title: Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction.
abstract: Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with increased ferritin immunoreactivity in basal ganglia regions except in the substantia nigra (SN). The unexpected dissociation of iron accumulation from ferritin-upregulation in the SN suggests iron dyshomeostasis in the SN. Occurring alongside microgliosis and astrogliosis, iron dyshomeotasis may contribute to the particular vulnerability of the SN. Dietary restriction (DR) has long been touted to ameliorate brain aging and we show DR attenuated age-related in vivo R2 increases in the SN over ages 7 - 19 months, concomitant with normal iron-induction of ferritin expression and decreased microgliosis. Iron is known to induce microgliosis and conversely, microgliosis can induce iron accumulation, which of these may be the initial pathological aging event warrants further investigation. We suggest iron chelation therapies and anti-inflammatory treatments may be putative 'anti-brain aging' therapies and combining these strategies may be synergistic.
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walker
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Christos
authors.initials: C
authors.lastname: Michaelides
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Antigoni
authors.initials: A
authors.lastname: Ekonomou
authors.affiliation: Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire, United Kingdom.
authors.forename: Kalotina
authors.initials: K
authors.lastname: Geraki
authors.affiliation: CR-UK Clinical MR Research Group, Institute of Cancer Research, London, United Kingdom.
authors.forename: Harold G
authors.initials: HG
authors.lastname: Parkes
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Suessmilch
authors.affiliation: Perspectum Diagnostics, Oxfordshire, United Kingdom.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Herlihy
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: William R
authors.initials: WR
authors.lastname: Crum
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Po-Wah
authors.initials: PW
authors.lastname: So
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007501:Iron / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D013052:Spectrometry, X-Ray Emission; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D005293:Ferritins; D007501:Iron
keywords: MRI; aging; basal ganglia; brain; dietary restriction; homeostatis; iron