “Centenarian Decathlete” Physical Goals (00:49:24) Importance of Exercise, Brain Health, MET hours  (00:55:23) Nicotine & Cognitive Focus (01:03:12) Menstruation, PMS & Menopause  (01:10:10) Hormone Replacement Therapy, Menopause & Breast Cancer Risk (01:22:06) Estrogen, Progesterone & Testosterone Therapies in Women (01:26:35) Hormone Replacement Therapy in Men, SHBG & Testosterone, Insulin (01:37:23) Clomid, Pituitary, Testosterone & Cholesterol, Anastrozole, HCG (01:47:46) Fadogia Agrestis, Supplements, Rapamycin  (01:52:06) Testosterone Replacement Therapy & Fertility  (01:59:26) Total Testosterone vs. Free Testosterone (02:02:51) Cholesterol & Dietary Cholesterol, Saturated Fat, LDL & HDL, Apolipoprotein B (02:17:42) Apolipoprotein B, Diet, Statins & Other Cholesterol Prescriptions  (02:25:15) Cardiovascular Disease, Age & Disease Risk  (02:28:53) Peptides, Stem Cells, BPC157, PRP (Platelet-Rich Plasma), Injury Rehabilitation  (02:37:40) Metabolomics & Exercise  (02:40:44) GLP-1 & Weight Loss  (02:47:06) Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Momentous Supplements, Instagram, Twitter, Neural Network Newsletter, Huberman Lab Clips Title Card Photo Credit: Mike Blabac Disclaimer

Should we be concerned with environmental Oestrogen? Do you know all the ways it creeps into our diet? There are 10 top offenders, and in this informative podcast with Dr Anthony G Jay, we uncover the dangers of Oestrogens and what we can do about it. For the purpose of your own research, the top 10 list we discussed are:  1. Phytoestrogens  2. Mycoestrogens  3. Atrazine  4. Triclosan & APE's  5. BP & 4-MBC  6. Red Numbers 3 & 40  7. Parabens  8. Phthalates  9. BPA & BPS  10. EE2  The link to the discussed research on Soy is here: https://www.researchgate.net/publication/309169877_Combinatory_estrogenic_effects_between_the_isoflavone_genistein_and_the_mycotoxins_zearalenone_and_alternariol_in_vitro  And: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176039  To find out more about Dr Jay's work visit: www.AJConsultingCompany.com  The doc on Twitter: https://twitter.com/ajcco_com  Â

On this episode we interview the inspiring Vitality Consultant and international speaker Kyle Vialli.This interview is packed with information and ideas that you really don't want to miss.   www.kylevialli.com www.orassy.com www.andycraig.net Book Recommendations

Hormones play such an important role when it comes to overall health and quality of life, but how much do we really know about them? Dr. Carrie Jones is a Naturopathic Physician with a Master's in Public Health who has over 12 years of experience in the field of functional and integrative medicine. She is a functional medicine women's health and hormone doctor who believes in the importance of both men and women understanding their hormones in a simplified manner so they can feel more empowered to take control of their own health. In this episode, we dive into what hormone imbalances actually mean, how they can affect the body, which lifestyle changes can help prevent them, and so much more. 

In this episode you’ll learn: 

• How Dr. Carrie got into women’s health 
• Why studying hormones is becoming more and more popular 
• About the deal with estrogen and how it can affect the body 
• Why men need estrogen too
• About the relationship between estrogen and progesterone 
• What estrogen dominance is 
• About some symptoms of estrogen dominance 
• Symptoms of high estrogen in men 
• Why deep sleep is so important for men’s testosterone levels
• About how Dr. Carrie likes to detox and rebalance hormones  
• Which supplements can help with hormone imbalances 
• How antibiotics can affect your microbiome and hormones 
• About some ways alcohol can affect how your body functions 
• How hormone imbalances affect women in menopause 
• About estrogen replacement therapy and who can benefit from it
• What you need to know about estrogen replacement therapy and it’s possible ties to breast cancer 
• When testosterone replacement can be helpful for men 
• All about cortisol and how it affects your entire body 
• Why sunlight early in the morning, movement are crucial for Cortisol Awakening Response 
• How you can help your cortisol fall at night for a good night’s sleep 
• About Dr. Carrie’s nighttime routine 
• That wifi at night may affect your circadian rhythm 
• How overtraining can affect your sleep 

Where to find her:

@dr.carriejones | dutchtest.com 

What’s it take to make a ketone?

