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 agerelated 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 ‘antibrain aging’ therapies and combining these strategies may be synergistic.
Highlights
Iron is essential for normal neuronal functioning [1], but in excess, labile reactive iron enhances free radical induced cell death [2]
In study 1, age-related changes in relaxation rates, striatal volumes, iron, and ferritin, ba1 and glial fibrillary acidic protein (GFAP) IHC were investigated, whereas in study 2, we studied the effects of Dietary restriction (DR) on these measurements
This is the first study to show DR-induced amelioration of iron dyshomeostasis in the substantia nigra (SN), a region known to be vulnerable to disease, intimating a potential pivotal role for SN in development of the aging phenotype
Summary
Iron is essential for normal neuronal functioning [1], but in excess, labile reactive iron enhances free radical induced cell death [2]. Cellular iron homeostasis is tightly regulated, including sequestration in a bioavailable and non-toxic form by ferritin, the major cellular iron storage protein [3]. The seminal human post-mortem study by Hallgren and Sourander (1958) showed iron accumulation within the globus pallidus (GP), striatum (STR, including both caudate and putamen), thalamus and various cortical regions [6]. Subsequent investigations have shown similar findings, with the basal ganglia exhibiting the greatest levels of iron accumulation [7]. Iron in the GP greatly increases during development, but plateaus in early adulthood, with continual iron accumulation in the STR into senescence (biological aging) [8]. Iron has been shown to accumulate with aging in the substantia nigra (SN) [8]
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