Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Abstract

We examined the effects of continuous overexpression of thioredoxin (Trx) 1 on aging in Trx1 transgenic mice [Tg(TXN)+/0]. This study was conducted to test whether increased thioredoxin expression over the lifespan in mice would alter aging and age-related pathology because our previous study demonstrated that Tg(act-TXN)+/0 mice had no significant maximum life extension, possibly due to the use of actin as a promoter, which may have resulted in loss of Trx1 overexpression during aging. To test this hypothesis, we generated new Trx1 transgenic mice using a fragment of the human genome containing the TXN gene with an endogenous promoter to ensure continuous overexpression of Trx1 throughout the lifespan. Universal overexpression of Trx1 was observed, and Trx1 overexpression was maintained during aging (up to 22–24 months old) in the Tg(TXN)+/0 mice. The levels of Trx1 are significantly higher (approximately 4 to 31 fold) in all of the tissues examined in the Tg(TXN)+/0 mice compared to the wild-type (WT) littermates. The overexpression of Trx1 did not cause any changes in the levels of Trx2, glutaredoxin, glutathione, or other major antioxidant enzymes. The survival study demonstrated that male Tg(TXN)+/0 mice slightly extended the earlier part of the lifespan compared to WT littermates, but no significant life extension was observed over the lifespan. The cross-sectional pathological analysis (22–25 months old) showed that Tg(TXN)+/0 mice had a significantly higher severity of lymphoma and more tumor burden than WT mice, which was associated with the suppression of the apoptosis signal-regulating kinase 1 (ASK1) pathway. Our findings suggest that the increased levels of Trx1 over the lifespan in Tg(TXN)+/0 mice showed some beneficial effects (slight extension of lifespan) in the earlier part of life but had no significant effects on median or maximum lifespans, and increased Trx1 levels enhanced tumor development in old mice.

Thioredoxin overexpression in mitochondria showed minimum effects on aging and age-related diseases in male C57BL/6 mice.

“…The cross-sectional pathological analyses of 23 Tg(TXN) +/0 and 19 WT mice (22-24 months old) showed that the major disease in these mice was neoplastic disease. The tumors observed were lymphoma, hemangioma/ hemangiosarcoma in the liver and spleen, pulmonary ad-enocarcinoma, hepatocellular carcinoma, and adenoma in the thyroid gland, and the most prevalent tumor was lymphoma, which is consistent with the pathology data from C57BL/6 mice and mice overexpressing Trx1 [11,13]. First, we compared the number of different types of tumors (tumor burden) for each mouse in both Tg(TXN2) +/0 and WT groups because aging mice may have several different types of tumors.…”

“…The severity of lymphoma was slightly higher in Tg(TXN2) +/0 mice compared to WT mice, although the difference was not statistically significant. These pathological observations indicate that overexpression of Trx2 in mitochondria may play a similar role in the development and growth of lymphoma as the overexpression of Trx1 [11,13], i.e., accelerate the growth and development of lymphoma as they age. Subsequently, we measured several signaling pathways (i.e., mTOR, NFκB, and c-Jun/Fos) because substantial evidence shows that these pathways play important roles in cancer development and lifespan and can also be attenuated by Trx.…”

“…In humans, Trx1 and Trx2 have been identified in different compartments of the cell, i.e., Trx1 in cytosol [8] and Trx2 in mitochondria [9]. To test the pathophysiological roles of Trx1 during aging, two transgenic mice overexpressing Trx1 were generated using: 1) a transgene containing the human thioredoxin cDNA fused to the β-actin promoter [Tg(act-TXN) +/0 mice] [10] and 2) clones of the human TXN gene containing endogenous promoters [Tg(TXN) +/0 ] [11]. The initial aging study demonstrated that Tg(act-TXN) +/0 mice had an increased lifespan compared to their WT littermates [10,12].…”

Thioredoxin and aging: What have we learned from the survival studies?

“…The study showed that the survival curve of Tg(TXN) +/0 mice was not significantly different from WT mice. Although the early part of lifespan (75% survival) showed a 6.3% extension compared to WT mice, no significant life-extending effect was observed over the lifespan [16]. Therefore, our survival data obtained from Tg(TXN) +/0 mice indicate that continuous Trx1 overexpression in mice had some benefits only in the early part of life.…”

“…Next, we generated a new line of Trx1 transgenic mice (Tg(TXN) +/0 ) in order to determine whether continuous overexpression of Trx1 throughout life could extend maximum lifespan. These mice were generated using a fragment of the human genome containing the TXN gene [16]. Tg(TXN) +/0 mice showed significantly higher (approximately 20% to 40%) levels of Trx1 in the tissues than WT mice.…”