Age-associated impairment in brain MAPK signal pathways and the effect of caloric restriction in Fischer 344 rats.
Age-associated impairment in brain MAPK signal pathways and the effect of caloric restriction in Fischer 344 rats.
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DOI：
10.1093/gerona/54.12.b539
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发表时间：
1999-12
期刊：
影响因子：
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通讯作者：
X. Zhen;K. Uryu;G. Cai;G. P. Johnson;E. Friedman
中科院分区：
文献类型：
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作者：
X. Zhen;K. Uryu;G. Cai;G. P. Johnson;E. Friedman
丝裂原激活蛋白激酶 (MAPK) 在细胞增殖、分化和凋亡中发挥重要作用。最近有人提出 MAPK 在有丝分裂后细胞中的重要功能作用。在本研究中，我们研究了衰老对 Fischer 344 大鼠大脑 ERK（细胞外信号调节激酶）和 p38 MAPK 信号通路的影响。结果显示，与 6 个月和 12 个月大的大鼠相比，24 个月大的大鼠皮质中基础酪氨酸磷酸化的 ERK1/ERK2 减少了 36%-59%（p<.05，24 与 12 或 6 个月大的大鼠相比）。同样，通过使用髓磷脂碱性蛋白 (MBP) 作为底物的体外免疫复合物激酶测定法测量的 ERK 和 p38 MAPK 磷酸转移酶活性，在 24 个月大的大鼠的大脑皮层中分别降低了约 50% 和 59%（p<.01，24 月龄大鼠与 12 月龄或 6 月龄大鼠相比）。根据 Western 分析评估，基础 ERK 和 p38 MAPK 活性的降低并不是由于这些激酶的蛋白质水平改变所致。免疫组织化学显示，没有观察到 ERK 表达和细胞分布与年龄相关的差异。然而，细胞质 ERK 倾向于在老年大鼠的脑神经元中聚集。相比之下，大脑中酪氨酸磷酸化的 PLCgamma1 并没有随着年龄的增长而改变。在 24 个月大的大鼠的皮质脑切片中，ERK 对 EGF 或 PMA 的激活也有所减少。这些结果表明 MAPK 信号通路存在与年龄相关的选择性损伤。此外，终身热量限制完全阻止了与年龄相关的基础脑 ERK 活性下降，并减少了与年龄相关的 p38 MAPK 活性下降。总而言之，这些数据表明 ERK 和 p38 MAPK 信号通路在衰老的大脑中受损，并且终身热量限制调节了大脑细胞内信号通路中的这些缺陷。
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.