Wide release date: November 2, 2025.

Episode Summary: Dr. Jon Brestoff talks about mitochondrial dynamics inside cells, their transfer between unrelated cells (distinct from inheritance during division), and its roles in adipose tissue communication, macrophage cleanup, and systemic metabolic signaling; they explore how high-fat diets disrupt this process, potential hormetic benefits, therapeutic mitochondria transplantation for diseases like Leigh syndrome and obesity, and broader immunometabolism crosstalk.

About the guest: Jon Brestoff, MD, PhD is an associate professor of pathology and immunology at Washington University School of Medicine in St. Louis, where he directs the Initiative for Immunometabolism.

Discussion Points:

* Mitochondria per cell range from ~100-5000; they move via fusion/fission, vertical inheritance (cell division), or horizontal transfer without division.

* Transfer mechanisms: free release, extracellular vesicles, or tunneling nanotubes using cytoskeleton transport.

* In healthy fat tissue, adipocytes routinely donate mitochondria to macrophages for degradation (quality control); high-fat (lard-based, long-chain FA) diets block macrophage uptake, diverting mitochondria to other organs.

* Diverted mitochondria may induce “mito-hormesis” (mild oxidative stress boosting antioxidants) or signal adipocyte metabolic status inter-organ.

* Mitochondria transplantation shows promise in animal models for ischemia-reperfusion, obesity, and mitochondrial diseases.

* Immune cells prefer glycolysis but have low mitochondrial biomass; transplanted mitochondria tilt T-cells toward anti-inflammatory regulatory phenotype.

* Circulating cell-free mitochondria rival immune cell numbers.

* Obesity inflammation stems from dying oversized adipocytes releasing lipids/mitochondria, forming crown-like structures with pro-inflammatory macrophages.

* Leigh syndrome from genetic mutations disrupting the electron transport chain.

* Transfer may be an evolutionary relic of endosymbiosis; cells may selectively use exogenous mitochondria like a “generator” during metabolic crisis.

Reference Paper:

* Study: The power and potential of mitochondria transfer

Related Episode:

* M&M 260: Energy Resistance Principle in Life, Healing & Disease | Martin Picard & Nirosha Murugan

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:03:44 Guest Intro & Lab Focus

00:05:09 Mitochondria Basics: Numbers, Movement & Life Cycle

00:08:55 Mitochondrial Transfer vs Vertical Inheritance

00:11:18 Mechanisms: Vesicles, MVBs & Tunneling Nanotubes

00:14:48 Contexts: From Yeast to Humans & In Vivo Evidence

00:15:55 Adipocyte-to-Macrophage Transfer in Healthy Fat

00:18:05 High-Fat Diet Disrupts Transfer & Diverts Mitochondria

00:19:09 Mitohormesis & Inter-Organ Metabolic Signaling

00:21:13 Dietary Long-Chain Fatty Acids & Heparan Sulfates

00:23:32 Cardioprotection via Adipocyte Mitochondria in Heart

00:25:55 Mitochondrial Transplantation: Animal Studies & Trials

00:27:53 Immune Response to Free Mitochondria & Tolerance

00:30:18 T-Cell Shift to Anti-Inflammatory Phenotype

00:32:15 Cell-Free Mitochondria in Blood & Stability

00:33:37 Obesity Inflammation: Dying Adipocytes & Crown Structures

00:35:33 Mitochondria Transplants Reduce Obesity in Rodents

00:40:21 Immunometabolism Co-Evolution & Fever Example

00:41:46 Origin Story: Platelets, Mitochondria & Obesity Hypothesis

00:45:47 Leigh Syndrome: Pathology & Mitochondria Transplant Rescue

00:51:12 Patient Fibroblasts & Compassionate Use Trials

00:52:51 Evolutionary Roots & Endosymbiosis Relic

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: October 28, 2025.

