Age-associated impairment in brain MAPK signal pathways and the effect of caloric restriction in Fischer 344 rats

Mitogen-activated protein kinases (MAPKs) play important roles in cell prol iferation, differentiation, and apoptosis. Important functional roles for M APKs ill postmitotic cells have recently been suggested. bl the present stu dy, we investigated the effect of aging oil the brain ERK (extracellular si gnal-regulated kinase) and p38 MAPK signaling pathways of Fischer 344 rats. The results show that basal tyrosine-phosphorylated ERK1/ERK2 in cortex of 24-month-old mts was reduced by 36%-59% compared to 6- and 12-month-old ra ts (p < .05, 24- vs 12- or 6-month-old rats). Similarly, the phos-photransf erase activities of ERE: and p38 MAPK, measured by in vitro immunocomplex k inase assays using myelin basic protein (MBP) as substrate, were shown to b e reduced approximately 50% and 59%, respectively, in the cerebrocortex of 24-month-old rats (p < .01, 24- vs 12- or 6-month-old rats). The reductions in basal ERK and p38 MAPK activities are not due to altered protein levels of these kinases as assessed by Western analysis. Immunohistochemically, n o age-related differences ill ERK expression and cellular distribution,were observed, However, cytosolic ERK tended to aggregate in brain neurons of a ged rats. In contrast, brain tyrosine-phosphorylated PLC gamma 1 did not ch ange with age. Activation of ERK in response to EGF or PMA was also reduced ill cortical brain slices of 24-month-old rats. These results demonstrate an age-associated selective impairment ill the MAPK signaling pathways. Mor eover lifelong caloric restriction completely prevented the age-related dec rease in basal brain ERK activity and diminished the age-related reduction of p38 MAPK activity. Taken together, these data ildicate that ERI( and p38 MAPK signaling pathways are impaired in the aged brain and that lifelong c aloric restriction modulates these defects in brain intracellular signaling pathways.