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

Food restriction of adult rodents increases lifespan, with commensurate att enuation of age-related pathological lesions in many organs, as well as att enuation of normal ageing changes that are distinct from gross lesions. Pre vious work showed that chronic food restriction attenuated age-associated a strocyte and microglial hyperactivity in the hippocampal hilus, as measured by expression of glial fibrillary acidic protein and major histocompatibil ity complex II antigen (OX6). Here, we examined other markers of astrocyte and microglial activation in gray and white matter regions of ad libitum-fe d (Brown Norway x Fischer 344) F-1 male rats aged three and 24 months and c hronic food-restricted rats aged 24 months. In situ hybridization and immun ohistochemical techniques evaluated glial expression of glial fibrillary ac idic protein, apolipoprotein E, apolipoprotein J (clusterin), heme oxygenas e-1, complement 3 receptor (OX42), OX6 and transforming growth factor-pr. A ll markers were elevated in the corpus callosum during ageing and were atte nuated by food restriction, but other regions showed marked dissociation of the extent and direction of changes. Astrocytic activation, as measured wi th glial fibrillary acidic protein expression (coding and intron-containing RNA, immunoreactivity), increased with age in the corpus callosum, basal g anglia and hippocampus. Generally, food restriction attenuated the age-rela ted increase in glial fibrillary acidic protein messenger RNA and immunorea ctivity. Food restriction also reduced the age-related increase in apolipop rotein J and E messenger RNA and heme oxygenase-1 immunoreactivity in the b asal ganglia and corpus callosum. However, astrocytes in the hilus of the h ippocampus showed an age-related decrease in apolipoprotein J and E messeng er RNA, which was further intensified by food restriction. The age-associat ed microglial activation measured by OX6 and OX42 immunoreactivity was redu ced 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 a geing changes reported by others. In particular, age has a differential eff ect 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. (C) 1999 IBRO . Published by Elsevier Science Ltd.