Episode Summary: A reframe of biology as energy flow through resistance rather than mere molecular machinery, introducing the Energy Resistance Principle (ERP): life requires a Goldilocks balance of electron flow from food to oxygen via mitochondria; too much or too little resistance drives aging, disease, and death. Explain mitochondria as energy transformers, link ERP to insulin resistance, psychiatric disorders, and healing, and explore health as a dynamic field-like state optimized by flux modulation.

About the guest: Nirosha Murugan, PhD is a biophysicist studying how physical signals pattern biology to decode and reprogram health; Martin Picard, PhD is a mitochondrial psychobiologist at Columbia University, exploring how mitochondrial energy dynamics connect to human experiences, health, and healing. They collaborate on biophotons, light emission, and multi-scale energy signaling.

Discussion Points:

* Mitochondria transform electrons from food into versatile electricity via proton gradients.

* Energy Resistance Principle: transformation needs resistance; chronic high resistance causes dissipative heat, damage, aging.

* GDF15 cytokine signals mitochondrial stress to brain, triggering energy conservation/mobilization.

* Insulin resistance: adaptive defense against electron overload, reversible by fasting/exercise.

* Psychiatric illness: excess brain energy resistance; exercise, keto, psychedelics redistribute flux.

* Health: dynamic optimization of energy resistance, not absence of disease.

* Healing: daily recovery from micro-damage via balanced resistance.

* Future: energy-based diagnostics/therapies (light, TMS) over molecule-only drugs.

Reference Paper: The energy resistance principle

Related Episode:

* M&M 70: Mitochondria, Aging, Cellular Energy, Metabolism, Gray Hair Reversal & Brain-Body Communication | Martin Picard

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:01:28 Guest Introductions

00:03:01 Collaboration at Columbia

00:04:56 Physics vs Stamp Collecting in Biology

00:10:47 Cadaver vs Living Organism

00:13:25 Energy Flow & Mitochondria Basics

00:19:05 Energy Resistance Principle Explained

00:26:44 ERP Goldilocks Zone & Aging

00:31:59 Flow Drives Metabolism

00:36:06 Dissipative Heat & Damage

00:39:00 Allometric Scaling & Lifespan

00:46:52 Mitochondrial Disease & Short Stature

01:19:59 GDF15 as Energy Stress Signal

01:29:57 Health & Healing via ERP

01:36:44 Intrinsic vs Realized Health

01:37:03 Insulin Resistance Reframed

01:43:54 Psychiatric Illness & Energy Resistance

01:53:51 Cancer as Chronic Resistance Adaptation

01:56:16 Electron Flow as Élan Vital

02:05:59 Closing Thoughts

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: September 12, 2025

Episode Summary: Dr. Christopher Morrison talks about how animals sense and prioritize nutrients like protein, discussing defense mechanisms for essentials such as oxygen, water, sodium, and energy; the brain's role in detecting protein deprivation via signals like FGF21; trade-offs between growth, reproduction, and longevity under protein restriction; and reconciling high-protein diets for satiety and muscle maintenance with low-protein benefits for metabolic health and lifespan extension.

About the guest: Christopher Morrison, PhD is a professor and researcher at the Pennington Biomedical Research Center in Baton Rouge, Louisiana, where he has worked for over 22 years focusing on nutrition, metabolism, and chronic diseases like obesity and diabetes.

Discussion Points:

* The body prioritizes nutrients hierarchically: oxygen and water first, then sodium, energy, and protein, with weaker defenses for carbs or fats.

* Animals develop specific appetites for deprived nutrients, like salt or protein, often through post-ingestive learning rather than just taste.

* Protein restriction (e.g., 5% vs. 20% in diets) increases food intake and energy expenditure in mice to maintain protein levels, even at the cost of extra calories.

* FGF21, a liver hormone, signals protein deprivation to the brain (via NTS region), driving protein-seeking behavior and metabolic changes; it's essential for low-protein responses.

* Protein restriction extends lifespan in lab animals by suppressing growth signals like IGF-1 and mTOR, but may impair immunity or wound healing in real-world conditions.

