Department of Pathophysiology, Yokohama College of Pharmacy, Matano-cho 601, Totsuka-ku, Yokohama 245-0066, Japan.
Arch Gerontol Geriatr. 2012 Mar-Apr;54(2):e1-7. doi: 10.1016/j.archger.2011.06.006. Epub 2011 Jul 23.
SAMP8 mice show spontaneously accelerated aging and a short life span with systemic accumulation of oxidative stress. Nrf2 translocates into the nucleus upon oxidative stress and induces the expression of detoxifying and antioxidant enzymes. Recently, several studies reported that Nrf2 is associated with aging and various diseases. In the present study, we investigated the levels of Nrf2 nuclear translocation and phosphorylation of Akt and GSK-3β in livers of SAMP8 and normal aging SAMR1 mice. The protein level of Nrf2 in the nucleus of the liver was significantly decreased in SAMP8 at 10 months old compared with that in age-matched SAMR1. The protein level of Keap1, which anchors Nrf2 in the cytoplasm, did not differ between SAMP8 and SAMR1. In addition, the mRNA expression of Nrf2 in the liver of SAMP8 was significantly lower than that of SAMR1. Moreover, mRNA levels of detoxification and antioxidant enzymes, GSTa1 and NQO1, were significantly decreased in SAMP8 compared with SAMR1. These results indicate that a higher level of oxidative stress in SAMP8 might be caused by a lower level of Nrf2. Furthermore, the phosphorylation of Akt and GSK-3β was significantly decreased in the liver of SAMP8 at 10 months old. Recent studies have suggested that the Akt/GSK-3β signaling pathway is involved in the nuclear translocation of Nrf2. Therefore, it is suggested that the reduction of the translocation of Nrf2 into the nucleus might be induced by a decrease of GSK-3β phosphorylation, resulting in an increase of oxidative stress in SAMP8 mice.
SAMP8 小鼠表现出自发性加速衰老和寿命缩短，伴有全身氧化应激积累。Nrf2 在氧化应激时易位到细胞核，并诱导解毒和抗氧化酶的表达。最近，有几项研究报道 Nrf2 与衰老和各种疾病有关。在本研究中，我们研究了 SAMP8 和正常衰老 SAMR1 小鼠肝脏中 Nrf2 核易位和 Akt 和 GSK-3β磷酸化的水平。与年龄匹配的 SAMR1 相比，10 个月大的 SAMP8 肝脏中 Nrf2 核内的蛋白水平显著降低。将 Nrf2 锚定在细胞质中的 Keap1 蛋白水平在 SAMP8 和 SAMR1 之间没有差异。此外，SAMP8 肝脏中 Nrf2 的 mRNA 表达明显低于 SAMR1。此外，与 SAMR1 相比，SAMP8 中的解毒和抗氧化酶 GSTa1 和 NQO1 的 mRNA 水平显著降低。这些结果表明，SAMP8 中更高水平的氧化应激可能是由于 Nrf2 水平较低引起的。此外，10 个月大的 SAMP8 肝脏中 Akt 和 GSK-3β 的磷酸化显著降低。最近的研究表明，Akt/GSK-3β 信号通路参与了 Nrf2 的核易位。因此，Nrf2 易位入核的减少可能是由于 GSK-3β 磷酸化减少引起的，导致 SAMP8 小鼠氧化应激增加。