 

Jody:  OK, so what’s up.  Last night at dinner I saw you guys order the exact same food, painstakingly divide up the olives and cheese and pickles on the charcuterie board, and then 50:50 split a dessert.  And you’ve been pricking your fingers and testing your blood. I know you’re both super weirdos, but I feel like there’s something more going on.

Matt:  You caught us.  So, we have a hypothesis about how we each metabolize ketones differently based on our genetics, and we’re doing a controlled 40 hour experiment where we eat the exact same calories, do the exact same workouts, sleep the same, and basically compare our BHB levels before and after exogenous ketones and also after a workout to look at utilization.

Jody:  Oh. that’s like one of the least weird things I’ve seen you guys do, but I do think I’d like to hear more.

 

Intro music

[1:33 -3:17]

Mike: Matt and I have been obsessed about ketones for some time now. First, we were both playing around with ketogenic diets. Actually, I did my first ketogenic diet back in 1998. Lost like 50 pounds, then immediately put 70 back on when I went back to carbs. But then after I got healthy, we both started playing around with ketosis, for its health benefits, not diet.

Matt: Yeah, a lot of people believe that ketones are the glue that hold together the fabric of longevity. Weather that’s true or not remains to be seen, but we at least know that ketones, specifically BHB has a host of beneficial effects for overall health. Alot which mimic calorie restriction.

Mike: Calorie restriction has been shown to extend lifespan in a host of animals. It does this through a reduction in the insulin and the growth hormone/IGF-1 axis which eventually leads to more FOXO proteins in the nucleus and an upregulation of antioxidant production by the cell. Ketones do the same thing generally, we think by inhibition of histone deacetylases that repress transcription of the FOXO3a gene - allowing for more antioxidant production, but because ketones also directly reduce blood glucose and igf, they also affect the GH/IGF axis.

In fact, it may have been the presence of ketone bodies during calorie restriction all along that lead to an increase in lifespan. (1)

[3:17-5:15]

Matt: Ketones, administered exogenously in non-human studies have been shown to extend lifespan as well, suggesting they ketones independently have an effect on lifespan, without the need for starvation or a ketogenic diet.

 

Jody: what are you guys even talking about? I thought we were going to talk about your stupid dieting crap you’re always texting me about.

Mike: Sorry man, maybe we jumped the gun. Matt and I just get so excited about ketones. I can’t help but get to talking about it in depth.

Jody: Yeah, ketones and everything else on this podcast. Alright so the other day I get the text from you with a picture of a blood ketone device and the number 1.9 on it, along with a text saying 24 hour fast + hard bike ride. I could tell you were super proud of yourself, but honestly, I have no clue what youre talking about.  I mean, I’m super proud about your fast bike, but that’s not groundbreaking. I remember talking a little bit about ketones in the fasting podcast, what are you doing with monitoring your ketones and why?

Matt: Well, as we got into in the beginning, Ketones appear to function as cellular signals which in essence may prolong lifespan.

Mike: Yeah basically independent of their effect on metabolism and the reduced oxidative stress associated with using fats instead of sugar for cellular energy, they also function on a molecular level to activate portions of your genome to promote longevity through transcription of FOXO3 gene which leads to production of things like superoxide dismutase and glutathione. Two huge players in the antioxidant world. Basically histone deacetaylaces block FOXO3 and BHB blocks these deacetylates.

[5:15-7:48]

Jody: there you go again. Can we do this with less biochem and more bro?

Matt: Sure, circulating ketones may be the reason calorie restriction works. I’d like to live forever, therefore, I want ketones in my blood.

Jody: So just go into ketosis, cool podcast over…..

Mike: Hold up, let’s be honest. Ketosis is pretty tough for most people. I’d say the minority, like 2%, can stay in ketosis all the time. In fact I don’t personally know anyone who has stayed in ketosis for more than a few years without at least cycling some. So the question Matt and I keep playing with is:

 

1. Can we increase our daily ketone value though time restricted eating?
2. How does exercise and fasting affect our ketone levels?
3. Do exogenous ketones have the same effect as endogenous. Meaning, can we just chug a $90 ketone ester drink everyday and get the same metabolic and cellular signaling effects?

