Abstract
ABSTRACTWe 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.
Highlights
Thioredoxin (Trx) was first recognized in the early 1960s as the reductant for a variety of enzymes and has been found in various mammalian species
Some of the physiologically important roles of Trx include: 1) acting as a hydrogen donor for enzymes involved in reductive reactions [3,4,5,6,7,8]; 2) maintaining a reduced environment in cells [9]; 3) controlling protein function via the redox state [10,11,12] and the expression of target genes; 4) protecting cells and tissues from oxidative stress [13]; and 5) having anti-apoptotic effects through the inhibition of the ASK [14] and mitochondrial pathways [15]
We previously conducted an aging study with Trx transgenic mice [transgenic mouse (Tg)(act-TXN)+/0] [20] and demonstrated that Trx overexpression showed resistance to oxidative stress, which was associated with an extension of only the earlier part of lifespan compared to WT littermates [20]
Summary
Thioredoxin (Trx) was first recognized in the early 1960s as the reductant for a variety of enzymes and has been found in various mammalian species. There are two forms of Trx in humans: 1) Trx, which is located in the cytosol [1]; and 2) Trx, which is located in the mitochondria [2] Both Trx and 2 play essential biological roles in mammals. We previously conducted an aging study with Trx transgenic mice [Tg(act-TXN)+/0] [20] and demonstrated that Trx overexpression showed resistance to oxidative stress, which was associated with an extension of only the earlier part of lifespan compared to WT littermates [20]. We hypothesized that the Tg(act-TXN)+/0 mice did not show an
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