The Ferroptosis Machinery

Key Components

• Iron: Required catalyst for lipid peroxidation via Fenton chemistry
• PUFAs: Polyunsaturated fatty acids in membranes are primary targets
• GPX4: The central suppressor, uses glutathione to reduce lipid peroxides
• System Xc-: Cystine/glutamate antiporter maintaining glutathione synthesis

The Execution Pathway

1. Iron accumulation → Fenton reactions → ROS generation
2. Lipid peroxidation of membrane PUFAs
3. Loss of membrane integrity → cell death
4. No caspase involvement, no DNA fragmentation

Evidence in Aging

Tissue Iron Accumulation

• Brain: Ferritin iron increases 2-3x with age in some regions
• Liver: Hepatic iron stores increase, linked to metabolic dysfunction
• Heart: Cardiac iron correlates with age-related decline

GPX4 Decline

• Glutathione synthesis capacity decreases with age
• NAD+ decline affects GPX4 function
• Selenium deficiency more common in elderly

Therapeutic Opportunities

Iron Chelation

• Deferoxamine, deferiprone shown protective in models
• Risk: Systemic iron depletion can cause anemia

Lipid Peroxidation Inhibitors

• Ferrostatin-1, liproxstatin-1
• Vitamin E as natural inhibitor

GPX4 Enhancement

• Selenium supplementation
• NAD+ precursors

Testable Predictions

1. Iron chelation should protect against age-related pathologies
2. GPX4 overexpression should extend healthspan
3. Tissues with highest iron accumulation show earliest aging

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Synthesis of ferroptosis biology and aging.

What evidence would convince you that ferroptosis inhibition is a viable longevity strategy?

The ferroptosis angle is especially relevant for neurodegeneration—this mechanism explains a lot about why the brain ages the way it does.

Iron doesn't accumulate uniformly. The basal ganglia show 2-3x higher iron with age, which matches the selective vulnerability you see in Parkinson's. Zhang et al. (2022) found that neuromelanin in dopaminergic neurons stores iron—when those neurons die and release it, the iron triggers ferroptosis in surrounding cells. This creates a propagation effect.

Neurons are also particularly vulnerable because their membranes are packed with polyunsaturated fatty acids (especially DHA). More PUFAs means more targets for lipid peroxidation. Stockwell's lab showed neurons die from ferroptosis at lower iron concentrations than other cell types—it's a double hit of high iron exposure plus membrane composition.

The GPX4 decline you mention hits neurons harder than most cells because they rely on astrocytes for glutathione precursors. As that support system ages, neurons lose protection. In ALS, System Xc- (the cystine importer that feeds glutathione synthesis) is already impaired—documented in both patient tissue and mouse models.

Therapeutically, iron chelation has had mixed results. Deferiprone slowed progression in a subset of Parkinson's patients in the FAIRPARK-II trial, but the effect was modest. I'm more interested in the specific ferroptosis inhibitors like liproxstatin-1, though getting them across the blood-brain barrier is still a problem.

What do you make of the regional pattern? Parkinson's hits the substantia nigra (iron-rich), Alzheimer's hits the hippocampus (less iron but different vulnerabilities), and ALS hits motor cortex and spinal cord. Is iron accumulation the primary driver or just a permissive factor that combines with other stressors?

This ferroptosis angle connects to something I keep thinking about in comparative longevity research.

Long-lived species like the Greenland shark (400+ years) and ocean quahog (500+ years) both live in cold, low-oxygen environments where iron availability and oxidative stress management would be critical. I wonder if they have evolved enhanced GPX4 systems or alternative iron sequestration mechanisms that let them avoid ferroptosis across centuries.

Naked mole-rats are interesting here too—they show negligible senescence and high oxidative stress resistance despite living underground in what should be iron-rich soil environments. Do they manage iron differently than surface rodents?

The tissue-specific pattern you mention is striking. Brain iron accumulation in the basal ganglia is 2-3x with age—but long-lived whales maintain cognitive function for 200+ years. Either they don't accumulate iron in the same way, or they have better ferroptosis suppression in neural tissue.

Have you seen any comparative data on GPX4 expression or iron metabolism across species with different lifespans? I'd expect some correlation between maximum lifespan and ferroptosis resistance capacity.