Roman Madeline G, Flores Lisa C, Cunningham Geneva M, Cheng Christie, Allen Colton, Hubbard Gene B, Bai Yidong, 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.
Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Aging Pathobiol Ther. 2020;2(3):126-133. doi: 10.31491/apt.2020.09.028.
Our laboratory has conducted the first systematic survival studies to examine the biological effects of the antioxidant protein thioredoxin (Trx) on aging and age-related pathology. Our studies with C57BL/6 mice overexpressing Trx1 [Tg(act-TRX1) and Tg(TXN)) demonstrated a slight extension in early lifespan compared to wild-type (WT) mice; however, no significant effects were observed in the later part of life. Overexpression of Trx2 in male C57BL/6 mice [Tg(TXN2)] demonstrated a slightly extended lifespan compared to WT mice. The pathology results from two lines of Trx1 transgenic mice showed a slightly higher incidence of age-related neoplastic diseases compared to WT mice, and a slight increase in the severity of lymphoma, a major neoplastic disease, was observed in Trx2 transgenic mice. Together these studies indicate that Trx overexpression in one compartment of the cell (cytosol or mitochondria alone) has marginal beneficial effects on lifespan. On the other hand, down-regulation of Trx in either the cytosol (Trx1KO) or mitochondria (Trx2KO) showed no significant changes in lifespan compared to WT mice, despite several changes in pathophysiology of these knockout mice. When we examined the synergetic effects of overexpressing Trx1 and Trx2, TXNTg x TXN2Tg mice showed a significantly shorter lifespan with accelerated cancer development compared to WT mice. These results suggest that synergetic effects of Trx overexpression in both the cytosol and mitochondria on aging are deleterious and the development of age-related cancer is accelerated. On the other hand, we have recently found that down-regulation of Trx in both the cytosol and mitochondria in Trx1KO x Trx2KO mice has beneficial effects on aging. The results generated from our lab along with our ongoing study using Trx1KO x Trx2KO mice could elucidate the key pathways (i.e., apoptosis and autophagy) that prevent accumulation of damaged cells and genomic instability leading to reduced cancer formation.
我们的实验室开展了首个系统性生存研究，以检验抗氧化蛋白硫氧还蛋白（Trx）对衰老及与年龄相关病理状况的生物学效应。我们对过表达Trx1的C57BL/6小鼠[转Tg(act-TRX1)和Tg(TXN)基因小鼠]的研究表明，与野生型（WT）小鼠相比，其早期寿命略有延长；然而，在生命后期未观察到显著影响。雄性C57BL/6小鼠[转Tg(TXN2)基因小鼠]过表达Trx2后，与WT小鼠相比，寿命略有延长。来自两系Trx1转基因小鼠的病理学结果显示，与WT小鼠相比，与年龄相关的肿瘤性疾病发病率略高，并且在Trx2转基因小鼠中观察到主要肿瘤性疾病淋巴瘤的严重程度略有增加。这些研究共同表明，在细胞的一个区室（仅胞质溶胶或线粒体）中过表达Trx对寿命具有边际有益效应。另一方面，胞质溶胶（Trx1基因敲除）或线粒体（Trx2基因敲除）中Trx的下调与WT小鼠相比，寿命未显示出显著变化，尽管这些基因敲除小鼠的病理生理学有若干改变。当我们检验过表达Trx1和Trx2的协同效应时，与WT小鼠相比，TXNTg×TXN2Tg小鼠的寿命显著缩短，癌症发展加速。这些结果表明，胞质溶胶和线粒体中Trx过表达对衰老的协同效应是有害的，并且与年龄相关癌症的发展加速。另一方面，我们最近发现，Trx1基因敲除×Trx2基因敲除小鼠的胞质溶胶和线粒体中Trx的下调对衰老具有有益效应。我们实验室产生的结果以及我们正在使用Trx1基因敲除×Trx2基因敲除小鼠进行的研究可能会阐明防止受损细胞积累和基因组不稳定从而减少癌症形成的关键途径（即凋亡和自噬）。
