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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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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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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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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 transcription factor, including sulforaphane from broccoli and certain flavonoids, upregulate antioxidant enzymes including GPX4 and may support long-term cellular resilience.

ABOUT THE GUEST: Pamela Maher, PhD is a research professor at the Salk Institute for Biological Studies in La Jolla, California. Her laboratory studies ferroptosis mechanisms in neurodegenerative diseases and works to identify compounds that inhibit iron-dependent lipid peroxidation. 

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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, with some losing over 25% body weight while others see minimal change.
• Emerging peptides under study may suppress appetite via brain pathways that avoid the gastric slowing responsible for common GI side effects of current GLP-1 drugs.
• Research peptides purchased online frequently show variable purity below pharmaceutical standards and may contain unsafe formulation components or aggregates.

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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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