Age-Associated Impairment in Brain MAPK Signal Pathways and the Effect of Caloric Restriction in Fischer 344 Rats

Abstract

Mitogen-activated protein kinases (MAPKs) play important roles in cell proliferation, differentiation, and apoptosis. Important functional roles for MAPKs in postmitotic cells have recently been suggested. In the present study, we investigated the effect of aging on the brain ERK (extracellular signal-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 rats was reduced by 36%-59%, compared to 6- and 12-month-old rats (p<.05, 24- vs. 12- or 6-month-old rats). Similarly, the phosphotransferase activities of ERK and p38 MAPK, measured by in vitro immunocomplex kinase assays using myelin basic protein (MBP) as substrate, were shown to be 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, no age-related differences in ERK expression and cellular distribution were observed However, cytosolic ERK tended to aggregate in brain neurons of aged rats. In contrast brain tyrosine-phosphorylated PLCgamma1 did not change with age. Activation of ERK in response to EGF or PMA was also reduced in cortical brain slices of 24-month-old rats. These results demonstrate an age-associated selective impairment in the MAPK signaling pathways. Moreover, lifelong caloric restriction completely prevented the age-related decrease in basal brain ERK activity and diminished the age-related reduction of p38 MAPK activity. Taken together, these data indicate that ERK and p38 MAPK signaling pathways are impaired in the aged brain and that lifelong caloric restriction modulates these defects in brain intracellular signaling pathways.

Age affects ERK1/2 and NRF2 signaling in the regulation of GCLC expression

“…This potentially linked together aging, VSMC proliferation and atherosclerosis (Rivard et al, 2000;Gennaro et al, 2003). These findings in VSMC are in contrast to reports of an age-related decrease in ERK1/2 activation in several different tissues or cells, such as the brain (Zhen et al, 1999), hepatocytes (Hutter et al, 2000), or systems of in vitro senescence (Lorenzini et al, 2002). This discrepancy likely represents tissue and cell specificity and differences in the proliferative capacity of cells.…”

Long-Term Potentiation and Memory

“…In a recent report, it was shown that BDNF mRNA expression in the CA1 of aged rats that performed well in a spatial learning task was enhanced after training, but this increase was not observed in rats which exhibited an impairment in spatial learning and, in addition, basal expression of BDNF mRNA was lower in this group (546). Interestingly, age-related decreases in TrkB expression (116, 544), TrkB phosphorylation (Gooney et al, unpublished data), and ERK activation (235,397,660) have been reported, whereas ERK phosphorylation was decreased in dentate gyrus of aged rats that did not sustain LTP (397).…”

Mitochondrial Energy Metabolism and Redox Signaling in Brain Aging and Neurodegeneration

“…It is unclear whether or not these discrepancies are due to tissue specificity of p38 and ERK responses to the aging process. Nevertheless, the activation of ERK in response to epithelial growth factor is decreased in cortical brain slices and hepatocytes from old rats (148,259), indicating reduced sensitivity to stimuli in these tissues during aging.…”