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How maternal obesity epigenetically reprograms liver metabolism in offspring, predisposing them to metabolic disease.

Episode Summary: Dr. Elvira Mass talks about macrophages, specialized immune cells that vary by tissue and play crucial roles beyond fighting infections, such as supporting organ function; Kupffer cells (liver macrophages) and how maternal obesity during pregnancy reprograms these cells in offspring, leading to fatty liver disease, fibrosis, and even cancer later in life, based on mouse studies showing epigenetic and metabolic shifts like increased glycolysis, with insights into developmental windows, nutritional mismatches, and broader implications for human health.

About the guest: Elvira Mass, PhD, is a Professor of Developmental Immunology at the University of Bonn in Germany, where her lab focuses on the development and function of macrophages in various tissues.

Discussion Points:

• Macrophages are diverse, tissue-specific cells that develop from embryonic precursors, performing unique tasks like providing growth factors in organs.
• Kupffer cells in the liver monitor blood from the gut and are exposed to maternal nutrients during fetal development.
• Maternal obesity (induced in mice via high-fat diets) programs offspring Kupffer cells epigenetically, leading to fatty liver in newborns and progression to diseases like cancer, even on normal diets.
• A "nutritional mismatch" between in utero high-fat exposure and postnatal normal diets worsens liver issues, as cells are "prepared" for excess high-fat intake but face scarcity.
• Key mechanism: Reprogrammed Kupffer cells overproduce apolipoproteins, driving excess lipid uptake in liver cells (hepatocytes), linked to transcription factor HIF-1α and a shift to inefficient glycolysis.
• Offspring from obese mothers show sex differences (males affected earlier) and persistent changes.
• Human parallels: Rising childhood fatty liver (once rare and tied to alcoholism) correlates with maternal obesity; studies like Dutch Hunger Winter show early gestational disruptions cause lifelong issues.
• Broader factors: Microbiome changes, specific fatty acids, and environmental toxins like microplastics may also reprogram macrophages; diets in studies vary beyond fat content, affecting results.
• Advice: Maintain consistent healthy habits pre- and during pregnancy; avoid sudden diet shifts, as developmental windows are critical for long-lived cells like Kupffer cells.

Reference Paper:

• Study: Kupffer cell programming by

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Aging, tissue repair, and the longevity benefits of psilocin.

Episode Summary: Dr. Louise Hecker discusses her research on tissue repair and regeneration, explaining how fibroblasts drive wound healing by forming scar tissue but fail to resolve properly with age, leading to fibrotic diseases like pulmonary fibrosis and liver cirrhosis; they discuss aging hallmarks such as oxidative stress and telomere shortening, and highlight Hecker's study showing psilocybin's active metabolite, psilocin, extends cellular lifespan in lab cultures by reducing oxidants and preserving telomeres, while monthly doses in aged mice improved appearance and survival rates.

About the guest: Louise Hecker, PhD is an Associate Professor of Medicine at Baylor College of Medicine, specializing in repair and regeneration processes, particularly in aging and fibrotic diseases.

Discussion Points:

• Fibroblasts are dormant cells that activate during injury to pull wounds closed and form scars, then de-differentiate or die; aging impairs this, causing persistent scarring and disease.
• Aging reduces the body's regenerative capacity; different organs vary in repair efficiency, with skin healing better than heart tissue.
• Oxidative stress, like "rust" in the body, accumulates with age due to imbalanced reactive oxygen species production and antioxidant defenses, contributing to cellular damage.
• Telomeres act as protective DNA caps that shorten with cell divisions, serving as a hallmark of biological aging; sirtuins are master regulators influencing aging processes.
• Hecker's in vitro study showed psilocin dose-dependently extended fibroblast lifespan by 29-50%, lowering oxidative stress below young cell levels and preserving telomeres.
• In aged mice (equivalent to 60-65 human years), monthly high-dose psilocybin (15 mg/kg) led to healthier appearance, regrown fur, and 80% survival when controls reached 50% mortality after 10 months.
• Psilocybin's effects may stem from serotonin receptors expressed in many cell types beyond the brain, suggesting broader anti-aging potential; future work explores mechanisms, optimal dosing, and applications for age-related diseases.
• Fungi like magic mushrooms represent an under-explored "kingdom" for medicine, with psilocybin's durable effects hinting at systemic impacts on aging.

Reference Paper:

• Study: Psilocybin treatment extends cellular lifespan and improves survival of aged mice

Related content:

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The effects of protein restriction on metabolism, liver hormones, brain, and behavior.

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

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

Discussion Points:

• The body prioritizes nutrients hierarchically: oxygen and water first, then sodium, energy, and protein, with weaker defenses for carbs or fats.
• Animals develop specific appetites for deprived nutrients, like salt or protein, often through post-ingestive learning rather than just taste.
• Protein restriction (e.g., 5% vs. 20% in diets) increases food intake and energy expenditure in mice to maintain protein levels, even at the cost of extra calories.
• FGF21, a liver hormone, signals protein deprivation to the brain (via NTS region), driving protein-seeking behavior and metabolic changes; it's essential for low-protein responses.
• Protein restriction extends lifespan in lab animals by suppressing growth signals like IGF-1 and mTOR, but may impair immunity or wound healing in real-world conditions.
• High protein aids satiety, weight loss, and muscle building, but overconsumption may shorten lifespan; optimal intake depends on age, activity, and goals (e.g., not for pregnant or elderly).
• No one-size-fits-all for protein: mild restriction may benefit middle-aged sedentary people for health, while athletes need more; balance avoids excesses.

