The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction

Food restriction of adult rodents increases lifespan, with commensurate attenuation of age-related pathological lesions in many organs, as well as attenuation of normal ageing changes that are distinct from gross lesions. Previous work showed that chronic food restriction attenuated age-associated astrocyte and microglial hyperactivity in the hippocampal hilus, as measured by expression of glial fibrillary acidic protein and major histocompatibility complex II antigen (OX6). Here, we examined other markers of astrocyte and microglial activation in gray and white matter regions of ad libitum-fed (Brown Norway x Fischer 344) F₁ male rats aged three and 24 months and chronic food-restricted rats aged 24 months. In situ hybridization and immunohistochemical techniques evaluated glial expression of glial fibrillary acidic protein, apolipoprotein E, apolipoprotein J (clusterin), heme oxygenase-1, complement 3 receptor (OX42), OX6 and transforming growth factor-β1. All markers were elevated in the corpus callosum during ageing and were attenuated by food restriction, but other regions showed marked dissociation of the extent and direction of changes. Astrocytic activation, as measured with glial fibrillary acidic protein expression (coding and intron-containing RNA, immunoreactivity), increased with age in the corpus callosum, basal ganglia and hippocampus. Generally, food restriction attenuated the age-related increase in glial fibrillary acidic protein messenger RNA and immunoreactivity. Food restriction also reduced the age- related increase in apolipoprotein J and E messenger RNA and heme oxygenase- 1 immunoreactivity in the basal ganglia and corpus callosum. However, astrocytes in the hilus of the hippocampus showed an age-related decrease in apolipoprotein J and E messenger RNA, which was further intensified by food restriction. The age-associated microglial activation measured by OX6 and OX42 immunoreactivity was reduced by food restriction in most subregions. The localized subsets of glial age changes and effects of food restriction comprise a mosaic of ageing consistent with the regional heterogeneity of ageing changes reported by others. In particular, age has a differential effect on astrocytic and microglial hyperactivity in gray versus white matter areas. The evident mosaic of glial ageing and responses to food restriction suggests that multiple mechanisms are at work during ageing.