* High protein aids satiety, weight loss, and muscle building, but overconsumption may shorten lifespan; optimal intake depends on age, activity, and goals (e.g., not for pregnant or elderly).

* No one-size-fits-all for protein: mild restriction may benefit middle-aged sedentary people for health, while athletes need more; balance avoids excesses.

Related content:

* M&M 106: Diet, Macronutrients, Micronutrients, Taste, Whole vs. Processed Food, Obesity & Weight Loss, Comparative Biology of Feeding Behavior | Stephen Simpson & David Raubenheimer

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:06:10 Nutrient Detection & Adequacy

00:11:11 Fluid & Sodium Defenses

00:16:20 Protein vs Other Macronutrients

00:21:21 Post-Ingestive Learning & Flavors

00:26:34 Hyperphagia on Low Protein

00:31:10 Restriction Effects on Growth

00:36:33 Longevity & Restriction Trade-Offs

00:41:47 Behavioral Changes & Choices

00:46:44 Preference in Choice Experiments

00:53:44 Innate vs Learned Appetite

00:58:39 Protein Digestion & Signals

01:04:40 FGF21 in Fasting & Restriction

01:10:40 FGF21 Knockouts & Relevance

01:15:20 Brain Receptors & Sites

01:20:49 Growth & Longevity Trade-Offs

01:25:04 High Protein Satiety & Muscle

01:30:33 FGF21 Scaling & Future Work

01:35:39 Final Thoughts & Recommendations

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: September 7, 2025

Episode Summary: Dr. Michael Levin talks about cognition manifesting at scales beyond brains, including in cells and tissues via bioelectric networks; analog vs. digital coding in biology; how bioelectric patterns guide development and regeneration (e.g., in planarians); creation of novel life forms like xenobots and anthrobots; philosophical ideas on a "platonic space" of mathematical patterns influencing biology; evolutionary trade-offs in regeneration and implications for regenerative medicine.

About the guest: Michael Levin, PhD is a biologist and computer scientist who directs the Allen Discovery Center at Tufts University, focusing on bioelectricity, regeneration, and cognition in non-neural systems.

Discussion Points:

* Cognition isn't limited to brains; tools from neuroscience reveal learning, memory, and goal-directed behavior in cells and tissues.

* Bioelectricity acts as "cognitive glue," enabling collective intelligence in non-neural systems, predating multicellular life.

* Analog coding in development uses slow voltage patterns across cells, contrasting fast digital spikes in neurons.

* Planarians regenerate perfectly due to bioelectric "memories"; altering patterns creates stable two-headed worms without genetic changes.

* Regeneration trade-offs: Mammals prioritize quick healing over full regrowth due to infection risks and load-bearing needs.

* Xenobots (from frog cells) and anthropots (from human cells) self-assemble, replicate, and heal tissues, revealing untapped cellular potentials.

* Patterns in biology may stem from a "platonic space" of mathematical truths, not just evolution or physics.

* Neuroscience studies mind scaling, not just neurons; diverse intelligences could exist in non-cellular systems.

Related content:

* M&M 95: Purpose, Value, Evolution, Consciousness, Sentience, Life & Emergence of Mind From Matter | Terrence Deacon

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:04:52 Cognition Definition

00:09:20 Development Timescales

00:12:01 Analog Signaling

00:15:12 Network Properties

00:18:03 Goals in Morphogenesis

00:21:40 Regeneration Mechanisms

00:25:41 Planarian Patterns

00:31:43 Regenerative Trade-offs

00:38:20 Pattern Sources

00:44:21 Xenobots

00:49:26 Anthropots

00:56:28 Platonic Space

01:02:47 Mind Scaling

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: September 3, 2025

Episode Summary: Dr. Justin Perry talks about the body's constant cellular turnover—about 3 million cells die per second in adults (double in children and women)—handled by phagocytes like macrophages that engulf and digest debris to prevent diseases like lupus. They explore phagocytosis steps, macrophage adaptations in tissues like the brain (microglia), and how high fructose intake impairs microglial function in developing mice, leading to uncleared brain cells and anxiety-like behaviors, with implications for human neurodevelopmental disorders amid rising fructose consumption.

