Neurodegenerative diseases such as Alzheimer’s and Parkinson’s affect millions of people worldwide, yet scientists are still trying to understand what causes neurons to fail gradually with age. Researchers at the Salk Institute have uncovered new evidence that iron accumulation within neurons may play a central role in this process. Their study, published in Cell Death Discovery, suggests that excess iron weakens the cells’ natural defences over time, making them increasingly vulnerable to stress and ultimately contributing to neurodegeneration. The researchers describe this newly identified process as chronoferroptosis, highlighting the importance of prolonged iron exposure rather than iron itself.
Iron is essential for human health, supporting oxygen transport, hormone production, immune function and energy metabolism. It is found in foods such as leafy green vegetables, whole grains, seafood and lean meats. According to co-corresponding author Dr Nawab John Dar, iron is not harmful in itself. Instead, problems arise when neurons gradually accumulate iron as people age. The researchers believe this buildup may occur because ageing neurons lose their ability to export excess iron after it has been used efficiently. While iron continues entering cells normally, it is not removed effectively, allowing it to accumulate over decades.
To investigate how this gradual buildup affects neurons, the team developed the first progressive laboratory model of chronic iron accumulation in human-derived nerve cells. Previous studies had typically examined the effects of iron exposure for only 24 to 48 hours, but neurodegenerative diseases develop over many years. The researchers therefore compared short-term exposure lasting several hours with chronic exposure over nine days. This approach allowed them to mimic the slow progression of iron accumulation that occurs during ageing and revealed biological changes that had not been observed in earlier experiments.
The study identified chronoferroptosis as a previously unrecognised pathway linked to long-term iron accumulation. Unlike classical ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, chronoferroptosis does not necessarily kill neurons immediately. Instead, it acts as a chronic cellular stress state that gradually erodes neuronal resilience. Neurons exposed briefly to iron remained largely unchanged and were able to cope with additional stress. In contrast, chronically exposed neurons showed widespread biochemical alterations, including increased lipid peroxidation, disruption of iron-handling and antioxidant defence systems, accumulation of harmful molecules and depletion of protective compounds. As a result, these cells became far less capable of surviving further stress.
The findings suggest that the duration of iron exposure, rather than the absolute amount of iron present, is the critical factor determining neuronal vulnerability. “It’s not the amount of iron that seals the fate of these cells,” said Dar. “It’s the amount of time they spend under stress.” Senior author Dr Pam Maher added that neurons appear to lose resilience once iron reaches a critical threshold, making them much more susceptible to the various stressors associated with ageing and neurodegenerative diseases. The researchers believe this progressive loss of resilience may help explain why neurons can tolerate iron accumulation for many years before symptoms emerge.
The discovery of chronoferroptosis offers a promising new direction for predicting, preventing and treating neurodegenerative diseases. If scientists can identify when neurons begin entering this vulnerable state, they may be able to intervene before irreversible damage occurs. Maher noted that her laboratory has already developed compounds capable of inhibiting this pathway, raising the possibility of future therapies that preserve neuronal resilience by limiting the harmful effects of long-term iron accumulation. Although further research is needed, the findings point to brain iron regulation as a promising target for delaying age-related neurodegeneration.
More information: Nawab John Dar et al, Sustained dysregulation of iron and glutathione homeostasis induces chronoferroptosis, a persistent ferroptotic adaptation in neuronal cells, Cell Death Discovery. DOI: 10.1038/s41420-026-03208-6
Journal information: Cell Death Discovery Provided by Salk Institute
