Mind & Matter
Whether food, drugs or ideas, what you consume influences who you become. Learn directly from the best scientists & thinkers alive today about how your mind-body reacts to what you feed it.
The weekly M&M podcast features conversations with the most interesting scientists, thinkers, and technology entrepreneurs alive today.
Not medical advice.
At M&M, we are interested in trying to figure out how things work, not affirming our existing beliefs. We prefer consulting primary rather than secondary sources and independent rather than institutional voices. If we encounter uncomfortable truths or the evidence suggests unfashionable ideas may be valid, so be it.
As the host, my aim is to help you better understand how the body & mind work by curating & synthesizing information in a way that yields science-based insights that you can choose to use or disregard in your own life. Taking ownership of your health starts with taking ownership of your information diet.
I am motivated to connect the dots and distill general principles from what I learn, preferring to ask questions and play devil’s advocate to debating or incessantly pushing my own viewpoint.
My beliefs:
- Taking ownership of your health starts with taking ownership of your information diet.
- All knowledge is provisional and we must work hard to prevent ourselves from becoming attached to our favorite ideas & preferred conclusions.
- Wisdom comes from an iterative, trial-and-error process of learning and unlearning. Letting go of pre-conceived notions can be painful, but pain is information.
Sometimes modern discoveries teach us we must unlearn received wisdom. Other times, modern information overload & historical chauvinism cause us to forget ancient wisdom which stills applies. The framework for learning that I embody is inspired by three Ancient Greek maxims inscribed in the Temple of Apollo at Delphi:
- “Γνῶθι σεαυτόν” (Know thyself)
- “Μηδὲν ἄγαν” (Nothing in excess)
- “Ἐγγύα πάρα δ Ἄτα” (Certainty brings insanity)
Mind & Matter
Iron Overload & Lipid Peroxidation in Cell Death & Neurodegenerative Disease | Pamela Maher | Episode 299
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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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