Mind & Matter

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315 afleveringen, van nieuw naar oud

1. GDF15, Morning Sickness & Mitochondrial Stress | Stephen O'Rahilly | Episode 311

   3 november 2026 · 1 uur 29 min

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   Dr. Stephen O'Rahilly explains GDF15, a stress hormone that makes us feel sick and eat less, and why morning sickness, and its severe form hyperemesis gravidarum (HG), comes from GDF15 made by the fetus.

   SPONSOR:

   Brain Bean: Smart-roasted coffee with high polyphenol content, ultra-pure grass-fed colostrum, and more. Use code MINDMATTER15 for 15% off.

   TOPICS DISCUSSED:

   • What GDF15 Is: A hormone made by stressed cells, sensed only in two small regions of the brainstem.

   • A Warning Hormone: It rises with toxins, chemotherapy and cellular stress, not with ordinary meals or overfeeding.

   • Rate of Change Matters: The brain tracks how fast GDF15 rises, and chronic exposure desensitizes it.

   • Mitochondria and Mortality: GDF15 helps diagnose mitochondrial disease and predicts mortality.

   • Metformin and GLP-1 Drugs: GDF15 explains metformin's modest weight loss and may overlap with GLP-1 nausea.

   • Morning Sickness and Hyperemesis Gravidarum: The fetus makes nearly all the GDF15; women with low prior GDF15 are most sensitive.

   • Drugs That Raise or Block GDF15: Disappointing weight-loss drugs, and blockers for cachexia and hyperemesis gravidarum.

   • Healthy vs. Unhealthy Fat Storage: Why fat cells largely decide who gets sick with weight gain.

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2. Psilocybin vs. SSRIs for Depression, Emotional Blunting & How Psychedelics Work | Robin Carhart-Harris | 310

   26 oktober 2026 · 1 uur 56 min

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   Robin Carhart-Harris explains why his trial of psilocybin therapy vs. the SSRI escitalopram for depression missed one primary measure but favored psilocybin on almost everything else, and why SSRIs can blunt emotion.

   SPONSOR:

   Brain Bean: Smart-roasted coffee with high polyphenol content, ultra-pure grass-fed colostrum, and more. Use code MINDMATTER15 for 15% off.

   TOPICS DISCUSSED:

   • Consciousness Matters: Why the mind can drive biology, with placebo as the clearest example.
   • Expectancy and Response: How beliefs and the quality of the experience shape outcomes.
   • The Psilocybin vs. Escitalopram Trial: Not significantly different on the primary measure, but ahead on nearly every other outcome.
   • The Blinding Problem: Why double-blind designs barely work here, and the case for open-label trials.
   • Emotional Blunting: SSRIs dampened brain responses to emotional faces; psilocybin did not.
   • Sexual Dysfunction: Worse on the SSRI, improved after psilocybin therapy.
   • What's Next: Metabolic markers, fibromyalgia and a new trial in young adults with depression.

   *Not medical advice.

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3. This Animal Survives 18 Minutes Without Oxygen | Gary Lewin | 309

   12 oktober 2026 · 1 uur 40 min

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   Nick talks with Prof. Gary Lewin (Max Delbrück Center, Berlin) about naked mole-rats, which in lab tests survived 18 minutes in pure nitrogen by shutting down brain activity, keeping the heart beating, and switching to fructose for fuel.

   TOPICS DISCUSSED:

   • From Pain Research to Mole-Rats: The work began when the animals turned out not to feel the burn of capsaicin.

   • Ecology & Eusociality: Colonies with a queen, one breeding male, workers, and soldiers, spread across semi-arid East Africa.

   • Where the Low Oxygen Comes From: Piling into one sleeping chamber, rather than the burrow air itself.

   • 18 Minutes in Pure Nitrogen: In lab tests they pass out, gasp about once a minute, and fully revive.

   • Brain Off, Heart On: Brain activity drops to zero while the heart holds 50 beats per minute.

   • Fructose as Backup Fuel: Fructose transporters in brain and heart let glycolysis keep running without oxygen.

   • Queens, Odor & Longevity: One queen molecule (IPM) suppresses breeding; a queen can live 39 years.

   • Pain, Acid & Navigation: Acid insensitivity, about 80% fewer pain receptors, and navigation by about 90 hairs.

   *Not medical advice.

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4. Low Selenium Doubles Your Heart Attack Risk | Lutz Schomburg | 308

   5 oktober 2026 · 1 uur 44 min

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   Nick talks with Prof. Lutz Schomburg about selenium biology in the endocrine system: selenoprotein P as the liver’s selenium transport protein and status biomarker, autoantibodies that can impair delivery despite normal blood selenium, thyroid autoimmunity (Hashimoto’s and Graves’), diabetes, aging, and what selenium supplementation trials show.

   TOPICS DISCUSSED:

   • Selenoprotein P: Liver-made transport protein that delivers selenium to tissues and serves as a status biomarker beyond total serum selenium.

   • Autoantibodies & Delivery: Anti-SELENOP antibodies can impair selenium delivery even when blood selenium looks normal.

   • Thyroid Autoimmunity: Links between selenium status and Hashimoto’s / Graves’ disease risk and course.

   • Supplementation Trials: What controlled selenium trials do and do not show for thyroid and metabolic outcomes.

   • Diabetes & Aging: How selenium biology intersects with diabetes risk and aging.

   • Practical Context: Interpreting selenium blood tests and why a “normal” result can still miss tissue delivery problems.

   *Not medical advice.

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5. What we're getting WRONG about cane sugar & corn syrup | Kimber Stanhope | 307

   15 september 2026 · 1 uur 52 min

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   Controlled human feeding trials show added fructose raises liver fat, triglycerides, uric acid, and insulin resistance at real-world doses.

   TOPICS DISCUSSED:

   Glucose vs Fructose in the Liver: Glucose and fructose are handled by the liver in distinct ways.

   Natural Sugars vs Processed Sugars: Whole fruit is mostly water, fiber, and micronutrients at modest sugar density; cookies and sodas pack far more sugar per weight and are easier to overconsume.

   HFCS on Store Shelves: Industry cites 55% fructose for beverages, but independent assays of sodas often land higher (around 60% on average, up to ~68%) with no tight standard of identity.

   Sucrose vs HFCS: In head-to-head controlled feeding, matched-calorie sucrose (~50/50) and HFCS (55/45) moved risk factors similarly versus an aspartame control; total dose mattered more than that small ratio gap.

   Dose Response: At roughly 10%, 17.5%, and 25% of energy as HFCS beverages, LDL, triglycerides, apoB, uric acid, liver fat, and insulin sensitivity worsen in a dose-dependent way.

   Fructose vs Glucose Beverages (10 Weeks): Fructose—not matched glucose—raised 24-h uric acid, RBP-4, and other biomarkers in overweight/obese adults.

   Fructose × Glucose Interaction: In some comparisons, HFCS raised LDL/apoB more than fructose alone, consistent with glucose amplifying the lipid signal.

   Orange Juice vs Sucrose Beverage: On a fully provided diet, both raised apoB/LDL/postprandial triglycerides even with slight weight loss; OJ lowered uric acid while sucrose did not.

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6. Why Bigger Brains Get More Mutations | Christopher Walsh | 306

   28 augustus 2026 · 1 uur 45 min

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   How genomics is used to study what makes a human brain, and how genetically damaged neurons get removed.

   TOPICS DISCUSSED:

   Scale & Size: A human brain is about three times a chimpanzee brain by mass, but the larger change is extra association cortex and extra upper-layer circuits that talk mostly to other cortex.

   When Development Ends: Most cortical neurons are born before birth. Myelin and other glia keep forming into the twenties. Synapses keep changing after that.

   Broken Genomes Get Edited: Walsh describes forthcoming work in which ~25–30% of late-fetal cortical neurons carry genetic defects, falling to ~5% by birth, with smaller defects still being removed through adult life.

   Regulation vs. New Genes: Humans and mice both have ~20,000 genes. Most human-specific change is in when and where those genes turn on, not in inventing new proteins.

   Human Accelerated Regions: About half of HARs involve the brain. Rare mutations in them show up more often in kids with intellectual disability and autism.

   ASPM & Microcephaly: Loss of one conserved cell-division gene can shrink a human brain toward chimpanzee volume and shape. The same knockout barely shrinks a mouse.

   Heritability of Genetic Disorders: Autism is highly heritable in twin studies. A whole-genome test today still finds a specific cause in only about a quarter to a third of kids.

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7. Why THC Users Eat More but Don't Gain Weight | Nephi Stella | 305

   20 augustus 2026 · 1 uur 41 min

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   The biology of endogenous cannabinoids & history of cannabinoid-based therapeutics

   TOPICS DISCUSSED:

   Anandamide vs 2-AG: The two major endocannabinoids with a shared arachidonic acid backbone but distinct head groups biological roles.

   On-demand production: Calcium-dependent enzymes release cannabinoids from membranes in response to neuronal activity patterns.

   Trafficking: Fatty acid binding proteins and extracellular microvesicles traffic endocannabinoids within and between cells.

   Adolescent THC: Global receptor activation during circuit wiring may contribute to cannabis use disorder and psychosis vulnerability in susceptible individuals.

   Enzyme inhibitors: Early FAAH clinical trial halted by off-target toxicity; MAGL inhibitors advancing in phase 2 for anxiety and addiction.

   Peripheral CB1: Liver receptors regulate metabolism; restricted antagonists aim to reduce weight without central psychiatric risks of the weight loss drug rimonabant.

   ABOUT THE GUEST: Nephi Stella, PhD is a professor at the University of Washington School of Medicine. He has studied endocannabinoid signaling for more than 25 years, focusing on therapeutic strategies that separate beneficial effects from side effects of cannabinoid-system modulation.

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8. The Gene Variant Linked to Living to 100 | Pinchas Cohen | 304

   12 augustus 2026 · 1 uur 47 min

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   Mitochondrial peptides act as stress signals that regulate metabolism, muscle mass, and neurodegeneration.

   TOPICS DISCUSSED:

   Mitochondria as Communication Hubs: Beyond ATP production, mitochondria encode peptides that regulate cell death, immunity, and inter-organ communication.

   Humanin Discovery: Identified independently by three labs; neuroprotective, longevity-linked, and capable of neutralizing APOE4 effects via a rare Jewish variant.

   Ethnic Genetic Variants: Ancestry-specific mutations in MOTS-c, MENTSH, and SHMOOSE influence diabetes, obesity, sarcopenia, and Alzheimer’s risk.

   MOTS-c & Muscle Preservation: Exercise-induced peptide prevents atrophy and may offset muscle loss seen with GLP-1 drugs.

   Peptide Classes: Fragments of larger proteins, endogenous microproteins from small genes, and emerging AI-designed artificial peptides.

   Diet Modulation: Mediterranean diet adherence raises circulating levels of the peptides humanin and SHMOOSE.

   Clinical Reality Check: Early MOTS-c trials showed metabolic benefits; unregulated products often contain inaccurate doses.

   ABOUT THE GUEST: Pinchas Cohen, MD is Dean of the USC Leonard Davis School of Gerontology and a leading researcher on mitochondrial peptides in aging, metabolism, and neurodegeneration.