About the guest: Justin Perry, PhD is an immunologist and clinical psychologist who leads a lab at Memorial Sloan Kettering Cancer Center focusing on how the body clears dead cells and debris to maintain homeostasis.

Discussion Points:

* The body turns over 1-2% of its 30 trillion cells daily, mostly blood cells, but neurons in kids and endometrium in women turnover at ~2x this rate

* Phagocytosis involves "find me," "eat me," and digestion signals; failures can cause autoimmunity.

* Microglia are brain macrophages that uptake fructose via GLUT5 transporter.

* Early high fructose exposure (comparable to one soda daily) impairs the pruning of synapses and dead neurons.

* In mice, prenatal or postnatal fructose causes phagocytosis deficits in the prefrontal cortex, leading to heightened fear responses and poor fear extinction, mimicking anxiety disorders.

* Fructose correlates with rising neurodevelopmental issues like autism and anxiety; it's passed via breast milk, and liquid forms (e.g., sodas) overwhelm metabolic shields more than solid fruits.

* Macrophages may hold keys to diseases from atherosclerosis to cancer; deleting GLUT5 in microglia reverses fructose's effects, hinting at evolutionary roles in aging or low-oxygen states.

Related content:

* M&M 215: Cancer Metabolism: Sugar, Fructose, Lipids & Fasting | Gary Patti

* Article | Dietary Fructose & Metabolic Health: An Evolutionary Perspective

Reference Paper:

* Study | Early life high fructose impairs microglial phagocytosis and neurodevelopment

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: August 30, 2025

Episode Summary: Dr. William Parker talks about autism spectrum disorder (ASD), its rising prevalence since the 1980s, and the controversial hypothesis that acetaminophen exposure in susceptible infants and children triggers most cases via oxidative stress. They discuss ASD's clinical definition; historical misconceptions like the "refrigerator mother" theory; genetic susceptibilities; acetaminophen's metabolism, which produces toxic byproducts in underdeveloped livers, leading to brain effects. The conversation covers evidence from animal studies, epidemiological data, and cultural variations, while addressing vaccine myths, policy implications, and safer alternatives for pain and fever in early life.

About the guest: William Parker, PhD spent nearly 30 years as a professor at Duke University researching underlying causes of chronic conditions, including discovering the immune function of the human appendix and pioneering studies on immune systems in wild animals.

Discussion Points:

* Autism is a spectrum disorder with core symptoms like social deficits, repetitive behaviors, and aversion to new stimuli; its prevalence has risen dramatically since the 1980s, likely due to both genuine increases and heightened awareness.

* Mainstream views attribute autism to complex gene-environment interactions, but Parker argues overwhelming evidence points to acetaminophen as the primary trigger in susceptible individuals, causing oxidative stress via toxic metabolite NAPQI.

* Acetaminophen, marketed as Tylenol or paracetamol, was not tested for neurodevelopmental effects in neonatal animals until 2014, despite widespread use since 1886; it's metabolized differently in babies, whose livers lack mature detox pathways.

* Susceptibility factors include low glutathione (an antioxidant), poor sulfation/glucuronidation metabolism, folate receptor autoantibodies, and events like immune reactions that prompt acetaminophen use during oxidative stress.

* Evidence includes: animal studies showing male-specific brain damage and autism-like behaviors; higher autism risk with perinatal acetaminophen exposure (e.g., in cord blood); low autism rates in non-modern societies without the drug; and more.

* Regressive autism, where children lose milestones after seeming normal, often follows acetaminophen given for fevers or illnesses, explaining parental vaccine suspicions (as shots coincide with drug use).

* Adult acetaminophen is generally safe but causes liver toxicity in overdoses or with alcohol; antidote is N-acetylcysteine to boost glutathione.

* Parker has suggested to policymakers that we should avoid acetaminophen during pregnancy, birth, and early childhood (under age 3-5); parents should plan ahead for fevers/pain without it, but seek medical help for unusual symptoms.

