This study provides a detailed overview of brain iron accumulation in older adults, highlighting the impact of specific nutrients in protecting against the negative effects of iron. This opens up new perspectives for dietary interventions that can mitigate brain aging and improve quality of life in old age.
Non-heme iron plays a crucial role in brain health, supporting vital neural functions and contributing to essential cellular processes such as the generation of energy in mitochondria (adenosine triphosphate, or ATP), the formation of synaptic connections (synaptogenesis), the synthesis of neurotransmitters, and the development of myelin, which protects neurons.
Despite its essential functions, non-heme iron can also act as an oxidizing agent, contributing to the production of reactive oxygen species (ROS). These molecules can cause damage to cellular structures such as lipids, proteins, and DNA, impairing the function of neurons, supporting (glial) cells, and myelin itself.
Recent studies have linked iron accumulation in the hippocampus to reduced production of brain growth factors such as brain-derived neurotrophic factor (BDNF). This effect occurs due to iron-mediated downregulation of key enzymes.
Under normal conditions, non-heme iron is stored within intracellular structures such as ferritin, and its release from mitochondria is tightly controlled to prevent cellular damage.
However, the aging process disrupts this balance, resulting in iron accumulation in brain areas and increased oxidative stress, which is associated with cognitive decline.
Although the effects of iron on brain aging are known, its specific spatial distribution and regional implications on cognitive functions are still poorly understood. Limited longitudinal studies have focused on subcortical areas, such as the striatum, while analyses of cortical areas, such as the prefrontal cortex, are scarce.
In addition, most research uses relaxometry-based techniques to measure brain iron, which can be influenced by external factors unrelated to iron, such as magnetic field heterogeneities.
To advance understanding of this topic, it is crucial to identify factors that can mitigate age-related brain iron accumulation.
Previous studies suggest that antioxidant nutrients and iron-chelating compounds, such as vitamins, flavonoids and polyunsaturated fatty acids, may offer protection by reducing oxidative stress and preventing iron-associated cellular damage. However, their long-term efficacy has not yet been adequately established.
In this longitudinal study, conducted by researchers at the University of Kentucky, USA, 74 healthy older adults were analyzed, who participated in a baseline assessment and a 2.5- to 3-year follow-up.
Brain iron levels were measured using quantitative susceptibility mapping (QSM), an MRI technique that provides more direct and accurate estimates of iron content, compared to traditional methods.
In addition, cognitive performance was assessed using neuropsychological tests that measure episodic memory and executive function, abilities that are often affected by aging.
Dietary intake of participants was recorded at baseline, focusing on nutrients such as antioxidants, flavonoids and fatty acids. These compounds were selected based on evidence from animal models suggesting their ability to cross the blood-brain barrier and protect the brain against the detrimental effects of iron.
In addition, lifestyle data, such as physical activity level, alcohol consumption and smoking status, were collected to control for non-dietary factors that may influence the results.
The results showed that brain iron accumulation over 2.5 years was detected in several cortical and subcortical regions, and was associated with poorer performance on tests of memory and executive function.
However, dietary intake of antioxidant nutrients and other beneficial compounds was correlated with lower iron levels in specific brain regions. This suggests that diet may play a protective role by slowing brain iron accumulation and preserving cognitive function.
This study provides a detailed overview of brain iron accumulation in older adults, highlighting the impact of specific nutrients in protecting against the detrimental effects of iron.
This opens up a new perspective for dietary interventions that can mitigate brain aging and improve quality of life in old age.
The Figure shows the results of voxel-by-voxel analyses performed to assess associations between longitudinal changes in QSM values (ΔQSM) and cognitive performance in two main domains: episodic memory (EMM) and executive function (EF). Correlations between ΔQSM and EEM are presented in panel (A), while correlations with EF are shown in panel (B). Increased iron accumulation in specific brain regions over time is associated with worsening episodic memory and executive function.
This supports the hypothesis that brain iron may be an important factor in age-related cognitive decline. Increased brain iron accumulation (ΔQSM) was observed to be negatively associated with performance in EEM and EF. This means that the greater the difference in QSM values between baseline and follow-up, the worse the performance in these cognitive domains. Warm colors (orange to yellow): Indicate positive correlations, suggesting that an increase in QSM would be associated with an improvement in performance (in this case, this is not predominant).
Cool colors (blue to cyan): Indicate negative correlations, suggesting that an increase in ΔQSM is related to a worsening in cognitive performance. L (left hemisphere) and R (right hemisphere): The acronyms indicate which hemisphere of the brain the analysis is focused on.
Brain Regions Identified: Fusiform gyrus (FG): Associated with visual recognition and memory processes. Hippocampus (HIPP): Crucial for episodic memory and spatial navigation. Medial orbitofrontal cortex (MOC): Involved in decision-making and integration of emotional information. Superior frontal gyrus (SFG): Associated with executive functions, such as planning and attention control. Precentral gyrus (PG): Mainly motor, but may also be involved in complex cognitive functions. Anterior cingulate cortex (ACC): Related to emotional regulation, attention, and executive control. Inferior temporal gyri (ITG) and middle temporal gyri (MTG): Involved in memory processing and semantic integration. Precuneus (PRECUN): Related to self-reference and episodic memory. Middle cingulate cortex (MCC): Associated with social cognition and decision making.
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Exploring the links among brain iron accumulation, cognitive performance, and dietary intake in older adults: A longitudinal MRI study
Valentinos Zachariou, Colleen Pappas, Christopher E. Bauer, Elayna R. Seago, and Brian T. Gold
Neurobiology of Aging. Volume 145, January 2025, Pages 1-12
Abstract:
This study evaluated longitudinal brain iron accumulation in older adults, its association with cognition, and the role of specific nutrients in mitigating iron accumulation. MRI-based, quantitative susceptibility mapping estimates of brain iron concentration were acquired from seventy-two healthy older adults (47 women, ages 60–86) at a baseline timepoint (TP1) and a follow-up timepoint (TP2) 2.5–3.0 years later. Dietary intake was evaluated at baseline using a validated questionnaire. Cognitive performance was assessed at TP2 using the uniform data set (Version 3) neuropsychological tests of episodic memory (MEM) and executive function (EF). Voxel-wise, linear mixed-effects models, adjusted for longitudinal gray matter volume alterations, age, and several non-dietary lifestyle factors revealed brain iron accumulation in multiple subcortical and cortical brain regions, which was negatively associated with both MEM and EF performance at T2. However, consumption of specific dietary nutrients at TP1 was associated with reduced brain iron accumulation. Our study provides a map of brain regions showing iron accumulation in older adults over a short 2.5-year follow-up and indicates that certain dietary nutrients may slow brain iron accumulation.
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