   RELATED CONTENT:

   Article | Metabolic Stress & the Peptide MOTS-c: How Much is Too Much?

   Podcast | MOTS-c & Mitochondrial Peptides in Health & Aging | David Lee

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9. Pain, Inflammation, Peptides & Healing | Isaac Chiu | 303

   5 augustus 2026 · 1 uur 45 min

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   How the nervous and immune systems communicate, using peptides and other signals, to regulate pain, itch, and inflammation.

   TOPICS DISCUSSED:

   Nociception & Pathogens: Sensory neurons detect bacterial toxins within seconds, enabling rapid host-defense coordination ahead of immune-cell recruitment.

   CGRP & neutrophils: Nociceptor-release the peptide CGRP, which blocks neutrophil (immune cell) recruitment; pathogens exploit this in necrotizing fasciitis and meningitis.

   Pain sensitization: Inflammation can lower neuronal thresholds for pain, which sometimes becomes a chronic problem.

   Gut barrier protection: CGRP from gut nociceptors drives goblet-cell mucus secretion, supporting the protective “weep and sweep” response.

   Skin-to-gut allergy priming: Early skin exposure to allergens plus scratching may promote food allergies.

   Vagus nerve circuits: Distinct vagal sensory neurons selectively suppress TNF or induce IL-10, allowing precise inflammatory control.

   Brain inflammatory memory: Insular neurons encode site-specific immune responses that can later be recalled by reactivating those circuits. The brain remembers past inflammatory events.

   ABOUT THE GUEST: Isaac Chiu, PhD is a professor in the Department of Immunology at Harvard Medical School. His lab studies nervous-immune system crosstalk in pain, itch, infection, and inflammatory disease.

   RELATED CONTENT:

   Article | Inflammation Regulation by Omega Fats: How High ω-6 Intake Impacts ω-3 Levels

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10. Mitochondrial Peptide That Doubled Running | David Lee | 302

    30 juli 2026 · 1 uur 50 min

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    Mitochondrial peptide MOTS-c is a stress-induced signal that reprograms cell metabolism.

    TOPICS DISCUSSED:

    Mitochondrial Roles: Not just ATP production, but “speaker of the house” via communication molecules that “talk” to the rest of the cell.

    Origin of Communication: Mitochondrial peptides were likely co-opted from ancient antimicrobial factors to synchronize nuclear and mitochondrial genomes.

    MOTC Discovery: Identified in mitochondrial ribosomal RNA regions linked to interferon responses.

    Stress Induction: MOTS-c is produced in response to exercise, immune activation, and nutrient withdrawal; circulates as a mitokine.

    Nuclear Regulation: MOTS-c translocates to the nucleus under stress and acts as a nonspecific cofactor that shapes chromatin accessibility and gene expression.

    Metabolic Effects: Prevents diet-induced obesity and fatty liver in mice without altering baseline weight; engages AMPK and suppresses anabolic pathways.

    Immune Modulation: Shifts immune cell programs to reduce autoimmune attack in type 1 diabetes models.

    Aging Phenotypes: Daily or intermittent dosing doubles running capacity and preserves walking ability in old mice.

    ABOUT THE GUEST: Changhan David Lee, PhD is Associate Professor at the University of Southern California Leonard Davis School of Gerontology. His laboratory investigates mitochondrial communication and microproteins in the biology of aging.

    RELATED CONTENT:

    Article | MOTS-c & Cellular Energy Homeostasis

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11. What we're getting WRONG about copper peptides | Rahi Sarbaziha | 301

    22 juli 2026 · 50 min

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    GHK-Copper and peptides in skin care, aging, and general health.

    TOPICS DISCUSSED:

    Endogenous Decline: GHK-copper levels peak in young adulthood then fall with age, reducing natural support for skin repair and collagen maintenance.

    Skin Penetration: Effective topical delivery depends on molecular size under and fat solubility, often improved by procedures such as microneedling that briefly disrupt the barrier.

    Mechanisms of Action: The peptide upregulates fibroblasts and vascular endothelial growth factor, stimulates glycosaminoglycan production, and alters expression of genes involved in tissue regeneration and oxidative stress reduction.

    Lasting Remodeling: Gene expression changes produce sustained collagen rebuilding that develops over weeks to months rather than delivering only transient effects.

    Administration Routes: Topical use is accessible and pairs well with hyaluronic acid for hydration; injectables may reach higher local concentrations but lack extensive human trial data and FDA approval for this purpose.

    Safety & Protocols: The compound is generally well tolerated with mild transient injection-site reactions; typical approaches use daily microgram doses for one to two months followed by off periods.

    Hair & Other Uses: Clinical observations indicate potential for hair shaft strengthening comparable to minoxidil with a favorable side-effect profile, alongside exploratory work in wound healing and neurological contexts.

    Research Needs: Expanded human studies are required to standardize dosing, confirm long-term safety, and evaluate value in neurodegeneration, lung repair, and related areas.

    ABOUT THE GUEST: Rahi Sarbaziha, MD is a physician in Beverly Hills, California whose practice focuses on regenerative aesthetics, hormone therapies, peptides, and interventions that support vitality, tissue repair, and overall wellness.

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12. What we're getting WRONG about the "leaky" aging brain | William Banks | 300

    15 juli 2026 · 1 uur 45 min

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    Blood-brain barrier as a dynamic interface allowing selective passage of nutrients, peptides, and gut hormones.

    TOPICS DISCUSSED:

    Blood-Brain Barrier Structure: Capillary endothelial cells with tight junctions, absent fenestrae, and minimal vesicles create a selective interface; supported by astrocytes and pericytes.

    Crossing Mechanisms: Lipid-soluble small molecules diffuse passively; glucose, amino acids, and regulatory peptides use saturable transporters whose rates vary by need.

    Peptide Transport: Many peptides cross via lipid solubility or specific transporters; rate, not all-or-none presence, determines biological relevance; efflux systems remove some (e.g. certain enkephalins).

    Dynamic Regulation: Transporters for leptin and insulin are modulated by epinephrine, triglycerides, and brain demand; changes occur in aging and Alzheimer’s (reduced glucose uptake, impaired Aβ efflux).

    Circumventricular Organs: Leaky capillary regions allow rapid sampling of blood signals while tanycytes limit spread to surrounding brain tissue.

    Drug Delivery Challenges: Small lipid-soluble drugs, barrier disruption (e.g. focused ultrasound), and “Trojan-horse” strategies each have limitations; intranasal delivery shows rapid brain distribution.

    Peptides & Brain Effects: Gut peptides like GLP-1 analogs, insulin, and ghrelin influence cognition and memory; brain entry predicts central effects.

    GUEST: William Banks, MD is a physician-scientist and leading researcher on the blood-brain barrier. He has focused on humoral brain-body communication, peptide transport, and the barrier’s role in health and disease.

    RELATED CONTENT:

    M&M 298 | GLP-1s & Novel Peptides in Obesity, Diabetes & Metabolic Health | Katrin Svensson

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13. Too Much Iron and the Aging Brain | Dr. Pamela Maher | 299

    8 juli 2026 · 1 uur 43 min

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    Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation; chronoferoptosis, in which chronic stress sensitizes neurons gradually.

    TOPICS DISCUSSED:

    Cell Death Pathways: Apoptosis proceeds through regulated steps with surface “eat me” signals that enable non-inflammatory clearance by phagocytes, whereas ferroptosis and related pathways release cellular contents that can amplify local damage and inflammation.

    Ferroptosis Discovery: Work on glutamate toxicity in neuronal cell lines first identified a glutathione-depletion pathway termed oxytosis; parallel studies in cancer cells renamed and generalized it as ferroptosis to highlight iron’s catalytic role.

    Lipid Peroxidation: Polyunsaturated fatty acids in membranes are oxidized non-enzymatically when ferrous iron reacts with hydrogen peroxide in the Fenton reaction, generating hydroxyl radicals that produce toxic lipid peroxides and reactive carbonyls that modify proteins.

    GPX4 & Glutathione: Glutathione peroxidase-4 is an enzyme that reduces lipid peroxides within membranes and requires glutathione as cofactor; depletion of either component removes this critical line of defense.

    Chronoferoptosis: Nine-day treatment of differentiated neuronal cells with chronic iron or glutathione synthesis inhibitor reduced GPX4 protein, raised basal lipid peroxidation, and increased cell death after addition of otherwise sublethal secondary stressors.

    Protective Compounds: Screening identified flavonoids such as fisetin and sterubin plus synthetic molecules J-147 and CMS-121 that block lipid peroxidation directly or indirectly and, in several cases, also raise glutathione levels.

    Human Disease Evidence: Postmortem brain tissue from Alzheimer’s and Parkinson’s patients shows elevated lipid peroxidation markers and altered iron handling in vulnerable regions; similar changes appear in animal models of multiple diseases.

    Dietary & NRF2 Links: Compounds that activate the NRF2 transcriptio…

14. Ozempic Reaches Your Brain in Ways Your Own GLP-1 Can't | Katrin Svensson | 298

    30 juni 2026 · 1 uur 35 min

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    Endogenous peptide diversity, GLP-1 drugs, and methods for novel peptide discovery.

    TOPICS DISCUSSED:

    Peptide Structure & Production: Short amino acid chains (3-50 residues) cleaved from larger precursors by PCSK enzymes, stored in dense-core vesicles, and released upon stimuli rather than acting as folded enzymes like proteins.

    Tissue-Specific Processing: The same precursor yields different peptides by tissue; preproglucagon produces glucagon in pancreas but GLP-1 in gut L-cells due to distinct cleavage patterns.

    Signaling Timescales: Peptides act over minutes via GPCRs and can drive longer transcriptional changes such as FOS expression, yet are cleared rapidly by proteases and kidneys.

    Endogenous GLP-1: Meal-stimulated incretin from gut that boosts insulin secretion with a half-life of only minutes, limiting primary action to periphery rather than deep brain structures.

    GLP-1 Engineering for Brain Access: DPP4 site mutations plus lipid conjugation enable albumin binding, extend half-life, and raise brain exposure.

    Dose-Dependent Effects: Low GLP-1 doses mainly lower blood glucose via pancreas; higher doses engage hindbrain and hypothalamic neurons to suppress appetite and alter food preference.

    Novel Peptide Discovery: Computational scans across the genome flag hundreds of uncharacterized precursors, facilitating new peptide discovery.

    BRP Peptide: This newly discovered brain-derived peptide suppresses feeding in GLP-1 receptor knockout mice, activates non-overlapping neurons, and does not slow gastric emptying.

    ABOUT THE GUEST: Katrin Svensson, PhD, is a biochemist and physiologist who leads a laboratory at Stanford University focused on peptide hormone physiology and the regulation of energy balance.

    PRACTICAL TAKEAWAYS:

    GLP-1 drugs require higher doses to engage brain satiety circuits for meaningful weight loss; lower doses primarily improve glucose control with little effect on appetite.

    Response varies widely across individuals…

15. Can Water Low in Deuterium Slow Cancer? | Gábor Somlyai | 297

    18 juni 2026 · 1 uur 33 min

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    The possible role of deuterium (heavy isotope of hydrogen) in regulating cell division, mitochondrial metabolism & cancer.

