Thioredoxin down-regulation in the cytosol in thioredoxin  2 transgenic mice did not have beneficial effects to extend  lifespan in male C57BL/6 mice

Madeline G. Roman; Lisa C. Flores; Geneva M. Cunningham; Christie Cheng; Colton Allen; Yidong Bai; Gene B. Hubbard; Yuji Ikeno

Thioredoxin down-regulation in the cytosol in thioredoxin 2 transgenic mice did not have beneficial effects to extend lifespan in male C57BL/6 mice

Madeline G. Roman, Lisa C. Flores, Geneva M. Cunningham, Christie Cheng, Colton Allen, Yidong Bai, Gene B. Hubbard, Yuji Ikeno

Abstract

Background: This study was conducted to test the effects of thioredoxin (Trx)1 down-regulation in Trx2 transgenic [Tg(TXN2) +/0] mice on lifespan and age-related diseases. Our previous study with Tg(TXN2) +/0 mice showed that mitochondrial Trx overexpression produced minimal life-extending effects with a slightly elevated severity of lymphoma and another study with a limited number of Trx1KO mice showed that there was a slight reduction of neoplastic lesions. Thus, this study was aimed to test if reduced Trx1 expression in combination with elevated Trx2 has beneficial effects on lifespan in mice by attenuating age-related diseases, specifically cancer.

Methods: Trx2 hemizygous transgenic and Trx1 heterozygous knockout mice [Tg(TXN2) +/0 x Trx1KO] were generated for survival and cross-sectional pathology experiments.

Results: Tg(TXN2) +/0 x Trx1KO mice showed significantly higher (approximately 1.5- to 3-fold) Trx2 levels and significantly less (approximately 50% less) Trx1 levels in all of the tissues we examined compared to wildtype (WT) littermates. Trx1 down-regulation along with Trx2 overexpression did not change the levels of glutathione or other major antioxidant enzymes. Male Tg(TXN2) +/0 x Trx1KO mice demonstrated only a slight extension of lifespan in the early part of life and no significant effects on the later part of life were observed, which was similar to our previous study with Tg(TXN2) +/0 mice. Tg(TXN2) +/0 x Trx1KO mice had similar tumor burden, disease burden, incidence and severity of lymphoma, and severity of glomerulonephritis compared to WT mice at 22-26 months.

Conclusions: Our findings suggest that the combined Trx down-regulation in cytosol along with upregulation in mitochondria of Tg(TXN2) +/0 x Trx1KO mice did not provide beneficial effects on aging, i.e., extend the lifespan or reduce age-related pathology compared to WT mice.

Keywords: Thioredoxin, transgenic mouse, knockout mouse, aging, cancer

Aging Pathobiology and Therapeutics