Open Access

Thioredoxin, oxidative stress, cancer and aging

  • Lisa C Flores1,
  • Melanie Ortiz1,
  • Sara Dube1,
  • Gene B Hubbard1, 2,
  • Shuko Lee4,
  • Adam Salmon1, 3, 5,
  • Yiqiang Zhang1 and
  • Yuji Ikeno1, 2, 4, 5Email author
Longevity & Healthspan20121:4

https://doi.org/10.1186/2046-2395-1-4

Received: 20 March 2012

Accepted: 20 June 2012

Published: 3 September 2012

Abstract

The Free Radical or Oxidative Stress Theory of Aging is one of the most popular theories in aging research and has been extensively studied over the past several decades. However, recent evidence using transgenic/knockout mice that overexpress or down-regulate antioxidant enzymes challenge the veracity of this theory since the animals show no increase or decrease in lifespan. These results seriously call into question the role of oxidative damage/stress in the aging process in mammals. Therefore, the theory requires significant modifications if we are to understand the relationship between aging and the regulation of oxidative stress. Our laboratory has been examining the impacts of thioredoxins (Trxs), in the cytosol and mitochondria, on aging and age-related diseases. Our data from mice that are either up-regulating or down-regulating Trx in different cellular compartments, that is, the cytosol or mitochondria, could shed some light on the role of oxidative stress and its pathophysiological effects. The results generated from our lab and others may indicate that: 1) changes in oxidative stress and the redox state in the cytosol, mitochondria or nucleus might play different roles in the aging process; 2) the role of oxidative stress and redox state could have different pathophysiological consequences in different tissues/cells, for example, mitotic vs. post-mitotic; 3) oxidative stress could have different pathophysiological impacts in young and old animals; and 4) the pathophysiological roles of oxidative stress and redox state could be controlled through changes in redox-sensitive signaling, which could have more diverse effects on pathophysiology than the accumulation of oxidative damage to various molecules. To critically test the role of oxidative stress on aging and age-related diseases, further study is required using animal models that regulate oxidative stress levels differently in each cellular compartment, each tissue/organ, and/or at different stages of life (young, middle and old) to change redox sensitive signaling pathways.

Keywords

Thioredoxin Transgenic mouse Knockout mouse Oxidative stress Cancer aging

Review

Oxidative stress theory of aging

The Free Radical or Oxidative Stress Theory of Aging is one of the most popular theories in aging research and has been extensively studied over the past several decades. This theory is based on the fact that cells exist in a chronic state of oxidative stress resulting from an imbalance between pro-oxidants and antioxidants. Because of this imbalance, which occurs as a consequence of aerobic metabolism, it is proposed that an accumulation of oxidative damage occurs with age in a variety of macromolecules within the cell. This steady state of increased oxidative damage is proposed to be an important factor in the age-related increase in pathology and the progressive decline in the functional efficiency of various cellular processes [13].

One consistent line of evidence to support the oxidative stress hypothesis of aging is the large amount of data that has shown an age-related increase of oxidative damage in a variety of molecules (lipids, proteins and DNA) in organisms ranging from invertebrates to humans [1, 410]. Another strong line of evidence comes from manipulation studies that increase lifespan. Calorie restriction (CR), which extends lifespan and delays aging in various species, has been shown to reduce the level of oxidative damage in tissues as measured by a decrease in lipofuscin [1113], lipid peroxidation [1318], protein oxidation [10, 1923] and DNA oxidation [2426]. Subsequently, CR mice have also been shown to be more resistant to oxidative stress [2]. Mutations in the insulin/IGF-1 signaling pathways (age-1 daf 2, and daf 16 mutants) of Caenorhabditis elegans showed an increase in lifespan, which was also correlated with increased resistance to oxidative stress [27] and reduced oxidative damage [28]. More recently, several genetic mouse models of longevity have been reported, for example, Ames and Snell dwarf mice, p66 sch−/− mice, and Igf1r +/− female mice [29], and the increased lifespan in these models has been correlated to increased resistance to oxidative stress [30]. Thus, the observations that experimental manipulations that increase lifespan in rodents and invertebrates are correlated to increased resistance to oxidative stress or reduced oxidative damage have provided strong evidence in support of the oxidative stress theory of aging. However, all the experimental manipulations that increase lifespan also alter processes beyond oxidative stress/damage; therefore, the increased longevity in these animal models could arise through other mechanisms. A recent study using naked mole-rats, which have a lifespan approaching 30 years, showed an increased amount of oxidative damage compared to the short-lived mouse [31] and calls into question the role of oxidative damage in aging.