Related episode:

* M&M 246: Appendix, Gut Worms, Allergies & Autoimmunity | William Parker

Reference Paper:

* Evaluating the Role of Susceptibility Inducing Cofactors and of Acetaminophen in the Etiology of Autism Spectrum Disorder

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:04:33 Autism Definition

00:09:00 Prevalence Changes

00:14:56 Controversy Reasons

00:19:51 Entry into Field

00:24:27 Acetaminophen Introduction

00:29:18 Metabolism & Effects

00:34:18 Historical Assumptions

00:39:20 Sensitivity Factors

00:44:07 Multiple Sensitivities

00:46:41 Connecting Dots

00:51:59 History of Use

00:57:26 Evidence Lines

01:02:00 Perinatal Metabolism

01:07:45 Oxidative Stress

01:13:12 Research Views

01:18:43 Regressive Autism

01:23:13 Adult Toxicity

01:28:00 Alternatives & Advice

01:32:29 Counter Arguments

01:37:56 Final Thoughts

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: August 25, 2025

Episode Summary: Dr. Uffe Ravnskov talks about his decades-long career challenging the idea that high cholesterol causes heart disease, discussing LDL's protective role in the immune system by binding to bacteria, the harms and biases in statin research influenced by pharmaceutical companies, evidence that high cholesterol benefits the elderly and reduces infection/cancer risks, and how mental stress or infections elevate cholesterol as a response rather than a cause.

About the guest: Uffe Ravnskov, MD, PhD is a physician and independent researcher who earned his MD from the University of Copenhagen in 1961 and a PhD in nephrology. He has worked in various clinics in Sweden since the 1960s, focusing his research on challenging the cholesterol hypothesis in heart disease. Now 91, he has published over 200 papers, authored books like "The Cholesterol Myths.”

Discussion Points:

* LDL cholesterol helps the immune system by sticking to bacteria, clumping them for removal; low LDL increases infection risk.

* Animal studies show injecting LDL protects against lethal infections, while historical data links severe infections to worse atherosclerosis.

* Elderly people with high cholesterol live longer; low cholesterol raises mortality risk more than high levels.

* Familial hypercholesterolemia (FH) doesn't cause early death via cholesterol alone—co-inherited coagulation factors are the issue, and FH patients often have lower infection rates.

* Statins lower LDL but increase infection risk, cause muscle weakness/brain issues (often blamed on aging), and show no clear benefit in unbiased meta-analyses.

* Research biases include cherry-picking studies, exaggerating benefits via relative (not absolute) risk, and pharma funding suppressing critical views.

* Mental stress can raise cholesterol by 10-50% in 30 minutes, often misread as a heart disease cause rather than an effect.

* Saturated fat and high cholesterol aren't proven harmful; Ancel Keys' claims ignored contradictory evidence.

* Stopping statins often reverses side effects quickly, improving quality of life.

Related episode:

* M&M 244: Seed Oils & Heart Disease: Oxidized LDL, Cholesterol, Fat & Cardiology | Tucker Goodrich

Reference Paper:

* LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:01:28 Guest Background & Career

00:05:15 Cholesterol & Immune Function

00:10:14 LDL Role in Infections

00:15:10 Statins & Industry Influence

00:20:26 Research Biases & Relative Risk

00:25:08 Pushback & Publication Challenges

00:30:13 FH & Coagulation Factors

00:35:02 Stress & Cholesterol Response

00:40:03 Mortality & Elderly Benefits

00:45:32 Statin Side Effects & Recommendations

00:50:30 Scandal in Medicine & Outro

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: August 18, 2025

Episode Summary: Dr. William Parker discusses gut anatomy, the appendix's role in harboring beneficial bacterial biofilms and immune tissue, and how modern hygiene depletes helminths (intestinal worms), causing immune overreactions like allergies, autoimmunity, and psychiatric conditions. He explores helminth self-therapy for treating relapsing multiple sclerosis, depression, and allergies; challenges in clinical trials due to patent issues; and why COVID-19 was milder in low-income, helminth-rich regions.