    TOPICS DISCUSSED:

    Deuterium Basics: Deuterium is twice as massive as regular hydrogen; natural water contains ~150 ppm, with stronger oxygen-deuterium bonds slowing reactions compared to oxygen-hydrogen.

    Mitochondrial Role: Healthy mitochondria produce deuterium-depleted metabolic water (~110 ppm from fat oxidation vs. ~150 ppm from carbs), helping maintain low cellular D:H ratios.

    Cell Growth Regulation: Lower deuterium slows cell division in vitro; cells sense small D:H changes, with higher levels (near/above 150 ppm) promoting growth.

    In Vitro Evidence: DDW (e.g., 25-125 ppm) can reduce proliferation and alters cancer-related gene expression.

    Animal Models: DDW caused tumor regression in mice with transplanted human cancers and showed possible efficacy in veterinary use for dogs and cats.

    Human Prostate Cancer: Phase 2 randomized study showed greater Prostate-Specific Antigen (PSA) reduction, tumor shrinkage, and better 1-year survival with DDW plus standard therapy vs. placebo.

    Dietary Modulation: Ketogenic/high-fat diets lower body deuterium from lipid oxidation.

    Broader Implications: Potential in neurodegeneration models; larger trials needed for registration as adjunct cancer therapy.

    ABOUT THE GUEST: Gábor Somlyai, PhD is a molecular biologist who pioneered deuterium depletion studies at the National Institute of Oncology in Hungary. His primary work focuses on the role of deuterium in living organisms and the development of deuterium-depleted water for cancer therapy.

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16. Antioxidant Supplements Raised Cancer Rates in Major Trials. Here's Why | Isaac Harris | 296

    11 juni 2026 · 57 min

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    New research finds that excess antioxidants can support tumor growth in preexisting cancers.

    TOPICS DISCUSSED:

    Oxidative Stress: Reactive oxygen species (ROS) generated by mitochondrial metabolism cause damage; context determines whether they promote or suppress cancer.

    Glutathione Biology: Primary cellular antioxidant made from cysteine, glycine, and glutamate; works with peroxidase enzymes to protect against ROS.

    Antioxidant Paradox: Clinical trials (SELECT vitamin E, beta-carotene) showed supplements increased cancer rather than preventing it.

    Cancer Antioxidant Hijacking: Tumors ramp up antioxidant systems to handle high metabolic rates and survive stress including metastasis.

    Extracellular Glutathione Catabolism: Cancer cells break down external glutathione into amino acids, particularly cysteine, to fuel growth (new findings).

    Therapeutic Window: Blocking glutathione breakdown slows tumors in models while sparing normal cells.

    Diet vs Supplements: Balanced diets support glutathione needs; excess isolated antioxidants may enrich the tumor microenvironment.

    ABOUT THE GUEST: Isaac Harris, PhD is a biologist working on the role of antioxidants in health, disease, and cancer metabolism.

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17. Your Body Makes Fructose From Glucose, and It Turns On Fat Storage | Richard Johnson | 295

    4 juni 2026 · 1 uur 36 min

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    Fructose survival hypothesis: how fructose metabolism in the liver triggers ATP depletion, uric acid production, oxidative stress, lipogenesis & leptin resistance.

    TOPICS DISCUSSED:

    Glucose vs Fructose Metabolism: Fructose is rapidly metabolized in the liver by fructokinase without feedback, causing ATP depletion and uric acid production, unlike glucose metabolism.

    Liver Effects: Fructose induces uric acid production, NADPH oxidase activation, mitochondrial oxidative stress, and de novo lipogenesis even under caloric restriction.

    Fructose Survival Hypothesis: Fructose signaling promotes fat storage, leptin resistance, foraging behavior, and metabolic syndrome as adaptations for hibernation or starvation, including metabolic water production.

    Brain Impacts: Endogenous fructose production from glucose (polyol pathway) triggered by high glucose, salt, or stress leads to insulin resistance, mitochondrial damage, and neuroinflammation in Alzheimer’s-vulnerable regions.

    Evolutionary Context: Human uricase mutation ~12 million years ago enhanced fructose effects for fat storage during seasonal starvation but increases vulnerability today.

    Modern Triggers: Added sugars, high fructose corn syrup, salt-sugar combinations, and omega-6 fats synergize with fructose to amplify inflammation, appetite, and disease risk.

    Alzheimer’s Link: Fructose-driven brain changes mirror Alzheimer’s pathology, with high brain fructose in patients and potential for fructokinase inhibitors as therapy.

    ABOUT THE GUEST: Richard Johnson MD, is a professor of medicine who has conducted clinical practice and NIH-funded research on sugar metabolism since the late 1990s. His work focuses on the role of fructose in metabolic syndrome, obesity, and related diseases.

    RELATED CONTENT:

    Article | Dietary Fructose & Metabolic Health: An Evolutionary Perspective

    M&M 249: Fructose, Microglia, Anxiety & Brain Development | Justin Perry | 249

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18. How to Lie With Science: Seed Oils & Inflammation | Livestream #1

    27 mei 2026 · 1 uur 13 min

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    Deep-dive into a 2026 cardiology review paper claiming seed oils reduce inflammation, exposing misrepresentations of cited clinical trials, and detailing how oxidized Ω-6 fats trigger inflammation.

    Companion article: Click HERE

    TOPICS DISCUSSED:

    Seed Oil Profiles: Typical seed oils like sunflower are high in linoleic acid (omega-6 PUFA), while canola is higher in monounsaturated fats and resembles olive oil.

    Review Paper Critique: The 2026 JACC review falsely claims sunflower oil reduce inflammation like olive oil, citing an RCT that showed benefits only for canola and olive.

    RCT Analysis: In Iranian women with metabolic issues, switching to canola or olive oil lowered CRP by increasing MUFA and decreasing PUFA intake; sunflower oil produced no change.

    CRP Biology: CRP responds to oxidized lipids and cellular damage patterns, rising with exercise or infection and marking oxidized Ω-6 metabolites in modern diets.

    Oxidized Lipids: Ω-6 fats in LDL and cardiolipin oxidize easily, generating 4-HNE, MDA, and other signals that trigger immune clearance, similar to bacterial threats.

    Sterile Inflammation: High dietary linoleic acid causes chronic immune activation without pathogens, potentially contributing to metabolic and cardiovascular issues.

    PRACTICAL TAKEAWAYS:

    Prioritize monounsaturated fats from olive or avocado oil over high-linoleic seed oils like standard sunflower or soybean for lower oxidative stress potential.

    Check labels for high-oleic versions of sunflower oil, which shift the profile toward monounsaturated fats.

    Evaluate nutrition claims by examining original studies and fatty acid compositions rather than accepting review summaries at face value.

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19. Your Ancestry Changes How Your Body Handles Omega-3 and Omega-6 Fats | Floyd Chilton | 294

    22 mei 2026 · 1 uur 52 min

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    Human genetic variation in dietary fat metabolism and its implications for health & disease.

    TOPICS DISCUSSED:

    Linoleic Acid Rise: Linoleic acid now comprises 6-8% or more of energy in Western diets.

    Metabolic Pathways: Omega-6 linoleic acid converts to arachidonic acid and pro-inflammatory oxylipins; omega-3 ALA converts via shared enzymes to EPA/DHA with anti-inflammatory effects.

    FADS Genetic Variants: Ancestry-linked haplotypes in the FADS cluster create large “pipe” size differences, altering fatty acid by up to 40% between ancestral and derived versions.

    Population Differences: African ancestry populations often have high-conversion “big pipe” genotypes; Indigenous American ancestry populations have low-conversion “small pipe” genotypes; European ancestry comes with a mix of both.

    Omega-3 Deficiency: High linoleic intake suppresses EPA production, especially in small-pipe populations, contributing to hypertriglyceridemia and fatty liver in Mexican cohorts.

    Clinical Evidence: Reanalysis of VITAL trial showed 83% reduction in myocardial infarction with omega-3 supplementation in African Americans; Mexican data link low EPA to unique diabetes forms.

    Methodological Issues: Compositional data (from GC-FID measurements) versus absolute concentration measurements can flip relationships between linoleic acid and key biomarkers.

    ABOUT THE GUEST: Floyd Chilton PhD is Professor and Director of the Center for Precision Nutrition and Wellness at the University of Arizona. His research focuses on functional genomics, fatty acid metabolism, and precision nutrition, particularly how genetic ancestry influences responses to dietary fats.

    RELATED EPISODE:

    M&M 291: Omega Polyunsaturated Fats & Inflammation | Philip Calder

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20. A Brain Steroid Showed Antidepressant Effects in Bipolar Disorder | Sherwood Brown | 293

    15 mei 2026 · 1 uur 2 min

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    Pregnenolone, a neurosteroid derived from cholesterol, affects brain activity and shows promise for treating mood and substance abuse disorders.

    TOPICS DISCUSSED:

    Steroid Biosynthesis: Cholesterol converted to pregnenolone, the precursor for all steroid hormones including cortisol, aldosterone, and sex hormones.

    Corticosteroids: Synthetic versions like prednisone primarily target glucocorticoid receptors for anti-inflammatory uses but can impact mood and cognition.

    Pregnenolone Mechanisms: Positive allosteric modulator of NMDA receptors for cognition and negative allosteric modulator of CB1 cannabinoid receptors.

    Allopregnanolone: GABAergic derivative of pregnenolone; its IV form Brexanolone is FDA-approved for postpartum depression.

    Clinical Trials: Pregnenolone at 100-500 mg improved depressive symptoms in placebo-controlled studies of bipolar disorder patients.

    Cannabis Interaction: THC robustly induces brain pregnenolone production; supplementation may reduce cannabis and alcohol use.

    Corticosteroid Brain Impact: Prednisone use associated with smaller hippocampal volumes and memory deficits.

    ABOUT THE GUEST: Sherwood Brown, MD, PhD is Vice Chair for Clinical Research in the Department of Psychiatry at the University of Texas Southwestern Medical Center in Dallas. With a background in chemistry, his research focuses on steroids and comorbidities in people with mood disorders.

    RELATED EPISODE:

    M&M 124: Hormonal Contraception, Sex Hormones, Menstruation, Pregnancy, Puberty, Estrogens, Androgens, Effects of Birth Control on Cognition | Adriene Beltz

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21. Most Americans Fall Far Below the Omega-3 Levels Linked to Better Health | Bill Harris | 292

    8 mei 2026 · 1 uur 46 min

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    How omega-3 fats in human health, including dietary intake needs, supplements, & omega fat testing.

    TOPICS DISCUSSED:

    ω-3 chemistry: EPA and DHA differ from plant ALA in chain length and double-bond count, making them structurally and biologically distinct — and largely irreplaceable by ALA conversion.

    ALA-to-EPA/DHA conversion: A small percentage of dietary ALA converts to EPA, and conversion to DHA is even lower; vegans rely on this inefficient pathway for all long-chain omega-3s.

    Cardiovascular mechanisms: ω-3s lower triglycerides, reduce platelet stickiness, improve endothelial function, and slow resting heart rate, reducing cardiovascular risk.

    ω-3 Index: Defined as red blood cell EPA+DHA as a percent of total fatty acids; 8–12% is the target range, while most Americans sit around 4–5%.

    Brain & dementia risk: Higher DHA blood levels are associated with significantly lower risk of dementia and Alzheimer’s in large cohorts including the UK Biobank and Framingham.

