Summary: New research finds that age-related failure of iron-regulating mechanisms allows iron to accumulate in the brain, raising oxidative stress and increasing the risk of cognitive decline and neurodegenerative disease.
Source: Northwestern University
Scientists at Northwestern Medicine report that regulatory breakdowns permit iron to accumulate in the aging brain, elevating oxidative stress and causing cellular damage. The study, published in eLife, highlights a potential mechanism linking iron buildup to age-related cognitive decline and neurodegenerative diseases such as Parkinson’s and Alzheimer’s.
According to Hossein Ardehali, MD, PhD, Thomas D. Spies Professor of Cardiac Metabolism and senior author of the study, brain iron is normally tightly controlled but this control weakens with age. The team suggests that restoring balanced iron levels in the brain may be a strategy to slow or prevent cognitive decline associated with aging.
Cells rely on antioxidant systems to neutralize reactive oxygen species, byproducts of normal respiration. As organisms get older, these detoxifying systems tend to falter, and oxidative stress increases across tissues. The researchers focused on whether iron accumulation in the brain contributes specifically to rising oxidative stress with age.
To investigate, the team measured both cytosolic and mitochondrial non-heme iron in young and aged mice across multiple organs. They discovered that, unlike liver and muscle where only cytosolic iron increased, the aged brain cortex uniquely showed increases in both cytosolic and mitochondrial iron. This compartment-specific iron accumulation points to a brain-centered mechanism driving oxidative damage during aging.
Gene expression analysis revealed a dramatic increase in the brain cortex of an iron-regulating hormone, hepcidin. Hepcidin is best known as a liver-derived hormone that controls systemic iron balance, but in this study the investigators found locally produced, cortex-derived hepcidin was markedly elevated in older animals. In the brain, hepcidin primarily acts by inhibiting ferroportin, the only known iron exporter from cells, thereby reducing iron efflux and promoting intracellular iron accumulation.
First author Tatsuya Sato, MD, PhD, noted that increased local hepcidin is likely a central contributor to iron buildup in the aged cortex. The team also observed that higher hepcidin levels are associated with increased ubiquitination and reduced levels of ferroportin-1 (FPN1), consistent with impaired iron export from neurons and supporting their mechanistic hypothesis.
The precise triggers that drive increased cortex-derived hepcidin with age remain under investigation. Ardehali and colleagues suggest that chronic, low-level inflammation associated with aging and altered expression of iron-sensing proteins such as transferrin receptor 2 could be upstream regulators. Elevated hepcidin could also promote excessive mitochondrial iron import—surpassing mitochondrial needs and antioxidant capacity—leading to organelle dysfunction and cell damage.
These findings suggest potential therapeutic approaches. Reducing brain iron levels by targeting locally produced hepcidin or by using iron chelators that cross the blood-brain barrier could restore intracellular iron balance and reduce oxidative stress. Ardehali emphasized that not all iron chelators penetrate the blood-brain barrier, but some compounds do; one agent is currently being tested in clinical trials for Parkinson’s disease. Exploring brain-permeable chelators or strategies to suppress cortex-derived hepcidin are logical next steps based on these results.
Sato added that if intracellular iron can be normalized by reducing local hepcidin action or by safely chelating excess iron in the brain, it may be possible to mitigate age-related cognitive decline. The study therefore highlights both a plausible molecular mechanism for brain-specific iron accumulation during aging and a set of translational targets that warrant further preclinical and clinical exploration.
About this aging and cognition research news
Author: Will Doss
Source: Northwestern University
Contact: Will Doss – Northwestern University
Image: The image is credited to Northwestern University
Original Research: Open access.
“Aging is associated with increased brain iron through cortex-derived hepcidin expression” by Tatsuya Sato et al., eLife
Abstract
Aging is associated with increased brain iron through cortex-derived hepcidin expression
Iron is essential for many biological functions, but excess iron can catalyze oxidative reactions that damage proteins, lipids and DNA, contributing to cell death. Iron accumulation is implicated in aging and several neurodegenerative conditions, yet how iron increases with age and whether the increase is confined to particular cellular compartments has been unclear.
In this study, researchers measured iron levels across tissues in aged mice and found that while non-heme cytosolic iron rises in liver and muscle, only the aged brain cortex shows elevated non-heme iron in both the cytosol and mitochondria. This brain-specific iron increase coincides with higher local expression of hepcidin mRNA and protein. Elevated hepcidin correlates with increased ubiquitination and reduced levels of the iron exporter ferroportin-1, suggesting decreased iron export as a driver of accumulation. Overall, the data support a mechanism in which cortex-derived hepcidin promotes brain iron accumulation during aging, with potential consequences for mitochondrial function and neuronal health.