The Aging of Iron Man

Abstract

Brain iron is tightly regulated by a multitude of proteins to ensure homeostasis. Iron dyshomeostasis has become a molecular signature associated with aging which is accompanied by progressive decline in cognitive processes. A common theme in neurodegenerative diseases where age is the major risk factor, iron dyshomeostasis coincides with neuroinflammation, abnormal protein aggregation, neurodegeneration, and neurobehavioral deficits. There is a great need to determine the mechanisms governing perturbations in iron metabolism, in particular to distinguish between physiological and pathological aging to generate fruitful therapeutic targets for neurodegenerative diseases. The aim of the present review is to focus on the age-related alterations in brain iron metabolism from a cellular and molecular biology perspective, alongside genetics, and neuroimaging aspects in man and rodent models, with respect to normal aging and neurodegeneration. In particular, the relationship between iron dyshomeostasis and neuroinflammation will be evaluated, as well as the effects of systemic iron overload on the brain. Based on the evidence discussed here, we suggest a synergistic use of iron-chelators and anti-inflammatories as putative anti-brain aging therapies to counteract pathological aging in neurodegenerative diseases.

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…A recent study observed increased amyloid plaque formation in a transgenic mouse model of amyloidosis using longitudinal MRI, while the plaque formation was found to coincide with an augmented R2 in the hippocampus and cerebral cortex . This result is consistent with human MRI findings, where elevated hippocampal iron levels were negatively correlated with cognitive performance . Another recent study, using multimodal MRI and MitoPark mice (a relatively new animal model of PD), showed reduced transverse relaxation time (T2*) of the substantia nigra and striatum, apparent diffusion coefficient in the substantia nigra, and fractional anisotropy in the corpus callosum and substantia nigra, indicative of abnormal iron accumulation, and neuronal loss with white‐matter damage .…”

“…During past decades, a great number of studies have focused on addressing whether the abnormally increased brain iron is an initial cause for the development of neurodegeneration and neuronal death. A number of excellent reviews on the updated understanding of this question have recently been published …”

“…Therefore, the discussion about whether iron is the cause or consequence of disease pathogenesis continues. However, cumulative evidence favors brain iron misregulation as one of the initial causes of neuronal death in these diseases . Amyloid‐β protein, α‐synuclein, and huntingtin, which are recognized as neuropathological characters of these diseases, have been linked to iron neurochemistry .…”

Brain iron transport

“…Iron is the most abundant metal in the brain (Ward et al, 2014;Ashraf, Clark, & So, 2018). Iron delivery to the brain is essential for multiple neurological processes including myelination, neurotransmitter synthesis, and energy production (Chiou et al, 2018a), and brain iron status is consistently maintained and tightly regulated at the level of the BBB (Duck et al, 2018).…”

G protein‐coupled oestrogen receptor stimulation ameliorates iron‐ and ovariectomy‐induced memory impairments through the cAMP/PKA/CREB signalling pathway

“…Neurodegenerative diseases such as AD are complex multifactorial pathologies, emerging from a multitude of alterations that include oxidative stress, protein aggregation, energetic failure, synaptic dysfunction and inflammation, which ultimately lead to cell death in specific brain regions . Disruption of iron homeostasis and consequently its accumulation has been associated with the pathogenesis of neurodegenerative disorders, such as Parkinson's disease (PD) and AD . Recently, it was suggested that exposure to high levels of iron during childhood increases susceptibility to neurodegenerative diseases such as PD and AD in elderly, considering a “window of vulnerability” in which, during the first 2 years of life, the blood‐brain‐barrier is more accessible to iron levels in the periphery leading to iron over storage in the brain .…”