    Linoleic acid nuance: Higher blood levels of dietary linoleic acid (omega-6) associate with lower dementia and cardiovascular risk; downstream omega-6 metabolites — not linoleic acid itself — associate with adverse outcomes.

    Supplementation practicalities: Most people need 1–2 g/day of EPA+DHA to reach an ω-3 Index >8%; oxidation concerns with fish oil supplements may be overstated.

    ABOUT THE GUEST: Bill Harris, PhD is founder of both OmegaQuant Laboratory and the Fatty Acid Research Institute (Sioux Falls, SD), where his work centers on blood fatty acid biomarkers as predictors of disease risk in large population cohort studies.

    KNOW YOURSELF:

    OmegaQuant: At-home blood testing to see fatty acid profiles, including omega-3 fatty acids. Use link to see options and support M&M.

    RELATED EPISODE:

    M&M 134: Omega Fats, Vegetable & Seed Oils, Sugar, Processed Food, Metabolic Health & Dietary Origins of Chronic Inflammatory Disease | Artemis Simopoulos

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22. Inflammation Doesn't Just Fade. Omega-3s Help Your Body Switch It Off | Philip Calder | 291

    1 mei 2026 · 1 uur 55 min

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    How dietary fatty acids regulate the initiation, propagation, and resolution of inflammation.

    TOPICS DISCUSSED:

    Parenteral nutrition history: IV nutrition evolved from soybean oil alone in the 1960s to complex blends including fish oil as the biology of ω-3s became understood.

    Three phases of inflammation: Initiation, propagation (driven by ω-6–derived prostaglandins and leukotrienes), and active resolution (driven by ω-3-derived resolvins and protectins).

    Pro-resolving mediators: Resolution is an active biological process, not passive; EPA and DHA generate resolvins and protectins that actively terminate inflammation.

    Aspirin’s ω-3 mechanism: Aspirin inhibits arachidonic acid metabolism but allows EPA/DHA to access COX-2, upregulating pro-resolution mediators — a likely underappreciated mechanism of action.

    Cell membrane competition: EPA and DHA physically displace arachidonic acid in membranes, shifting the balance of mediators produced and improving resolution capacity.

    Linoleic acid & EPA synthesis: High linoleic acid intake saturates shared desaturase enzymes, inhibiting the body’s conversion of ALA to EPA — meaning reducing ω-6 can raise ω-3 levels without supplementation.

    Dose & timing of ω-3 incorporation: ~2g/day of EPA+DHA shifts the arachidonic acid-to-EPA ratio enough to measurably reduce prostaglandin E2 production; white blood cells reflect changes within a month.

    ABOUT THE GUEST: Philip Calder, PhD is Professor of Nutritional Immunology in the Faculty of Medicine at the University of Southampton. His research focuses on how dietary fatty acids — particularly omega-3s — modulate immune responses and inflammatory processes across clinical and healthy populations.

    RELATED EPISODE:

    M&M 200: Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade

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23. Reversing Alzheimer's Memory Loss in Mice Without Clearing Plaques | Andrew Pieper | 290

    24 april 2026 · 1 uur 24 min

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    A metabolic view of Alzheimer's disease & the recent discovery of compounds that reverse advanced disease symptoms in mouse models by restoring mitochondrial health.

    TOPICS DISCUSSED:

    Classic Alzheimer’s pathology: amyloid plaques and tau tangles identified over 120 years ago, long assumed to drive irreversible neuron loss.

    Limitations of amyloid focus: plaques appear in some cognitively normal brains; antibody therapies have shown limited clinical benefit.

    Metabolic perspective: brain energy failure as a tipping point where repair mechanisms are overwhelmed, linking genetics, injury, and aging.

    Neuroprotection via P7C3 compounds: discovered through hippocampal neurogenesis screen; preserves mitochondrial function and normalizes NAD/NADH ratio without elevating NAD excessively.

    Recovery in models: treatment after symptom onset reversed cognitive deficits, blood-brain barrier damage, oxidative stress, and axon issues in amyloid and tau mouse models, despite persistent plaques.

    Broader implications: energy restoration enables surviving neurons to function; similar protective effects seen in TBI and other organs under stress.

    ABOUT THE GUEST: Andrew Pieper, MD, PhD, is a board-certified psychiatrist and neuroscientist, professor at Case Western Reserve University, and director of the Brain Health Medicines Center at the Harrington Discovery Institute. He directs a research group focused on neuroprotection after brain injury and neurodegenerative disease.

    RELATED EPISODE:

    M&M 208: Glyphosate, Choline & Alzheimer’s: Toxins & Nutrition to Prevent Neurodegeneration | Ramon Velazquez

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24. Parents' Exercise Improves Offspring Metabolism via Sperm and Milk | Kristin Stanford | 289

    17 april 2026 · 51 min

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    How exercise in parents can improve the metabolic and cardiovascular health of their offspring through epigenetic mechanisms.

    TOPICS DISCUSSED:

    Parental exercise & offspring metabolic health: exercise before and during pregnancy improves glucose tolerance and reduces fat gain in offspring.

    Paternal effects via sperm: moderate voluntary wheel running alters small non-coding RNAs, especially tRNA fragments, in sperm and enhances glucose clearance, with stronger benefits in female offspring.

    Maternal exercise mechanisms: benefits arise from in utero environment, placental changes, and breast milk composition rather than major oocyte alterations.

    Human milk oligosaccharides: exercise increases 3’-sialyllactose in milk, linked to better offspring microbiome and metabolic outcomes.

    Sex-biased & intergenerational effects: maternal exercise impacts male offspring metabolism more; effects can transmit to F2 generation depending on the transmitting parent’s sex.

    ABOUT THE GUEST: Kristin Stanford, PhD is an associate professor in the Department of Physiology and Cell Biology at The Ohio State University Wexner Medical Center, where she serves as associate director of the Diabetes and Metabolism Research Center. Her lab investigates molecular mechanisms by which exercise enhances metabolic and cardiovascular health, with a focus on intergenerational effects.

    RELATED EPISODE:

    M&M 145: Epigenetics, Endocrine Disruptors, Obesogens & Obesity, Inheritance of Acquired Characteristics | Bruce Blumberg

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25. Your Vagus Nerve Can Switch Off Inflammation | Kevin Tracey | 288

    10 april 2026 · 2 uur

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    How the vagus nerve regulates inflammation; bioelectronic therapies to treat inflammatory conditions.

    Nick speaks with Dr. Kevin Tracey about inflammation as a major driver of modern diseases, the vagus nerve’s role in balancing immune responses via reflexes, limitations of anti-cytokine drugs, and emerging bioelectronic medicine using targeted nerve stimulation.

    TOPICS DISCUSSED:

    Inflammation is related to diseases that contribute to most deaths today: heart disease, diabetes, neurodegeneration, and cancer.

    Molecular signals involved in inflammation, such as cytokines.

    Homeostasis is maintained by push-pull mechanisms, with excitatory and inhibitory responses co-deployed in ways that maintains balance.

    The vagus nerve’s anatomy, sensory/motor fibers, and the inflammatory reflex that suppresses cytokine production in the spleen via acetylcholine and norepinephrine.

    Vagus nerve stimulation devices delivering brief daily pulses to reduce inflammation without broad immunosuppression, now FDA-approved for refractory rheumatoid arthritis.

    Challenges in measuring inflammation and oversimplifications online about “stimulating” the vagus nerve.

    ABOUT THE GUEST: Kevin Tracey, MD is a neurosurgeon, president and CEO of the Feinstein Institutes for Medical Research at Northwell Health, and professor of molecular medicine and neurosurgery. He discovered the inflammatory reflex, showing how the vagus nerve controls immune responses, and co-founded SetPoint Medical to develop FDA-approved vagus nerve stimulation for rheumatoid arthritis.

    RELATED EPISODE:

    M&M 143: Gut-Brain Communication, Vagus Nerve, Fats & Sugars, Food Addiction, Gut Hormones & Weight Loss Drugs | Will de Lartigue

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26. Sunlight Curbs Appetite Through a Hormone Unrelated to Vitamin D | Alexis Cowan | 287

    3 april 2026 · 1 uur 51 min

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    How light regulate circadian rhythms, mitochondrial function, hormones, and appetite.

    Nick & Dr. Alexis Cowan discuss non-image-forming effects of light on the body, from melanopsin-driven circadian signaling in the eye to UV-stimulated pathways in skin and brain that influence melatonin, cortisol, melanin production, and energy balance.

    TOPICS DISCUSSED:

    Melanopsin & non-image-forming light: blue light signals daytime to the SCN master clock, suppressing melatonin and promoting alertness.

    UV light, POMC & peptide hormones: UVB exposure in skin and hypothalamus produces alpha-MSH (reduces appetite, boosts energy expenditure) and beta-endorphin (improves mood), independent of vitamin D.

    Mitochondrial effects of light: red/infrared supports function like a gas pedal; isolated blue light acts as brakes, impairing energy production and biophoton signaling.

    Artificial light: Evening blue light from screens inhibits melatonin, poisons mitochondria, and creates discordant timing signals versus balanced natural sunlight.

    Melanin beyond skin: produced via UVB, it harnesses energy, buffers oxidative stress, and links to dopamine pathways; low sun exposure ties to metabolic issues and conditions like Parkinson’s.

    Vitamin D as biomarker: supplementation shows limited benefits because it reflects broader UVB-driven processes, not a standalone fix.

    ABOUT THE GUEST: Alexis Cowan, PhD earned her PhD in molecular biology at Princeton in the Rabinowitz lab, a leading metabolism research group, where she studied fasting, ketogenic diets, and exercise; she completed a postdoc at UPenn before shifting focus to circadian and quantum biology. She now educates on light, mitochondria, and quantum biology.

    RELATED EPISODE:

    M&M 221: Regenerative Energy & the Light Inside You | Jack Kruse

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27. Being Awake Damages Brain Fats, and Sleep Clears Them Out | Amita Sehgal | 286

    29 maart 2026 · 1 uur 9 min

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    Is the fundamental purpose of sleep to remove oxidized fats from the brain?

    Nick & Dr. Amita Sehgal talk about the latest science on why animals sleep. Using fruit flies, her lab shows that waking generates oxidized lipids in neurons that are shuttled to glia and then cleared by macrophage-like cells during sleep. This process protects mitochondria, supports memory, and links sleep to metabolic cleanup rather than just rest.

    TOPICS DISCUSSED:

    Drosophila as a model: Fruit flies sleep with immobility, reduced responsiveness, and homeostatic rebound; their genetics reveal conserved mechanisms found in humans.

    Circadian vs homeostatic sleep: Circadian timing sets when we sleep; homeostatic drive builds need from prolonged wakefulness independent of time of day.

    Metabolic waste during wake: Neuronal activity oxidizes lipids in mitochondria; these damaged lipids transfer to glial support cells via apolipoproteins.

    Immune cells clear brain trash: Macrophage-like hemocytes dock at the brain during sleep, phagocytose oxidized lipids, and remove them; blocking this docking reduces sleep and impairs memory.

    Peroxisomes & oxidative stress: These organelles handle specific fats and rise with wakefulness; disrupting them increases brain oxidation that can be partially rescued by antioxidants like N-acetylcysteine.

