Mind & Matter

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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.

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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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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.

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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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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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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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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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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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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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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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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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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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