Related content:

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

*Not medical advice.

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Cellular clean up by immune cells and how early-life fructose exposure leads to neurodevelopmental problems.

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

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

Discussion Points:

• The body turns over 1-2% of its 30 trillion cells daily, mostly blood cells, but neurons in kids and endometrium in women turnover at ~2x this rate
• Phagocytosis involves "find me," "eat me," and digestion signals; failures can cause autoimmunity.
• Microglia are brain macrophages that uptake fructose via GLUT5 transporter.
• Early high fructose exposure (comparable to one soda daily) impairs the pruning of synapses and dead neurons.
• In mice, prenatal or postnatal fructose causes phagocytosis deficits in the prefrontal cortex, leading to heightened fear responses and poor fear extinction, mimicking anxiety disorders.
• Fructose correlates with rising neurodevelopmental issues like autism and anxiety; it's passed via breast milk, and liquid forms (e.g., sodas) overwhelm metabolic shields more than solid fruits.
• Macrophages may hold keys to diseases from atherosclerosis to cancer; deleting GLUT5 in microglia reverses fructose's effects, hinting at evolutionary roles in aging or low-oxygen states.

Related content:

• M&M 215: Cancer Metabolism: Sugar, Fructose, Lipids & Fasting | Gary Patti
• Article | Dietary Fructose & Metabolic Health: An Evolutionary Perspective

Reference Paper:

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

*Not medical advice.

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The potential link between acetaminophen (Tylenol) and autism, with a surprise phone call from RFK partway through.

Episode Summary: Dr. William Parker talks about autism spectrum disorder (ASD), its rising prevalence since the 1980s, and the controversial hypothesis that acetaminophen exposure in susceptible infants and children triggers most cases via oxidative stress. They discuss ASD's clinical definition; historical misconceptions like the "refrigerator mother" theory; genetic susceptibilities; acetaminophen's metabolism, which produces toxic byproducts in underdeveloped livers, leading to brain effects.

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

Discussion Points:

• Autism is a spectrum disorder with core symptoms like social deficits, repetitive behaviors, and aversion to new stimuli.
• Parker argues overwhelming evidence points to acetaminophen as the primary trigger in susceptible individuals, causing oxidative stress via toxic metabolite NAPQI.
• Acetaminophen, marketed as Tylenol or paracetamol, was not tested for neurodevelopmental effects in neonatal animals until 2014, despite widespread use since 1886; it's metabolized differently in babies, whose livers lack mature detox pathways.
• Susceptibility factors include low glutathione (an antioxidant), poor sulfation/glucuronidation metabolism, folate receptor autoantibodies, and events like immune reactions that prompt acetaminophen use during oxidative stress.
• Regressive autism, where children lose milestones after seeming normal, often follows acetaminophen given for fevers or illnesses, explaining parental vaccine suspicions (as shots coincide with drug use).
• Adult acetaminophen is generally safe but causes liver toxicity in overdoses or with alcohol; antidote is NAC to boost glutathione.
• Parker has suggested to policymakers that we should avoid acetaminophen during pregnancy, birth, and early childhood (under age 3-5); parents should plan ahead for fevers/pain without it, but seek medical help for unusual symptoms.

*Not medical advice.

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Wide release date: August 25, 2025

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

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

Discussion Points:

• LDL cholesterol helps the immune system by sticking to bacteria, clumping them for removal; low LDL increases infection risk.
• Animal studies show injecting LDL protects against lethal infections, while historical data links severe infections to worse atherosclerosis.
• Elderly people with high cholesterol live longer; low cholesterol raises mortality risk more than high levels.
• Familial hypercholesterolemia (FH) doesn't cause early death via cholesterol alone—co-inherited coagulation factors are the issue, and FH patients often have lower infection rates.
• Statins lower LDL but increase infection risk, cause muscle weakness/brain issues (often blamed on aging), and show no clear benefit in unbiased meta-analyses.
• Research biases include cherry-picking studies, exaggerating benefits via relative (not absolute) risk, and pharma funding suppressing critical views.
• Mental stress can raise cholesterol by 10-50% in 30 minutes, often misread as a heart disease cause rather than an effect.
• Saturated fat and high cholesterol aren't proven harmful; Ancel Keys' claims ignored contradictory evidence.
• Stopping statins often reverses side effects quickly, improving quality of life.

Related episode:

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

Reference Paper:

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

*Not medical advice.

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The appendix's hidden role and how "good" parasites like helminths shape immune health.

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

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

Discussion Points:

• Appendix is not vestigial; it concentrates immune tissue and biofilms to cultivate good gut bacteria, preventing pathogens via mucus and IgA antibodies.
• Hygiene hypothesis: Soap, toilets, and clean water reduce helminths/protozoa, leading to untrained, hyperactive immunity and rising allergies/autoimmunity since the 1800s.
• Helminths (worms) stimulate immune "exercise," training immunity; biohackers use hookworms (cheap, skin-entry), porcine whipworms, or rat tapeworms orally for relief from allergies, MS flares, depression/anxiety.
• Effects are temporary; need ongoing exposure (e.g., replenish every 6 months); immigrants from helminth-rich areas develop Western diseases within a few years.
• COVID-19: Hyper-immunity caused severe reactions in hygienic West, but helminth presence in low-income Africa/Asia prevented cytokine storms, leading to empty clinics.
• Therapy barriers: Non-patentable organisms require $100M+ trials; push for open-source, government-funded biome restoration over crude immunosuppressants.

Related episode:

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

*Not medical advice.

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