    Sickness sleep differs from normal sleep: Infection-induced sleep redirects energy to immune defense and depletes rather than restores brain energy stores.

    ABOUT THE GUEST: Amita Sehgal, PhD is the John Herr Musser Professor of Neuroscience at the University of Pennsylvania, an HHMI Investigator, and director of the Chronobiology and Sleep Institute. She uses Drosophila genetics to uncover basic mechanisms of circadian rhythms and sleep.

    RELATED EPISODE:

    M&M 257: Sleep, Mitochondrial Metabolism & Oxidative Stress | Gero Miesenbock

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28. BPC-157 Heals Rats but Has Barely Been Tested in Humans | Flynn McGuire | 285

    22 maart 2026 · 1 uur 6 min

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    The science, hype, and unknowns surrounding popular peptides like BPC-157 & TB-500 ("Wolverine stack") for injury recovery & tissue repair.

    Nick & Dr. Flynn McGuire discuss the surge in peptide use for injury recovery. They cover peptide basics, the preclinical evidence for BPC-157 and TB-500, mechanisms like angiogenesis and tissue repair, the lack of robust human trials, sourcing risks, regulatory bans, and the gap between anecdotal reports and scientific certainty.

    TOPICS DISCUSSED:

    Peptide basics: Short amino acid chains (e.g., insulin, GLP-1 agonists); BPC-157 derived from gastric juice, TB-500 a fragment of thymosin beta-4.

    Rise in popularity: Driven by podcasts, social media, biohacking culture, and post-COVID distrust in institutions; “bro science” often precedes formal research.

    BPC-157 mechanisms: Pleiotropic effects including VEGF upregulation, nitric oxide pathways, angiogenesis, reduced fibrosis, and possible neuromuscular stabilization.

    TB-500 & “stacking”: Often combined with BPC-157 for presumed synergy; marketed as “Wolverine stack” for rapid healing.

    Evidence limitations: Strong rodent data for tendon/muscle repair, but almost no high-quality human trials; one small retrospective study and ongoing phase 2 trial in China.

    Safety and risks: Unknown long-term effects, potential cancer concerns via angiogenesis; no established dosing, potency, or administration route in humans.

    Sourcing & quality issues: Often obtained as “research chemicals” online; variable purity, stability concerns, no reliable regulation or third-party verification for most users.

    ABOUT THE GUEST: Flynn Mcguire, MD is a physical medicine and rehabilitation resident at the University of Utah; he conducts clinical work in neurologic recovery and musculoskeletal care and has authored a narrative reviews on peptides for musculoskeletal healing.

    RELATED EPISODE:

    M&M 252: Scarring, Fibrosis, Oxidative Stress, and Psilocybin & Aging | Louise Hecker

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29. Why Some People Stay Thin Even When They Overeat | Jens Lund | 284

    13 maart 2026 · 1 uur

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    Biology of obesity resistance and factors influencing weight gain in humans and animals.

    TOPICS DISCUSSED:

    Historical views on obesity: In some cultures, like northern Africa or Stone Age societies, high body fat signaled status or attractiveness due to food scarcity, unlike today’s focus on leanness amid calorie abundance.

    Energy balance components: Metabolizable energy (95% absorption on average, but varying 1-11%) and unabsorbed nutrients excreted as waste significantly influence weight.

    Obesity resistance in animals: Inbred mouse strains show wide variation in weight gain on high-fat diets, often somewhat uncoupled from overeating, suggesting roles for feed efficiency, energy expenditure, or waste rather than intake alone.

    Genetic & twin studies: Monozygotic twins overfed 1,000 extra calories daily vary widely in weight gain (4-13 kg), indicating genetic influences, while mouse litter size affects lifelong obesity propensity via early-life programming.

    Bloodborne factors & hormones: Parabiosis studies led to leptin’s discovery for defending against weight loss, but evolutionary logic suggests systems also prevent excess gain, though modern environments may weaken this.

    Human thinness research: Constitutionally thin people snack more, move less, yet have better cardiometabolic health, but we don’t yet understand why.

    GLP-1 drugs & future directions: These slow gut transit and suppress appetite, but obesity’s root causes remain unclear; emerging thinness studies could inform prevention beyond drugs.

    ABOUT THE GUEST: Jens Lund, PhD is a postdoctoral researcher at the University of Copenhagen’s Novo Nordisk Foundation Center for Basic Metabolic Research.

    RELATED EPISODE:

    M&M 132 | Obesity Epidemic, Diet, Metabolism, Saturated Fat vs. PUFAs, Energy Expenditure, Weight Gain & Feeding Behavior | John Speakman

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30. Your Mother's Mitochondrial DNA Shapes Metabolism and Disease Risk | Douglas Wallace | 283

    5 maart 2026 · 1 uur 42 min

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    Mitochondria in human evolution, climate adaptation, maternal genetics, aging, and disease.

    TOPICS DISCUSSED:

    Endosymbiotic theory: Mitochondria arose from oxidative bacteria engulfed by archaea-like hosts, confirmed by phylogenetic analysis.

    Maternal mtDNA inheritance: Mitochondrial DNA is inherited from the mother, not the father. There are adaptive reasons for this.

    Haplogroups & adaptation: Tropical lineages tightly couple energy production for efficiency; northern ones uncouple to generate heat.

    Heteroplasmy & aging: Mixed mutant and normal mitochondria accumulate in cells, eroding energy in high-demand tissues like brain and heart.

    Bioenergetics in disease: Many common conditions, from Parkinson’s to cancer, stem from mitochondrial-nuclear interactions rather than nuclear genes alone.

    Ketogenic diets: High-fat intake fuels mitochondrial beta-oxidation, which may compensate for brain energy deficits in epilepsy and bipolar disorder.

    Warburg effect: Cancer cells shift to glycolysis to prioritize biosynthetic building blocks over maximal ATP production.

    Modern mismatches: Global travel pairs ancestral mtDNA with mismatched diets and climates, raising risks for metabolic dysfunction.

    ABOUT THE GUEST: Douglas Wallace, PhD is a geneticist and evolutionary biologist who has studied mitochondria for over 50 years. He currently directs the Center for Mitochondrial and Epigenomic Medicine at Children’s Hospital of Philadelphia and the University of Pennsylvania.

    RELATED EPISODE:

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

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31. Half Your Cholesterol Exits as Bile Acids, and Diabetes Alters Them | Rebecca Haeusler | 282

    28 februari 2026 · 53 min

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    Role of bile acids in cholesterol regulation, digestion & metabolic diseases like diabetes.

    TOPICS DISCUSSED:

    Bile acids basics: They enable cholesterol excretion, with about half of bodily cholesterol eliminated this way, and also aid digestion by emulsifying fats to increase enzyme access.

    Bile production & pathway: Synthesized in liver hepatocytes, bile flows via ducts to the gallbladder for storage or directly to the small intestine; post-meal, cholecystokinin triggers gallbladder contraction for fat emulsification.

    Regulation of bile acids: Self-regulated to prevent cytotoxicity, as excess can damage cell membranes; insulin and bile acids themselves influence synthesis and transport, with defects in insulin-resistant states.

    Bile acids in metabolic diseases: Increased synthesis, especially 12-hydroxylated types, occurs in type 2 diabetes and insulin resistance, potentially as an adaptation for better nutrient absorption during perceived scarcity.

    Gallbladder removal & gallstones: Common due to cholesterol supersaturation forming stones; removal eliminates concentration but preserves bile flow, reducing tolerance for high-fat meals.

    Bariatric surgery impacts: Procedures like gastric bypass increase circulating bile acids without major synthesis changes, while more extreme ones boost synthesis due to impaired intestinal sensing.

    Cholesterol homeostasis: Cells tightly regulate membrane cholesterol for fluidity and signaling; most bodily cholesterol is synthesized internally, with LDL receptors key to blood levels.

    Ongoing research: Haeusler’s lab explores manganese’s role in metabolism, bile acids in liver inflammation, and insulin’s effects on lipoproteins.

    ABOUT THE GUEST: Rebecca Haeusler, PhD is an associate professor at Columbia University in the departments of medicine and pathology and cell biology, affiliated with the Naomi Berrie Diabetes Center and the Digestive and Liver Diseases Research Center.

    RELATED EPISODE:

    M&M 269 |…

32. Why Eating at the Wrong Time of Day Adds Weight | Joseph Bass | 281

    23 februari 2026 · 1 uur 31 min

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    How the body's internal circadian clocks regulate metabolism, energy balance, and health.

    TOPICS DISCUSSED:

    Master circadian clock in the brain: Light detection via retina entrains the suprachiasmatic nucleus, which coordinates body-wide rhythms; intrinsic period slightly deviates from 24 hours, allowing seasonal flexibility.

    Peripheral clocks in organs: Nearly all cells have autonomous clocks; liver and fat clocks rapidly adjust to feeding time, while brain clock aligns more tightly to light.

    Clock mutations and metabolism: Disrupting core clock genes (e.g., CLOCK, BMAL1) causes obesity, liver fat accumulation, and impaired insulin secretion without hyperinsulinemia.

    Timing of food intake: Eating the same high-fat calories during rest phase causes more weight gain than during active phase due to differences in energy dissipation.

    Modern disruptions (jet lag, shift work, blue light): Create desynchrony between brain and peripheral clocks, contributing to metabolic issues; late-night eating impairs glucose handling.

    Critical illness & feeding: Tube feeding at night (opposite natural cycle) induces rapid insulin resistance, highlighting mismatch costs.

    Hormone rhythms: Testosterone, glucocorticoids, and others peak at specific times; misalignment affects stress, reproduction, and metabolism.

    Weight loss drugs & maintenance: GLP-1 drugs reduce intake effectively, but regain involves neuroendocrine adaptations tied to brain clock pathways.

    ABOUT THE GUEST: Joseph Bass, MD, PhD is Chief of Endocrinology, Metabolism and Molecular Medicine at Northwestern University Feinberg School of Medicine, Director of the Center for Diabetes and Metabolism, and a leading researcher who pioneered the link between circadian clock genes and metabolic disorders including obesity and diabetes.

    RELATED EPISODE:

    M&M 237 | Circadian Biology: Genetics, Behavior, Metabolism, Light, Oxygen & Melatonin | Joseph Takahashi

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33. A Single Psilocybin Dose Reduced Heroin Seeking in Rats | Stephanie Daws | 280

    19 februari 2026 · 1 uur 18 min

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    Gene regulation through RNAs, the neurobiology of opioid addiction, and how psychedelics affect drug-seeking by modulating inflammation and plasticity. Not medical advice.

    TOPICS DISCUSSED:

    Gene regulation basics: DNA transcribes to RNAs, including non-coding types like microRNAs that inhibit mRNA translation into proteins, influencing up to 60% of the proteome.

    Non-coding RNAs in neuroplasticity: MicroRNAs and circular RNAs regulate synaptic changes, with activity-induced ones like miR-485-5p linked to rapid responses in drug cue memory and addiction reinforcement.

    Opioid addiction models: Rats self-administer heroin or fentanyl via levers, showing compulsive seeking; fentanyl’s higher potency drives faster learning but similar long-term effects to heroin when doses are equated.