About the guest: William Parker, PhD conducted research at Duke University for over 27 years on immunology, appendicitis, and the hygiene hypothesis. He now serves as a visiting scholar at the University of North Carolina at Chapel Hill, leading efforts on biome reconstitution via helminths.

Discussion Points:

* Appendix is not vestigial; it concentrates immune tissue and biofilms to cultivate good gut bacteria, preventing pathogens via mucus and IgA antibodies.

* Hygiene hypothesis: Soap, toilets, and clean water reduce helminths/protozoa, leading to untrained, hyperactive immunity and rising allergies/autoimmunity since the 1800s.

* Helminths (worms) stimulate immune "exercise," training immunity; biohackers use hookworms (cheap, skin-entry), porcine whipworms, or rat tapeworms orally for relief from allergies, MS flares, depression/anxiety.

* Effects are temporary; need ongoing exposure (e.g., replenish every 6 months); immigrants from helminth-rich areas develop Western diseases within a few years.

* COVID-19: Hyper-immunity caused severe reactions in hygienic West, but helminth presence in low-income Africa/Asia prevented cytokine storms, leading to empty clinics.

* Therapy barriers: Non-patentable organisms require $100M+ trials; push for open-source, government-funded biome restoration over crude immunosuppressants.

Related episode:

* M&M 144: Inflammation, Innate Immunity, Allergies & Allergens, Immune System Evolution, Fasting & Metabolism | Clare Bryant

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:03:24 Gut Anatomy & Appendix

0:09:18 Appendicitis & Inflammation

00:14:46 Biofilms & Immune Support

00:19:48 Hygiene Hypothesis History

00:25:24 Appendicitis Emergence

00:30:13 Appendix Evolution

00:36:21 Natural Biome Components

00:42:22 Worms & Autoimmunity

00:47:03 Biohacking with Helminths

00:52:24 Worm Administration Methods

00:57:23 Treated Conditions

01:03:08 Clinical Trials & Challenges

01:08:18 Covid-19 Morbidity Differences

01:13:23 Rat Immune Comparisons

01:15:52 Final Thoughts & Future

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: August 13, 2025

Episode Summary: Dr. Giovanni Marsicano is a neuroscientist based in Bordeaux, France, where he leads a research group at INSERM focusing on the endocannabinoid system.

About the guest: Giovanni Marsicano, PhD discusses the endocannabinoid system, starting with its core components like CB1 receptors and lipid-based molecules such as anandamide and 2-AG, derived from omega-6 fatty acids; he explains its cellular signaling, evolutionary role in energy storage for uncertain futures (exostasis vs. homeostasis), and effects across tissues like the liver, gut, and brain, including motivation, appetite, pain relief, and anxiety regulation, while touching on biphasic effects of cannabinoids.

Discussion Points:

* The endocannabinoid system acts as an "exostatic" regulator, promoting energy accumulation for future needs by enhancing food palatability, nutrient absorption, and fat storage, unlike "endostatic" systems that address immediate hunger.

* CB1 receptors appear in vertebrates with adipose tissue, suggesting an evolutionary link to storing fat for survival in unstable environments.

* Endocannabinoids are lipids from omega-6 fats; high intake boosts their levels, potentially fueling obesity by creating a self-perpetuating cycle of overeating.

* Activation of CB1 can have biphasic effects (e.g., low doses reduce anxiety, high doses increase it), due to receptors on different cell types like excitatory vs. inhibitory neurons.

* Pregnenolone, a steroid precursor, acts as a natural CB1 inhibitor to prevent excessive activation, blocking harmful effects like psychosis from high THC doses.

* The system influences motivation beyond food, including sex and even human activities like sports or storytelling, by rewarding actions for potential future benefits.

* In the brain, CB1 on mitochondria and astrocytes modulates energy use, olfaction, and social stress transmission, with implications for disorders like Alzheimer's.