 

Jody: Finally 15 min into the podcast to tell me what we’re talking about.

 

Matt: Yeah, this is super cool. So Mike and I have been playing around with blood ketone monitors. Basically a glucose monitor like where you prick your finger and get a value for your blood ketones. The number will usually be in the 0-3 mmol/L although some people in deep ketosis can crank it up to 5.

Jody: Right, I’m familiar with this to some degree. But I thought you had to be on a ketogenic diet for like 3 days to really drop into ketosis.

Mike: Ketosis is the body’s response to starvation. You can dip into mild ketosis pretty quickly through combining a relatively low carb diet at baseline, fasting, and throwing in some exercise to help deplete your glycogen stores early.

Matt: Yeah Valter Longo’s work on the FMD is  basically doing the same thing, just over a longer period of time. Granted, what we’re talking about is bigger shock to the system, but it’s also a lot faster

Mike: yeah and we think, could put you into a spot of ketone production, histone acetylation, FOXO3 activation, and mTOR inhibition much quicker.

Jody: Right, what data do you have to support that.

Matt: 0%

[7:48-10:30]

Mike: Yeah, let's be clear here, there is no data to support this, kinda. Well actually, now that I think about it there is some mouse data. This study in SCIENCE, yes I said SCIENCE from 2011 showed that fasting, CR and the administration of exogenous ketones to human and mouse tissue decreased histone deacetylase activity. IN human kidney cells treated with bHB levels as low as 1 mmol, with an almost linear relationship. Meaning the higher the ketones, the higher to blockage and the more advantage.

 

Next they tested the theory on live mice through fasting 24 hours (about the equivalent of 3 days for humans) a CR diet, and also with exogenous ketone administration. They found ketone levels of 1.5 with 24 hour fast, 0.6 with CR and 1.2 with exogenous ketones. All levels and methods of increasing bhb at the cellular level lead to histone deacetylation, as well as FOXO3 activation and in this study even helped protect kidney cells from oxidative stress.

 

 

Jody: So, what are those empty bottles over on the counter?  I feel like they’re relevant to this discussion.

Matt: Yep.  That’s 2 25g bottles of ketone esters.   

Jody: Seriously, sign me up so basically anyway I can get ketones in my body is the way to go?

Mike: According to this study, I don’t really see a downside. Although there is some evidence that people like me, with PPARalpha mutations may have increased cholesterol production in the face of circulating ketone bodies. I’ve been enacting my plan for some time now, with pretty regular ketone production and exogenous ingestion, and haven’t seen a big spike in cholesterol.

--Personal test N of 1.

Matt: This is super interesting, because I can’t get my ketones as high as you. If I fast all day, workout, and ingest exogenous ketones, I’m maybe at like 1.2. Not the 1.9 you’re getting.

Mike: Yeah could be my cells just aren’t as good at utilizing ketones. In which case, that could make for some pretty nice advantages assuming they still have the histone deacetylase activity. Wow we are way off topic now, and in the realm of fake science. Let’s get back to the pseudo science instead.

 

[10:30-16:00]

 

Discussion of previous day foods and results

 

Jody: Yep, Matt, tell me how you do this, whats the protocol.

[16:00-22:11]

Matt: So i’ve told you how I eat previously, but briefly, I wake up, have breakfast which is black coffee, cinnamon and chaga. Then skip lunch. Drink a bunch of water. Exercise late morning or midday, then have some MCT oil around lunchtime.  Sometimes I’ll take exogenous instead, but that’s expensive, so usually not. If I do, I prefer the ketone esters because I’m not a huge fan of some of the other stuff in ketone salts, and also cause a higher bump in bHB. That’s sort of my lunch. Then I don’t eat again until dinner. The goal, is to deplete glycogen stores as soon as possible to push the liver into fatty oxidation and increase bhb in the blood. That way I spend more time with ketones circulating during the day and get all the benefits we are talking about.