    Differences between opioids: Heroin and fentanyl both activate mu-opioid receptors for euphoria and dopamine release, but fentanyl lingers longer; no major behavioral differences in seeking once potency is matched.

    Psilocybin’s effects on addiction: A single psilocybin dose post-abstinence reduces heroin-seeking in rats by dampening neuroinflammation in brain regions like the nucleus accumbens and prefrontal cortex.

    Brain Inflammation: Opioids induce pro-inflammatory changes via cytokines like IL-17A and pathways like TNF-alpha, leading to glial activation and blood-brain barrier leaks; psilocybin counters this.

    MicroRNA biomarkers: Blood microRNAs reflect gene expression patterns tied to disease states, with potential to predict opioid relapse risk, treatment response, or neonatal withdrawal severity non-invasively.

    Future research: Ongoing work links psilocybin’s serotonin 2A activation to anti-inflammatory gene changes, plus human studies on microRNAs for personalized addiction treatments.

    ABOUT THE GUEST: Stephanie Daws, PhD is an associate professor at Temple University in the Center for Substance Abuse Research and Department of Neurosciences, where she re…

34. Why Women Gain Belly Fat After Menopause | Victoria Vieira-Potter | 279

    14 februari 2026 · 1 uur 40 min

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    The biology of fat tissue, estrogen's role in metabolism and health, and how exercise interacts with these processes, especially during menopause.

    TOPICS DISCUSSED:

    Adipose tissue basics: White fat primarily stores energy in large lipid droplets, while brown fat burns fatty acids for heat via high mitochondrial density; white fat can “brown” with exercise or certain foods like capsaicin.

    Fat distribution & health: Subcutaneous fat (under skin) is more insulin-sensitive and less problematic than visceral fat (around organs), which links to metabolic issues; females store more subcutaneously pre-menopause, shifting to visceral post-menopause.

    Estrogen signaling: Estradiol binds nuclear and membrane receptors to regulate gene expression and mitochondrial function; it enhances insulin sensitivity and browning in fat cells, with receptors like ER-alpha feminizing fat distribution.

    Fat storage: Fat cells enlarge (hypertrophy) more than multiply in obesity, leading to hypoxia, inflammation, and insulin resistance; excess fatty acids spill to liver and muscle, worsening metabolic dysfunction.

    Menopause effects: Estrogen drop causes visceral fat gain, reduced energy expenditure, insulin resistance, and higher metabolic disease risk; symptoms include hot flashes and reduced exercise motivation, modeled in rodents via ovary removal.

    Exercise & estrogen links: Exercise boosts estrogen receptor expression and mitochondrial density in fat, mimicking estrogen’s browning effects; synergism may explain reduced exercise responsiveness post-menopause.

    Brain-fat connections: Estrogen in the nucleus accumbens influences exercise motivation and fat browning; manipulations there alter running behavior and adipose metabolism in rodents.

    ABOUT THE GUEST: Victoria Vieira-Potter, PhD leads a lab at the University of Missouri, studying how estrogen and exercise influence adipose cells.

    RELATED EPISODE:

    M&M 174 | Adipose Tissue & Body Fat: Obesity, Insulin, Leptin,…

35. A Thin, Hidden Brain Structure Kicks In When Tasks Get Hard | Brian Mathur | 278

    9 februari 2026 · 1 uur 36 min

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    The brain's mysterious claustrum region, its role in cognitive flexibility, and how substances like alcohol and psychedelics affect neural circuits and behavior. Not medical advice.

    TOPICS DISCUSSED:

    Cerebral cortex structure: Described as a six-layered structure with pyramidal neurons and inhibitory interneurons; information flows between layers and regions to process sensory input and enable complex behaviors.

    Claustrum anatomy & connectivity: A sheet-like subcortical structure embedded in white matter, bidirectionally connected to cortical areas, especially prefrontal regions in rodents, with broader connections in primates and humans suggesting an integrative role.

    Claustrum function in cognition: Experiments show claustrum activation during task switches from easy to demanding modes, synchronizing cortical networks via inhibition and rebound excitation, potentially enabling flexible behavior.

    Mouse models in neuroscience: Mice are used for genetic tractability to manipulate and monitor specific circuits, revealing claustrum’s role in vigilance tasks but not simple ones.

    Alcohol’s effects on brain circuits: Chronic alcohol promotes inflexible behaviors by altering striatal interneurons and inhibitory inputs, leading to compulsive drinking despite aversive consequences.

    Psychedelics & brain networks: Psilocybin disrupts default mode and other networks, inhibits claustrum via serotonin 1B receptors, with effects persisting 24 hours, possibly contributing to therapeutic benefits.

    Evolution of claustrum: Connectivity expands from rodents to humans, shifting from cognitive-specific to broader network control, including anti-correlated states like default mode versus task-engaged.

    Integration of claustrum & basal ganglia: Claustrum funnels prefrontal signals to basal ganglia for action selection; alcohol may impair this, exacerbating inflexibility in addiction.

    ABOUT THE GUEST: Brian, PhD is a professor in the Department of Pharmacology an…

36. Psychedelics Hit Female Mice Harder but Helped Males More | Javier González-Maeso | 277

    5 februari 2026 · 1 uur 11 min

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    Pharmacology & neurobiology of psychedelics & MDMA, focusing on isomers, sex-specific effects, and mechanisms in animal models. Not medical advice.

    TOPICS DISCUSSED:

    Biased agonism: Different drugs activate the same receptor (e.g., 5-HT2A) but trigger varied intracellular pathways, explaining why LSD is psychedelic while similar lisuride is not.

    Enantiomers & isomers: Mirror-image versions of drugs like MDMA (S and R forms) and LSD (four isomers) often produce distinct effects; only one LSD isomer is psychedelic, for example.

    MDMA isomer effects: S-MDMA induces stronger head twitches (psychedelic proxy) via serotonin release, and increases dendritic spines in male mice but not females; R-MDMA has somewhat different effects.

    Sex-specific drug responses: In mice, females show stronger psychedelic effects (head twitches) from psilocybin and DOI at the same dose, but males exhibit greater post-acute benefits like reduced opioid withdrawal.

    Psilocybin in opioid addiction models: A single dose reduces place preference for oxycodone and withdrawal symptoms in male mice more than females, with opposite spine density effects in reward-related brain areas.

    Mechanisms beyond 5-HT2A: Psychedelics involve other receptors like metabotropic glutamate receptors, forming dimers with 5-HT2A to enable dual signaling pathways; effects in subcortical regions like nucleus accumbens are 5-HT2A-independent.

    Clinical implications: Street MDMA may vary in S/R ratios, affecting experiences; clinical trials often use racemic mixtures without weight-adjusted dosing, potentially missing sex differences.

    ABOUT THE GUEST: Javier Gonzalez-Maeso, PhD is a professor of pharmacology and toxicology at Virginia Commonwealth University, with a PhD in medicine from Spain focused on G-protein coupled receptors and human brain studies in depression and addiction.

    RELATED EPISODE:

    M&M 230 | Psilocybin & MDMA: Inflammation, Stress & Brain-Body Communication | Michael Wheeler

    Sup…

37. The Enzyme That Fasting, Exercise, Metformin & Ozempic All Switch On | Greg Steinberg | 276

    25 januari 2026 · 1 uur 20 min

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    The AMP kinase pathway's role in cellular energy sensing, nutrient allocation, and its connections to health practices like fasting, exercise, and diet.

    TOPICS DISCUSSED:

    Cellular energy basics: ATP/ADP/AMP as energy currencies; AMP kinase activates on low ATP to conserve and redirect resources, like a budget manager.

    AMP kinase mechanics: Heterotrimeric enzyme phosphorylating 100+ substrates; localizes dynamically in cytosol, mitochondria, nucleus to integrate signals.

    Nutrient detection: Senses fatty acids in fasting/ketogenic states, boosting fat oxidation and mitochondria independent of energy drops.

    Fasting/exercise impacts: Elevate AMP kinase for mitophagy, better fuel switching; mimic historical scarcity absent under modern constant feeding.

    mTOR relationship: AMP kinase inhibits mTOR to stop growth in low energy states; feedback loop disrupted by abundance, promoting tissue buildup.

    Disease links: Low AMP kinase in obesity/diabetes reduces flexibility; activation prevents cancer but may aid tumor survival in therapy.

    Drugs/diets: Metformin and GLP-1s like Ozempic activate AMP kinase for glucose control/weight loss; ketogenic diets activate at intermediate levels for fat efficiency.

    ABOUT THE GUEST: Gregory Steinberg, PhD is a Professor of Medicine at McMaster University and co-directs the Centre for Metabolism, Obesity, and Diabetes Research, focusing on cellular energy sensors like AMP kinase.

    RELATED EPISODE:

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

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38. Even Pasture-Raised Eggs Mostly Reflect Corn and Soy Feed | Ashley Armstrong | 275

    19 januari 2026 · 1 uur 36 min

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    How industrial farming, seed oils, soy, and pesticides impact food nutrition and health. Not medical advice.

    TOPICS DISCUSSED:

    Soy’s rise in farming: Originating from paint uses and wartime chemicals, soy became dominant due to subsidies and large-scale farming practices, but introduces high PUFAs, phytoestrogens, and pesticides into animal feeds.

    Feed’s impact on eggs: Chicken feeds high in soy and corn raise linoleic acid levels in eggs compared to low-soy alternatives; low-PUFA eggs improve digestibility for many.

    PUFAs & health effects: Feeding PUFAs fattens animals faster and disrupts human gut lining and metabolism; body fat composition changes take time, linking to chronic issues like low energy.

    Phytoestrogens in soy: These compounds pass into animal products, affecting estrogen signaling and gut health; mainstream nutrition often overlooks their risks despite historical low exposure.

    Dairy variations: Raw milk retains lactoferrin for iron regulation and gut support, plus enzymes and probiotics destroyed in pasteurization; it may resolve dairy intolerances for some.

    Regenerative farming model: Armstrong’s cooperative emphasizes traditional feeds to “resaturate” foods, reducing PUFAs; supports small farms amid declining farm numbers.

    Ancestral diets insight: Traditional diets vary but share low PUFA levels, avoiding modern chronic illnesses tied to industrial fats.

    ABOUT THE GUEST: Ashley Armstrong, PhD co-founded Angel Acres Farm in Michigan and now runs Nourish Food Club, a cooperative of small farms producing low-PUFA, soy-free animal foods.

    RELATED EPISODE:

    M&M 273: Nutrition Content of Animal & Plant Foods: Beef, Plant-Based Meat, Raw vs. Processed Milk

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39. Why the Same Food Spikes One Person's Blood Sugar and Not Another's | Michael Snyder | 274

    14 januari 2026 · 1 uur 21 min

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    How individuals vary in responses to carbs, fibers, and fats.

    TOPICS DISCUSSED:

    Personalized health profiling: Snyder’s lab sequences genomes and measures molecules from blood, urine, and microbiomes to detect diseases early, emphasizing data-driven discovery over assumptions.

    Fiber variations and effects: Responses to dietary fibers vary individually, with microbiome playing a key role.

    Glycemic responses to carbs: People spike differently to foods like rice, potatoes, or bread; tied to insulin resistance subtypes in muscles, liver, or pancreas.