Reference Paper:

* The CB1 Receptor as the Cornerstone of Exostasis

Related episode:

* M&M 123: Endocannabinoids, Stress, Exercise, Cortisol, Anxiety, Cannabis & Effects of Marijuana on Brain Development | Matthew Hill

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:05:01 CB1 Receptor Overview

00:10:58 Endocannabinoids & Lipids

00:16:00 CB1 as GPCR

00:21:04 Mitochondrial Signaling

00:26:09 Biphasic Effects

00:31:13 Homeostasis & Energy

00:37:40 Unstable Environments

00:43:59 ECS as Exostatic

00:50:13 Cue-Induced Feeding

00:55:00 Gut & Glucose Effects

01:00:32 Omega-6 Link

01:07:02 Pregnenolone Inhibitor

01:12:05 Modulation Mechanisms

01:17:03 Clinical Applications

01:22:15 Exostatic Coordination

01:26:19 Rewards Beyond Food

01:31:39 Cultural Motivations

01:36:43 Current Lab Work

01:42:12 Final Thoughts

Full AI-generated transcript below. Beware of typos & mistranslations!

Wide release date: August 7, 2025

Episode Summary: Tucker Goodrich is an engineer by training who has become a prominent independent researcher and blogger on nutrition and metabolic health, focusing on the harms of seed oils and polyunsaturated fats.

About the guest: Nick Jikomes and Tucker Goodrich explore atherosclerosis and heart disease, critiquing the standard model that blames high LDL cholesterol while highlighting how oxidized LDL—driven by dietary linoleic acid from seed oils—plays a key role in plaque formation and inflammation; they discuss historical shifts in heart disease rates, genetic factors like familial hypercholesterolemia, the limitations of animal studies, and why reducing seed oil intake could prevent issues more effectively than just lowering cholesterol.

Discussion Points:

* Atherosclerosis involves plaque buildup in arteries, often leading to heart attacks, but plaques contain oxidized fats and cholesterol, not just native cholesterol.

* Dietary cholesterol has little impact on blood levels or heart disease in humans, unlike in rabbits used in many studies.

* High LDL may not be inherently bad; oxidized LDL from polyunsaturated fatty acids (PUFAs) like linoleic acid causes macrophages to overeat and form harmful foam cells.

* Familial hypercholesterolemia patients only show higher heart disease rates in modern, industrial diets high in seed oils, not historically.

* Populations like the Kitavans and Tsimané have high apoB but no heart disease on traditional diets low in industrial foods.

* Fried foods are oxidized seed oils, explaining why they're unhealthy despite omega-6 fats being labeled "heart-healthy."

* Omega-3 fats can displace omega-6 in cells, reducing oxidation risk.

Reference Papers:

* Witztum & Steinberg (1991)

* Boren et al. (2022)

Related episode:

* M&M 136: Seed Oils, Omega-6 PUFAs, Inflammation, Obesity, Diabetes, Chronic Disease & Metabolic Dysfunction | Chris Knobbe

*Not medical advice.

* Full audio version: [Apple] [Spotify] [Elsewhere]

* Full video version: [YouTube]

* Support M&M if you find value in this content.

* Episode transcript below.

Episode Chapters:

00:00:00 Intro

00:05:12 Atherosclerosis Basics

00:10:25 Foam Cells & Plaques

00:15:53 Cholesterol Regulation

00:21:26 LDL Predictiveness

00:26:28 FH Variability

00:31:42 FH Historical Data

00:37:13 Oxidized LDL

00:43:10 LDL Dissociation

00:47:33 Boren Mechanisms

00:53:34 Heart Disease Epidemiology

00:59:21 Traditional Populations

01:05:37 PUFA LDL Effects

01:10:32 Minnesota Experiment

01:15:26 Statins & Oxidation

01:19:23 ApoB Types

01:23:59 Diet & PUFAs

01:28:35 Fried Foods Paradox

01:33:14 Key Takeaways

Full AI-generated transcript below. Beware of typos & mistranslations!