Calorie Restriction Down-Regulates Expression of the Iron Regulatory Hormone Hepcidin in Normal and d-Galactose–Induced Aging Mouse Brain

Abstract

It has been shown that iron progressively accumulates in the brain with age. Calorie restriction (CR) may allay many of the adverse effects of aging on the brain, yet the underlying mechanisms, in particular in relation to brain iron metabolism, remain unclear. This study aimed to investigate the role of CR in the regulation of cerebral cellular iron homeostasis. C57BL/6 mice were randomly divided into four groups of eight. The control group was fed a conventional diet ad libitum; the CR group received 70% of the calories of the control mouse intake per day; the D-galactose (D-gal) group received subcutaneous injection of D-gal at a dose of 100 mg/kg once daily to produce mouse model of aging; the D-gal plus CR group received both of the two interventions for 14 weeks. The Morris water maze (MWM) was employed to test the cognitive performance of all animals, and the expression of iron regulatory genes, ferroportin and hepcidin, in the cortex and hippocampus were detected by quantitative real-time PCR. Compared to the controls, the D-gal group mice showed significant spatial reference memory deficits in the MWM test, whereas the D-gal-CR group mice exhibited almost normal cognitive function, indicating that CR protects against D-gal-induced learning and memory impairment. Hepcidin mRNA expression was increased in the D-gal group, decreased in the CR group, and was basically unchanged in the D-gal-CR group. There was no statistical difference in the transmembrane iron exporter ferroportin expression between control and any of the experimental groups. The results suggest that the anti-aging effects of CR might partially lie in its capacity to reduce or avoid age-related iron accumulation in the brain through down-regulating expression of brain hepcidin--the key negative regulator for intracellular iron efflux--and that facilitating the balance of brain iron metabolism may be a promising anti-aging measure.