    Type 2 diabetes heterogeneity: 90% of diabetes cases are type 2 with subtypes like muscle or hepatic resistance; triggers include genetics and infections, with prediabetes often undetected.

    Continuous glucose monitors (CGMs): Affordable tools measure glucose every five minutes, revealing personal food triggers; spikes link to risks like cardiovascular disease and cancer.

    Lipidomics: Lipids are diverse, serving as energy sources, structural components, and signaling molecules; understudied but key in metabolism and gene expression.

    Maternal health & pregnancy: Metabolomics shows thousands of changes, including hormone shifts; cord blood analysis reveals fetal nutrient use and drug transfers, with markers for preterm birth or healthy outcomes.

    Future research: Exploring epigenetic changes in diabetes, personalized nutrition mitigation, and digital markers from wearables for mental health tied to diet and gut-brain axis.

    ABOUT THE GUEST: Michael Snyder, PhD is the Stanford W. Ascherman Professor of Genetics and former chair of the Department of Genetics at Stanford University School of Medicine, where he directs the Center for Genomics and Personalized Medicine.

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40. Most of What's in Your Food Isn't on the Nutrition Label | Stephan van Vliet | 273

    9 januari 2026 · 1 uur 36 min

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    How agricultural practices influence the nutrient density of foods, particularly meat, and the importance of hidden compounds beyond standard nutrition labels.

    TOPICS DISCUSSED:

    Nutrient density profiling: Labs analyze thousands of compounds beyond macros and vitamins; this “dark matter” includes phytonutrients that may support health despite not being essential.

    Phytonutrients in foods: Plant secondary metabolites like polyphenols act as antioxidants and influence pathways like mTOR; animals convert plant compounds into bioactives humans access via meat.

    Red meat definition: Refers to meats high in myoglobin, including beef and lamb; most meats are red in wild forms, but human intervention affects color and classification.

    Ruminant animals: Animals like cows that have multi-chambered stomachs to digest plants; this metabolism differs from non-ruminants (e.g. chickens), affecting nutrient profiles in their meat.

    Grass-fed vs. grain-fed beef: Grass-fed has higher omega-3 fats and phytonutrients from diverse plants; studies show it improves human omega-6:3 ratios and biomarkers from grass-fed, pastured-raised animals.

    Farming practices & variations: Plant diversity boosts beef nutrients.

    Upcoming research: Long-term trials on effects of pasture-raised foods on human health; interactive dashboards for farmers to profile nutrients and inform policy.

    ABOUT THE GUEST: Stephan Van Vliet, PhD is an Assistant Professor in the Department of Nutrition, Dietetics, and Food Sciences at Utah State University, where he directs the Center for Human Nutrition Studies, focusing on linking food production systems to nutrient profiles and conducting clinical trials on health impacts.

    Support the show

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    Good Chemistry: Personalized, science-based health consulting. Work with Dr. Nick Jikomes directly.

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41. Why Fructose Acts Like Alcohol on Your Mitochondria | Robert Lustig | 272

    5 januari 2026 · 2 uur 11 min

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    Cellular metabolism, mitochondrial health, and the roles of diet and environment in metabolic health, fetal & child development, and Alzheimer's.

    TOPICS DISCUSSED:

    Cellular growth vs. burning: Cells alternate between growing (using glucose for building blocks in low-oxygen environments) and burning (generating ATP in mitochondria with oxygen); dysregulation leads to metabolic issues.

    Key regulatory enzymes: PI3 kinase imports glucose, AMP kinase builds mitochondria, and mTOR drives cell division; their synchronization determines healthy modes, while desynchronization causes diseases.

    Fructose as a dose-dependent mitochondrial toxin: High fructose intake inhibits AMP kinase, reducing mitochondrial function and diverting energy to fat storage; it is dose-dependent, like alcohol, and unnecessary in the diet.

    Obesogens & endocrine disruptors: Chemicals like tributyltin (TBT) alter gene expression across generations, promoting obesity unrelated to calories; modern exposures increase reactive oxygen species (ROS), burdening cells.

    Fetal & neonatal development: Maternal diet, especially high sugar or formula feeding, can cause neonatal obesity and fatty liver; breastfeeding supports proper jaw development and oxygen intake.

    Brain metabolism & Alzheimer’s: The brain’s high energy needs make it vulnerable to mitochondrial issues and ROS; energy deficits from diet, stress, and toxins lead to synapse loss and inflammation, treatable via prevention.

    ROS & health: Mitochondria produce ROS as a byproduct of ATP generation; excess from diet or environment causes damage, but antioxidants and lifestyle can mitigate risks.

    PRACTICAL TAKEAWAYS:

    Limit added sugars in your diet to reduce mitochondrial stress and ROS, focusing on whole foods over ultra-processed items for better metabolic health.

    Prioritize breastfeeding for infants when possible to support proper physical development and reduce future metabolic risks.

    Incorporate regular exercise and socia…

42. Keto Athletes Performed as Well as Carb Loaders Once Adapted | Andrew Koutnik | 271

    2 januari 2026 · 2 uur 10 min

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    Deep dive into how ketogenic diets and carbohydrate intake effect exercise performance, and misconceptions in sports nutrition.

    TOPICS DISCUSSED:

    Insulin as a powerful metabolic hormone: regulates nutrient storage across tissues, overriding others like glucagon to promote fat and glucose storage during abundance.

    Glucagon & GLP-1 roles in metabolism: Glucagon mobilizes liver glucose during scarcity; GLP-1, amplified in drugs like Ozempic, suppresses hunger but originated as a diabetes treatment.

    Transition to ketosis in fasting or low-carb diets: Low insulin enables fat breakdown into ketones for brain fuel, allowing survival for weeks without food, with adaptation taking about four weeks.

    Hypoglycemia vs. glycogen depletion: Low blood sugar causes fatigue and irritability due to brain energy deficit, while muscle glycogen levels do not directly limit performance.

    Ketogenic diets & exercise performance: Studies show no difference in endurance after adaptation, with some athletes performing better on low-carb due to enhanced fat oxidation.

    High-carb diets in athletes: In one study, about 30% developed prediabetes-like fasting glucose elevations, linked to total carb intake, despite leanness and fitness.

    Misconceptions in sports nutrition: Guidelines recommend 60-90g carbs/hour, but evidence shows 10g suffices to maintain blood sugar and performance, avoiding insulin spikes that impair fat use.

    Individual variability in diet response: Athletes vary in optimal fuel sources; it’s possible to by athletic and lean but also metabolically unhealthy.

    PRACTICAL TAKEAWAYS:

    For workouts over ~60 minutes, consume ~10g carbs per hour (e.g., a third of a banana) to maintain blood sugar and prevent fatigue, regardless of overall diet.

    Allow at least four weeks for adaptation when trying a ketogenic diet, enabling the body to fully transition to the ketogenic state.

    Monitor personal responses to carb intake, as high levels can elevate fasting glucose …

43. Postpartum Psilocybin Made Mouse Moms Anxious and Harmed Pups | Danielle Stolzenberg | 270

    26 december 2025 · 1 uur 52 min

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    Neurobiology of maternal care in mammals: hormonal influences, stress effects & a study on psilocybin's unexpected effects during the postpartum period.

    Sponsor: SporesMD. Use code TRIKOMES for 20% off pharmaceutical-grade mushroom liquid cultures & mycology products.

    Topics Discussed:

    Maternal care behavior in rodents: Nursing, pup retrieval, grooming, and nest-building, essential for altricial pups’ survival; conserved across mammals but varies by species.

    Hormonal changes in pregnancy: Estradiol and progesterone surge then drop at birth, crossing the blood-brain barrier to enable infant attraction and care via gene expression and neuroplasticity.

    Brain circuitry for parenting: Medial preoptic area acts as a central hub, coordinating motivation and sensory inputs; present in both sexes but activated differently by hormones and experience.

    Stress impacts on mothers: Social stressors like male intruders dysregulate care, leading to frantic behaviors and avoidance; models human psychosocial stress linked to postpartum mood disorders.

    Sex differences in pup care: Mothers groom male pups more, influencing sexual behaviors, which effects future behavior.

    Psilocybin in postpartum mice: Single dose increased anxiety in mothers, showed no antidepressant effects, and transferred via milk, causing long-term anhedonia and impairments in offspring as adults.

    Serotonin system development: Early exposure to serotonergic drugs like psilocybin or SSRIs alters lifelong behavior, highlighting sensitive periods in brain reorganization.

    Practical Takeaways:

    Reduce postpartum stress through social support to enhance maternal bonding and minimize mood disorder risks.

    Approach psychedelics cautiously during postpartum due to potential anxiety increases and offspring effects via milk.

    Recognize hormonal shifts heighten sensitivity to infant cues, aiding natural caregiving instincts.

    Monitor environmental factors like food availability or threats that could…

44. Soybean Oil Made Mice Fatter Than Coconut Oil | Frances Sladek | 269

    21 december 2025 · 1 uur 50 min

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    Metabolic effects of soybean oil and linoleic acid on obesity, fatty liver, and liver function.

    Topics Discussed:

    Historical trends in soybean oil use: Consumption increased dramatically since the 1960s due to farming subsidies, now providing over 10% of calories for many Americans, far exceeding the 1-2% required biologically.

    Soybean oil’s effects in mice: Diets with 8-10% linoleic acid cause obesity, fatty liver, and diabetes over weeks, unlike coconut oil diets; effects persist even after diet switch unless combined with fasting.

    Role of HNF4 protein: This conserved liver transcription factor binds linoleic acid, regulating gene expression for metabolism; variants shift between carbohydrate and fat processing, with imbalances linked to fatty liver and cancer.

    Oxylipins from linoleic acid: Conversion in liver drives obesity; mice unable to produce them resist weight gain on soybean oil, suggesting these metabolites are key culprits.

    Vitamin B1 & soybean oil: Diets deplete B1 in liver and blood, contributing to obesity; supplementation with B1 analogs prevents weight gain, unlike beef tallow diets which preserve B1 levels.

    Gut & microbiome impacts: Soybean oil alters gut bacteria, potentially reducing B1 production and increasing permeability, leading to inflammation; farm animals fed soybean meal pass effects to consumers.

    Broader health implications: Reanalysis of old human studies questions linoleic acid’s heart benefits; focus on reducing processed foods and seed oils, while noting olive oil’s advantages from historical contexts.

    Practical Takeaways:

    Limit processed foods and seed oils like soybean to reduce linoleic acid intake, aiming for 1-2% of calories; read labels and opt for olive oil or home-cooked meals.

    Incorporate intermittent fasting, such as 12-16 hours without eating daily, to help reverse obesity effects from high-linoleic diets, based on mouse reversibility studies.

    Choose grass-fed or naturally fed animal product…

45. The Fats You Eat Change How Fast Your Body Clock Adjusts | Louis Ptáček | 268

    17 december 2025 · 1 uur 25 min

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    How seasonal changes in light and dietary unsaturated fats affect circadian rhythms in mammals.

    Topics Discussed:

    Evolutionary context of circadian rhythms: All organisms have adapted to Earth’s 24-hour day for survival, with internal clocks slightly offset and adjusted by environmental cues.

    Molecular clock mechanism: Involves a feedback loop where proteins turn on/off genes, lasting ~24 hours, regulated by phosphorylation and degradation for timing precision.

