Roman Madeline G, Flores Lisa C, Cunningham Geneva M, Cheng Christie, Dube Sara, Allen Colton, Van Remmen Holly, Bai Yidong, Hubbard Gene B, Saunders Thomas L, Ikeno Yuji
Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Aging Pathobiol Ther. 2020;2(1):20-31. doi: 10.31491/apt.2020.03.009. Epub 2020 Mar 27.
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]]. 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) mice.
Trx2 levels were significantly higher (approximately 1.6- to 5-fold) in all of the tissues we examined in Tg(TXN2) 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) 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) 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) 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.
在本研究中，使用硫氧还蛋白2（Trx2）转基因小鼠【Tg(TXN2)】研究Trx2过表达对衰老及与年龄相关疾病的影响。由于我们之前的研究表明，胞质中硫氧还蛋白（Trx）过表达（Trx1）并未延长最大寿命，因此本研究旨在测试线粒体中Trx2表达增加是否对衰老及与年龄相关的病理变化具有有益作用。
使用包含TXN2基因的人类基因组片段构建Trx2转基因小鼠。在雄性Tg(TXN2)小鼠中研究Trx2过表达对生存、与年龄相关的病理变化、氧化应激和氧化还原敏感信号通路的影响。
与野生型（WT）同窝小鼠相比，在我们检测的所有Tg(TXN2)小鼠组织中，Trx2水平显著更高（约1.6至5倍），且其表达水平在衰老过程中（直至22至24月龄）保持稳定。Trx2过表达未改变Trx1、谷氧还蛋白、谷胱甘肽或其他主要抗氧化酶的水平。与WT小鼠相比，Trx2过表达与线粒体活性氧（ROS）生成减少及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)小鼠的平均、中位数和第10百分位数寿命略有延长（约8 - 9%）；然而，生存曲线与WT小鼠无显著差异。横断面病理分析（22至24月龄）显示，Tg(TXN2)小鼠淋巴瘤的严重程度略高；然而，肿瘤负荷、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过表达还与更高的c-Jun和c-Fos水平有关；然而，mTOR活性以及NFκB p65和p50水平与WT同窝小鼠相似。
我们的研究结果表明，Tg(TXN2)小鼠一生中线粒体中Trx2水平升高显示出轻微的寿命延长效应，减少了线粒体ROS生成和脂质氧化损伤，但对衰老及与年龄相关疾病无显著影响。
