Thioredoxin overexpression in mitochondria showed minimum effects on aging and age-related diseases in male C57BL/6 mice.
Thioredoxin overexpression in mitochondria showed minimum effects on aging and age-related diseases in male C57BL/6 mice.
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DOI：
10.31491/apt.2020.03.009
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Ikeno Y
中科院分区：
文献类型：
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作者：
Roman MG;Flores LC;Cunningham GM;Cheng C;Dube S;Allen C;Van Remmen H;Bai Y;Hubbard GB;Saunders TL;Ikeno Y
本研究采用Trx2转基因小鼠[Tg(TXN2]+/0]检测过表达硫氧还蛋白2 （Trx2）对衰老及年龄相关疾病的影响。由于我们之前的研究表明，细胞溶胶（Trx1）中硫氧还蛋白（Trx）的过表达并不能延长最大寿命，因此本研究旨在测试线粒体中Trx2表达的增加是否对衰老和年龄相关病理有有益影响。利用含有TXN2基因的人类基因组片段生成Trx2转基因小鼠。研究了Trx2过表达对雄性Tg(TXN2)+/0小鼠的生存、年龄相关病理、氧化应激和氧化还原敏感信号通路的影响。我们检测的Tg(TXN2)+/0小鼠的所有组织中Trx2水平均显著高于野生型（WT），其表达水平在衰老过程中保持不变（直至22-24个月大）。Trx2过表达不会改变Trx1、谷胱甘肽、谷胱甘肽或其他主要抗氧化酶的水平。与WT小鼠相比，Trx2的过表达与线粒体活性氧（ROS）产生减少和异前列腺素水平降低有关。当我们进行生存研究时，雄性Tg(TXN2)+/0小鼠的平均、中位数和第10百分位寿命略有延长（约8-9%），但生存曲线与WT小鼠无显著差异。横断面病理分析（22-24月龄）显示Tg(TXN2)+/0小鼠淋巴瘤严重程度稍高；然而，肿瘤负担、疾病负担以及肾小球肾炎和炎症的严重程度与WT小鼠相似。Trx2过表达也与较高的c-Jun和c-Fos水平相关；然而，mTOR活性和NFκB p65和p50水平与WT幼崽相似。我们的研究结果表明，在Tg(TXN2)+/0小鼠的一生中，线粒体中Trx2水平的增加显示出轻微的延长寿命的作用，减少线粒体ROS的产生和脂质氧化损伤，但对衰老和年龄相关疾病没有显著影响。
In this study, the effects of overexpression of thioredoxin 2 (Trx2) on aging and age-related diseases were examined using Trx2 transgenic mice [Tg(TXN2]+/0]. Because our previous studies demonstrated that thioredoxin (Trx) overexpression in the cytosol (Trx1) did not extend maximum lifespan, this study was conducted to test if increased Trx2 expression in mitochondria shows beneficial effects on aging and age-related pathology. Trx2 transgenic mice were generated using a fragment of the human genome containing the TXN2 gene. Effects of Trx2 overexpression on survival, age-related pathology, oxidative stress, and redox-sensitive signaling pathways were examined in male Tg(TXN2)+/0 mice. Trx2 levels were significantly higher (approximately 1.6- to 5-fold) in all of the tissues we examined in Tg(TXN2)+/0 mice compared to wild-type (WT) littermates, and the expression levels were maintained during aging (up to 22-24 months old). Trx2 overexpression did not alter the levels of Trx1, glutaredoxin, glutathione, or other major antioxidant enzymes. Overexpression of Trx2 was associated with reduced reactive oxygen species (ROS) production from mitochondria and lower isoprostane levels compared to WT mice. When we conducted the survival study, male Tg(TXN2)+/0 mice showed a slight extension (approximately 8-9%] of mean, median, and 10th percentile lifespans; however, the survival curve was not significantly different from WT mice. Cross-sectional pathological analysis (22-24 months old) showed that Tg(TXN2)+/0 mice had a slightly higher severity of lymphoma; however, tumor burden, disease burden, and severity of glomerulonephritis and inflammation were similar to WT mice. Trx2 overexpression was also associated with higher c-Jun and c-Fos levels; however, mTOR activity and levels of NFκB p65 and p50 were similar to WT littermates. Our findings suggest that the increased levels of Trx2 in mitochondria over the lifespan in Tg(TXN2)+/0 mice showed a slight life-extending effect, reduced ROS production from mitochondria and oxidative damage to lipids, but showed no significant effects on aging and age-related diseases.