    Genetic variations in sleep: Families with mutations in clock genes like PER2 cause extreme morning lark behavior, altering protein stability and period length by hours.

    Light entrainment: Morning light shortens human clocks (average 24.2 hours) to match 24-hour days; seasonal day length changes require gradual adjustments.

    Food & metabolic links: Seasonal food scarcity/abundance affects clock via glucose and fatty acids competing for protein modifications, as shown in diabetic mouse models.

    Role of unsaturated fats: Paper finds MUFA/PUFA ratios in diet alter phosphorylation of clock proteins, speeding or slowing adaptation to winter/summer light cycles in mice.

    Modern environmental impacts: Artificial light extends “daytime” signals, while constant food access erases seasonal patterns, contributing to obesity and diabetes risks.

    Jet lag & adaptations: Sudden time shifts mimic seasonal experiments; high-sugar/fat intake may phenocopy genetic effects to aid adjustment, though not recommended for health.

    Practical Takeaways:

    Expose yourself to morning natural light to help synchronize your internal clock and improve daily energy.

    Consume main meals during daylight hours and avoid late-night eating to align with natural metabolic rhythms.

    Limit evening screen time to reduce artificial blue light disrupting sleep onset.

    Consider varying diet seasonally, favoring diverse, whole foods to mimic natural availability patterns for better health.

    About the guest: Louis Ptacek, MD is a n…

46. Ketones Are More Than Fuel. They Act Like Hormones | Dominic D'Agostino | 267

    12 december 2025 · 1 uur 41 min

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    How ketosis and ketogenic diets work and how these tools can improve metabolic health, brain function, and even cancer management.

    Topics Discussed:

    Organs have different fuel preferences: brain strongly prefers glucose, heart prefers fatty acids, skeletal muscle is flexible and likes fat/ketones.

    Humans evolved with high metabolic flexibility; regular ketosis was normal for ancestors, but today most people never experience it.

    “Keto flu” is largely glucose withdrawal plus electrolyte/sodium loss; proper salt and hydration prevent most symptoms.

    Classic medical ketogenic diet is ~90% fat (historically saturated); modern versions often use more monounsaturated fats, MCTs, and higher protein.

    Saturated fat is not inherently atherogenic in the context of weight stability or caloric deficit; excess calories from any source can dysregulate metabolism.

    Exogenous ketones (e.g. BHB) provide energy, reduce ROS, stabilize membranes, increase inhibitory tone (GABA), and have hormone-like signaling effects independent of diet.

    Cancer cells often show Warburg effect (damaged mitochondrial respiration → heavy reliance on glycolysis); lowering glucose and raising ketones can stress cancer cells.

    True keto-adaptation for athletic performance requires 6–12 weeks; after that, elite athletes can match or exceed prior high-carb performance at sub-maximal and endurance efforts.

    Practical Takeaways:

    Therapeutic carbohydrate restriction (50–100 g/day for many people) plus occasional fasting or ketone supplements can restore metabolic flexibility with far fewer side effects than strict keto.

    Prioritize whole-food fats (eggs, fatty fish, beef, olive oil, butter/lard) and minimize processed keto products loaded with seed oils.

    Supplementing BHB (salts or esters) or MCT oil can ease the transition into ketosis, boost ketones without strict dieting, and may support brain and metabolic health.

    Regularly check basic blood markers (glucose, lipids, electrolytes) a…

47. Too Much Omega-6 Keeps Inflammation From Shutting Off | Ganesh Halade | 266

    7 december 2025 · 1 uur 31 min

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    How dietary polyunsaturated fats, especially omega-6 from seed oils, influence inflammation & heart health.

    Topics Discussed:

    Polyunsaturated fatty acids (PUFAs): Omega-6 from seed oils like safflower and corn can convert to pro-inflammatory molecules, while omega-3s produce resolving ones; imbalance biases toward chronic inflammation.

    Inflammation regulation: Acute inflammation aids healing but requires active “on” and “off” signals from lipid mediators; chronic inflammation arises from excess omega-6, delaying resolution.

    Heart health & diet: High omega-6 diets worsen post-heart attack outcomes in mice by elevating pro-inflammatory lipids.

    Evolution & historical context: PUFAs are essential but naturally balanced in pre-industrial diets; modern processing skews ratios, contributing to diseases, as shown in early rat experiments needing minimal fats for survival.

    Aging & lifestyle factors: Excess omega-6 exacerbates inflammation in older mice; sleep, exercise, and balanced fats are crucial for metabolic health and enzyme function in processing lipids.

    Cannabis & omega-6 interaction: In mice on high omega-6 diets, CBD-rich cannabis smoke reaches the heart quickly, suppresses immune response, and weakens cardiac strain, unlike in balanced-diet controls.

    Genetic models: FAT-1 mice converting omega-6 to omega-3 show better healing and neuroprotection; FAT-2 mice doing the opposite exhibit liver fibrosis and metabolic issues, highlighting omega-6 excess harms.

    Practical Takeaways:

    Balance omega-6 and omega-3 intake by reducing seed oils in processed foods and increasing sources like fish or algae to support inflammation resolution and heart health.

    Monitor and adjust fat intake with age, as older individuals are more sensitive to omega-6 excess leading to immune dysregulation.

    Avoid combining high omega-6 diets with smoking, as it may impair immune and cardiac responses based on animal data.

    About the guest: Ganesh Halade, PhD is a cardio…

48. Why Observational Studies Keep Getting Nutrition Wrong | George Davey Smith | 265

    2 december 2025 · 1 uur 26 min

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    Methods & challenges of establishing causal relationships in health research, emphasizing epidemiology, randomized trials, and genetic approaches.

    Topics:

    Epidemiology: Studies disease influences using observational designs like case-control and prospective cohorts, plus trials, to identify patterns and test hypotheses.

    Hierarchy of evidence critique: Rejects rigid pyramids favoring RCTs, as all studies can be biased; advocates triangulation integrating varied data types for robust conclusions.

    RCT strengths & weaknesses: Randomization balances confounders, but issues like poor blinding, attrition, or subversion can undermine results; large samples may yield spurious precision if biased.

    Confounding & reverse causation: Examples include yellow fingers and lung cancer (both from smoking) or early atherosclerosis inflating CRP-disease links; hard to fully control statistically.

    Nutrition epidemiology: Observational studies often overstate benefits (e.g., vitamin E for heart disease), leading to failed trials; incentives favor new findings over revisiting errors.

    Mendelian randomization: Uses genetic variants as proxies for exposures (e.g., ALDH2 for alcohol metabolism) to mimic randomization; reveals no heart benefits from alcohol, unlike observational data.

    Negative controls: Tests implausible outcomes (e.g., smoking and murder) or exposures (e.g., paternal smoking in pregnancy) to check for confounding artifacts.

    Evidence triangulation: Combines diverse studies with different biases (e.g., cross-cultural comparisons) for causality; applied to dismiss HDL-raising drugs despite initial promise.

    Practical Takeaways:

    Scrutinize health claims by checking for negative controls or variety in evidence sources to avoid mistaking correlation for causation.

    For personal decisions like alcohol intake, consider genetic studies showing risks at all levels, and aim for moderation or abstinence based on overall evidence.

    When evaluating supplements o…

49. Why Your Brain Is Far More Energy-Efficient Than Any Computer | Luis Felipe Barros | 264

    26 november 2025 · 1 uur 24 min

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    Integration of brain metabolism with neural signaling, highlighting how core metabolites regulate energy use and protect neurons.

    Topics Discussed:

    Brain energy efficiency: Brains are much more energy-efficient than computers for similar processing, relying on adaptive metabolic strategies evolved under energy scarcity.

    Metabolism vs. information processing: Core metabolites like glutamate bridge basic cellular energy production and neural signaling.

    Lactate as a signal: Produced during exercise, lactate diffuses from muscles to brain, modulating neuronal excitability and providing neuroprotection.

    BHB in ketosis: During fasting or ketogenic diets, beta-hydroxybutyrate displaces glucose as fuel, enhances antioxidant defenses, and activates protective potassium channels in neurons.

    Adenosine and sleep: Accumulates from ATP breakdown during wakefulness, triggering sleep and locally inhibiting overactive neural networks for energy conservation.

    Glial cells’ role: Astrocytes and oligodendrocytes handle sophisticated metabolism, release signaling molecules like lactate, and modulate synapses, and influence diseases like Alzheimer’s.

    Practical Takeaways:

    Regular exercise elevates lactate, which signals the brain to adapt metabolism and may enhance neuroprotection against stress.

    Intermittent fasting or ketogenic diets can induce ketosis with BHB, potentially boosting brain antioxidant defenses and preconditioning against metabolic stress.

    Prioritizing sleep helps clear adenosine buildup, restoring energy balance and supporting long-term neural health.

    About the guest: Dr. Luis Felipe Barros, MD, PhD is a Chilean neurobiologist and professor at the Universidad de Valparaíso, where he leads a lab studying brain metabolism from glucose transport to mitochondrial function.

    Related Episode:

    M&M 255 | Unlocking Energy: How Nutrition & Drugs Impact Your Mitochondria | Chris Masterjohn

    *Not medical advice.

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50. Disrupting How Mitochondria Make Fat Impairs Blood Sugar Control | Sara Nowinski | 263

    18 november 2025 · 57 min

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    Mitochondrial fatty acid synthesis is a little-known but essential pathway that supports energy production and metabolic health.

    Summary: Dr. Sara Nowinski explains how mitochondria not only burn fuels to make ATP but also synthesize their own fatty acids inside the matrix; this conserved pathway produces lipoic acid (an essential enzyme cofactor) and longer-chain fats required for proper assembly of the electron transport chain, and disrupting it impairs respiration, glucose handling, and insulin sensitivity while enhancing it appears protective against obesity and heart injury.

    About the guest: Sara Nowinski, PhD is an assistant professor in the Department of Metabolism and Nutritional Programming at Van Andel Institute in Grand Rapids, Michigan, where since 2021 she has led a lab focused on mitochondrial biology and the mitochondrial fatty acid synthesis (mitoFAS) pathway.

    Topics Discussed:

    Basic mitochondrial energy production: food → pyruvate/fatty acids → acetyl-CoA → TCA cycle → electron transport chain → ATP

    Mitochondrial fatty acid synthesis (mitoFAS): a bacterial-like pathway that builds fats on an acyl carrier protein inside the matrix

    Lipoic acid: an 8-carbon fatty acid made only by mitoFAS, covalently attached to key enzymes (e.g., pyruvate dehydrogenase); cannot be rescued by supplements for cofactor use

    Longer mitoFAS products (14–16 carbons) stabilize electron transport chain assembly factors, explaining why pathway loss collapses respiration even when lipoic acid is intact

    Knocking out mitoFAS causes embryonic lethality, insulin resistance, poor glucose homeostasis, and a rare neurodegenerative disorder (MEPAN syndrome)

    Overexpressing the mitochondrial acyl carrier protein protects mice from diet-induced obesity, insulin resistance, and cardiac injury

    Muscle cell differentiation fails without mitoFAS, hinting at a role in tissue development and repair

    Practical Takeaways:

    Supplemental lipoic acid can act as an antioxid…