Mike: Similar for me, although I try to workout in the morning. Get that glycogen depleted as soon as possible. The advantage here, as you might notice is that we’re only doing time restricted eating. So still consuming the same number of calories, but getting several hours of ketosis and pumping it up with exogenous ketones to improve the histone deacetylation. The other thing that matter is to have a relative low glycogen store in the first place. You’ll see higher ketone levels sooner if you’re not filled to the brim with glycogen. So a higher fat diet at baseline say 60% or so, along with regular exercise should put you closer to nutritional ketosis and allow you to jump off the cliff a little sooner.

Jody: Ok, so in general, low carb diet at baseline. Start fasting after dinner the night before. Work out the next morning, don’t eat until dinner and take some exogenous ketones in the afternoon.

Matt: That’s one way to do it. Of course you could just water fast for 3 days or do the FMD for 5 days and probably get a similar response, although you may be in ketosis a bit longer.

Mike: Yeah, but the nice thing about this protocol is it allows me to spend more days in doing this. If I do a 3 day water fast or a 5 day FMD, realistically, I’m gonna refeed for a few weeks before doing it again. With this protocol, I can get away with this every other day. Thats a lot of time with ketones, granted not as much as long term keto diet, but a nice alternative, especially for someone like me to cannot tolerate ketosis with my genetics.

[22:11- 23:37]

Jody: So what sort of exercise are you guys doing.

Mike: My preference is HIIT stuff. I want glycogen depletion, so I I’m going for intensity. Studies have shown that work near your VO2 max or lactate threshold deplete glycogen the fastest, to the tune of 5 x faster than easier slower efforts. (3) If you think about it physiologically you get 32 mols of ATP for every glucose molecule during aerobic exercise versus 2 mmol of atp for every glucose molecule from anaerobic exercise. Thus for the same cellular energy usage, you burn way more glucose with anaerobic exercise. So interval anaerobic efforts should burn way more glycogen than a slow easy talkative aerobic effort.

Matt: Furthermore, HIIT has also been shown to improve basal metabolic rate for hours after exercise leading to even more glycogen depletion.

[23:37-27:45]

Jody: How about the exogenous ketones. You guys mentioned esters and salts. How do I know which one to buy.

Matt: That’s pretty easy, how rich are you.

Jody: like in pesos?

Matt: Exactly, you’re probably buying the salts then. They are way cheaper, like maybe a 2-3$ per serving, but have a ton of salt in the form of sodium, potassium, and magnesium. They use the salts to stabilize the ketones. They are pretty salty, but not too bad tasting. Many of them come with some MCT power as well, which you may or may not want. Technically the MCT is breaking the fast, , but you should still have a relative uptick of ketone levels - which is out goal.

Mike: Yeah, I’m not a fan of the MCT, too much sat fat for me and messes up my cholesterol. You can find ketone salts without the MCT as well.

Matt: And then there are esters. They taste like rocket fuel and cost as much as I paid for my first car.

Jody: that's not much.

Matt: well, per serving, they are close to $30 per serving. But they have about double the effect on blood ketones. Which is hard to argue with. I think basically if money isn’t an issue, esters are the way to go, although there have been some concerns about contaminants.

Jody: Ok, so to summarize:

Wake up fasted and continue with some black coffee and water, exercise sometime in the morning with a long HIIT workout to deplete glycogen. Drink plenty of water, and down some ketones after your workout to bump your ketones back up. Esters are best, but salts are cheaper, with or without MCT in them. Then stay fasting for the rest of the afternoon, and eat dinner. This should get your blood bHB to at least the mmol range and should be causing some histone deacetylation, activation of antioxidant, life prolonging genes like FOXO3 as well as improving your insulin sensitivity, and spending more time with inactivation of the GH/IGF-1 axis which can prolong life as well.

Mike: You got it. So Tomorrow, let's all do this together. Jody, you can use my old used finger lancets to check your bHB. Sorry, those things are expensive, can’t have you using fresh ones. Then we’ll report back and record a follow up talking about how we felt and how high we got our ketones and thus our FOXO3 activation.

[28:05-end]

Dudes prick their fingers(!!) and discuss results

 

1. https://iubmb.onlinelibrary.wiley.com/doi/full/10.1002/iub.1627
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735349/
3. https://www.ncbi.nlm.nih.gov/pubmed/4278539