Mind & Matter

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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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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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Health Products by M&M Partners:
AquaTru: Water filtration devices that remove microplastics, metals, bacteria, and more from your drinking water. Through link, $100 off AquaTru Carafe, Classic & Under Sink Units; $300 off Freestanding models.
KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)
Seed Oil Scout: Find restaurants with seed oil-free options, scan food products to see what they’re hiding, with this easy-to-use mobile app.
SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off.
Lumen device: Optimize your metabolism for weight loss or athletic performance. MINDMATTER gets you 15% off.
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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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Health Products by M&M Partners:
AquaTru: Water filtration devices that remove microplastics, metals, bacteria, and more from your drinking water. Through link, $100 off AquaTru Carafe, Classic & Under Sink Units; $300 off Freestanding models.
KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)
Seed Oil Scout: Find restaurants with seed oil-free options, scan food products to see what they’re hiding, with this easy-to-use mobile app.
SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off.
Lumen device: Optimize your metabolism for weight loss or athletic performance. MINDMATTER gets you 15% off.
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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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Health Products by M&M Partners:
AquaTru: Water filtration devices that remove microplastics, metals, bacteria, and more from your drinking water. Through link, $100 off AquaTru Carafe, Classic & Under Sink Units; $300 off Freestanding models.
KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)
Seed Oil Scout: Find restaurants with seed oil-free options, scan food products to see what they’re hiding, with this easy-to-use mobile app.
SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off.
Lumen device: Optimize your metabolism for weight loss or athletic performance. MINDMATTER gets you 15% off.
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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
Support the show
Health Products by M&M Partners:
AquaTru: Water filtration devices that remove microplastics, metals, bacteria, and more from your drinking water. Through link, $100 off AquaTru Carafe, Classic & Under Sink Units; $300 off Freestanding models.
KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime)
Seed Oil Scout: Find restaurants with seed oil-free options, scan food products to see what they’re hiding, with this easy-to-use mobile app.
SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off.
Lumen device: Optimize your metabolism for weight loss or athletic performance. MINDMATTER gets you 15% off.
For all the ways you can support my efforts