Thioredoxin-2 affects lifespan and oxidative stress in Drosophila

Svensson, Malin J.; Larsson, Jonas

doi:10.1111/j.2007.0018-0661.01990.x

Cited by 53 publications

(36 citation statements)

References 30 publications

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“…Moreover, the trx-2;dhd and trx-2;trxT double mutants were similar in longevity to the trx-2 single-mutant flies. Using a P-element Trx-2 transgene, it was possible to not only rescue the longevity deficits for all of the mutants, but also to slightly extend the life span relative to the wild-type control under both normal conditions and under OS (exposure to paraquat) (112). Because only one transgenic line was used and because the randomness of transgene insertion in the genome can have a confounding effect, the results of these experiments should be regarded as tentative.…”

Section: Thioredoxinsmentioning

confidence: 99%

Involvement of Redox State in the Aging ofDrosophila melanogaster

Orr

Radyuk

Sohal

2013

Antioxidants & Redox Signaling

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Significance: The main objective of this review was to provide an exposition of investigations, conducted in Drosophila melanogaster, on the role of reactive oxygen species and redox state in the aging process. While early transgenic studies did not clearly support the validity of the oxidative stress hypothesis of aging, predicated on the accumulation of structural damage, they spawned a broader search for redox-related effects that might impact the aging process. Recent Advances: Initial evidence implicating the thiol redox state as a possible causative factor in aging has been obtained in Drosophila. Overexpression of genes, such as GCL, G6PD, Prx2, and Prx5, which are involved in the maintenance of thiol redox homeostasis, has strong positive effects on longevity. Further, the depletion of peroxiredoxin activity in the mitochondria through the double knockdown of Prx5 and Prx3 not only results in a redox crisis but also elicits a rapid aging phenotype. Critical Issues: Herein, we summarize the present status of knowledge about the main components of the machinery controlling thiol redox homeostasis and describe how age-related redox fluctuations might impact aging more acutely through disruption of the redox-sensitive signaling mechanisms rather than via the simple accumulation of structural damage. Future Directions: Based on these initial insights into the plausible impact of redox fluctuations on redox signaling, future studies should focus on the pathways that have been explicitly implicated in aging, such as insulin signaling, TOR, and JNK/FOXO, with particular attention to elements that are redox sensitive. Antioxid. Redox Signal. 19, 788-803. Historical BackgroundLinkage between energy utilization and life span S tudies in the fruit fly, Drosophila melanogaster, have historically made important contributions toward the development of basic concepts in many areas of biology, including the aging process, especially in defining the role of oxygen metabolism in the determination of life span. In 1917, Loeb and Northrop showed that the life span of D. melanogaster is inversely associated with the ambient temperature (61), which, in turn, was later demonstrated to be linked to the rate of oxygen consumption within the physiological range, whose upper limit for long-term survival and optimal fecundity is *27°C (67). A major advance in the field of aging that can be largely credited to the Drosophila model was Pearl's (77) interpretation of the effects of temperature on longevity, namely, shorter life spans at elevated temperatures are ascribable to a relatively higher physical activity or the rate of living (ROL). As originally proposed, the length of life of an individual organism is governed by two distinct factors: (i) a genetically determined metabolic potential, that is, the total amount of energy consumed during life, which varies in different genotypes, and (ii) the rate at which this metabolic potential is expended by the individual or the rate of its metabolism. It is a widely recognized phe...

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Section: Thioredoxinsmentioning

confidence: 99%

Involvement of Redox State in the Aging ofDrosophila melanogaster

Orr

Radyuk

Sohal

2013

Antioxidants & Redox Signaling

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“…The Trx-2 gene is located in region 30C on chromosome 2L, and the protein has been crystallized, in both reduced and oxidized forms (Wahl et al 2005), and characterized in vitro (Bauer et al 2002). In vivo, Trx-2 has been shown to have moderate effects on both life span and resistance to oxidative stress (Svensson and Larsson 2007). In contrast to Trx-2, both DHD and TrxT are sexspecific thioredoxins.…”

Section: Introductionmentioning

confidence: 99%

Organization and regulation of sex-specific thioredoxin encoding genes in the genus Drosophila

2007

Self Cite

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Thioredoxins are small thiol proteins that have a conserved active site sequence, WCGPC, and reduce disulfide bonds in various proteins using the two active site cysteines, a reaction that oxidizes thioredoxin and renders it inactive. Thioredoxin reductase returns thioredoxin to its reduced, active form in a reaction that converts NADPH to NADP(+). The biological functions of thioredoxins vary widely; they have roles in oxidative stress protection, act as electron donors for ribonucleotide reductase, and form structural components of enzymes. To date, three thioredoxin genes have been characterized in Drosophila melanogaster: the generally expressed Thioredoxin-2 (Trx-2) and the two sex-specific genes ThioredoxinT (TrxT) and deadhead (dhd). The male-specific TrxT and the female-specific dhd are located as a gene pair, transcribed in opposite directions, with only 470 bp between their transcription start points. We show in this study that all three D. melanogaster thioredoxins are conserved in 11 other Drosophilid species, which are believed to have diverged up to 40 Ma ago and that Trx-2 is conserved all the way to Tribolium castaneum. We have found that the intriguing gene organization and regulation of TrxT and dhd is remarkably well conserved and identified potential conserved regulatory sequences. In addition, we show that the 50-70 C terminal amino acids of TrxT constitute a hyper-variable domain, which could play a role in sexual conflict and male-female co-evolution.

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“…The important roles of Trx in oxidative stress and longevity have been well documented by studies with C. elegans and Drosophila [18,19]; however, the exact roles of Trx in aging and age-related diseases in mammals have not been fully explored. Thus, 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].…”

Section: Introductionmentioning

confidence: 99%

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

Flores

Roman

Cunningham

et al. 2018

Pathobiology of Aging & Age-related Diseases

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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.

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Thioredoxin-2 affects lifespan and oxidative stress in Drosophila

Cited by 53 publications

References 30 publications

Involvement of Redox State in the Aging ofDrosophila melanogaster

Involvement of Redox State in the Aging ofDrosophila melanogaster

Organization and regulation of sex-specific thioredoxin encoding genes in the genus Drosophila

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

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