Transgenic (TG)/knockout (KO) animal models for the free radical/oxidative stress theory of aging

Transgenic/knockout animals provide investigators with a unique system for studying the underlying mechanisms of various biological processes and have been used to conduct numerous studies to test the various theories of aging. The most direct test of the oxidative stress hypothesis of aging is to alter the accumulation of oxidative damage and determine its effect on aging/lifespan. Over the past two decades, investigators have used Drosophila or mice with genetic alterations in the antioxidant defense system as a strategy to alter the age-related accumulation of oxidative damage. Data from these studies have the potential to establish a causative role for oxidative stress/damage in aging. However, studies between Drosophila and mice have shown inconsistent results, raising the possibility that differences in species might affect the outcome of a genetic manipulation on lifespan.

Drosophila

In the initial studies using P-element mediated transformation, researchers introduced either Cu/Zn superoxide dismutase (SOD) [3234] or catalase [35] into Drosophila; the survival of the resulting flies was not significantly different from their wild-type controls. Subsequently, Orr and Sohal [36] reported that overexpression of both Cu/ZnSOD and catalase significantly increased (from 14 to 34%) maximum lifespan and increased the mortality rate doubling time from 20% to 37%. Additionally, these transgenic lines of Drosophila had significantly lower levels of protein and DNA oxidation [36, 37]. However, these studies are complicated because the placement of P-elements has been shown to alter lifespan independently [38, 39]. Using a combined total of over 90,000 flies to minimize the problem of P-element insertion, Orr et al.[40] found that the overexpression of both Cu/ZnSOD and catalase had no beneficial effects on survivorship and was in fact associated with slightly decreased lifespans in long-lived Drosophila strains. Investigators have also used inducible systems to overexpress antioxidant genes in Drosophila to circumvent the problem of P-element insertion. These studies have shown that overexpression of Cu/ZnSOD or MnSOD increased the lifespan of Drosophila, but overexpression of catalase had no benefit [41, 42]. Parkes et al.[43] showed that the induced overexpression of Cu/ZnSOD selectively targeted to motor neurons resulted in a 40% increase in lifespan in Drosophila and increased resistance to oxidative stress. Two groups studied the effect of inducing the overexpression of methionine sulfoxide reductase A (MsrA), which repairs oxidized methionine, in Drosophila. Chavous et al.[44, 45] showed that overexpressing MsrA 3- to 7-fold resulted in a 32% to 39% extension in lifespan, while Ruan et al.[46] showed that the overexpression of MsrA in the nervous system of Drosophila increased the fly’s lifespan and resistance to oxidative stress.

Mice

Several groups have genetically altered various components of the antioxidant defense system in mice. In 1987, Epstein’s laboratory produced a transgenic mouse that overexpressed human Cu/ZnSOD 1.6- to 6-fold in various tissues [47]. These transgenic mice were more resistant to cerebral ischemia [48, 49], but their lifespan was the same as the wild-type mice [50]. Survival studies with various transgenic mice have also shown negative results. Our group has conducted survival studies using mice that overexpress Cu/ZnSOD, MnSOD, catalase (in peroxisomes), Cu/ZnSOD and MnSOD, and Cu/ZnSOD and catalase; these transgenic mice were not observed to have an increased lifespan compared to their wild-type littermates [51]. On the other hand, transgenic mice that overexpressed catalase in mitochondria showed an increase in lifespan, which was associated with reduced oxidative damage [52]. In contrast, Shriner et al.[52] and Richardson’s laboratory showed that the overexpression of catalase in the cytosol (peroxisomes) did not significantly increase lifespan. Therefore, overexpression of antioxidant enzymes does not appear to increase the lifespan of mice, except for the study by Schriner et al.[52], which indicates that altering the antioxidant defense system in mitochondria may be more important than in the cytosol.

There is also considerable information on the effect of under-expressing antioxidant enzymes on aging.

Our group has studied the effect of reduced expression of MnSOD on aging and pathology using mice heterozygous for the Sod2 gene (Sod2 +/− mice). The Sod2 +/− mice showed higher levels of DNA oxidation and a higher incidence of cancer. However, there was no difference in the lifespan between the Sod2 +/− and wild-type mice [53]. Cu/ZnSOD null mice, which lack Cu/ZnSOD, were shown to have a shorter lifespan compared to the wild-type control mice [54]. The short lifespan of these knockout mice (in the C57BL/6 background) appears to be due to a high incidence (approximately 90%) of hepatocellular carcinoma, which was not observed in wild-type mice in the C57BL/6 genetic background. Our recent studies demonstrated that the survival curves of mice that were deficient in Glutathione peroxidase 1 (GPX1) and MnSOD (including genotypes: Gpx1 −/− Sod2 +/− Gpx1 +/− x Sod2 +/− Gpx1 −/− x Sod2 +/− ) are essentially the same as wild-type mice. These results are also inconsistent with the oxidative stress theory of aging.

Lethality (either by developmental defects or increased uncommon cancers) by the complete absence of some antioxidant enzymes strongly suggests the essential roles antioxidant enzymes play in maintaining cellular and physiological homeostasis in the body. However, based on the data obtained from transgenic and knockout mice, the changing oxidative damage levels by alterations of major antioxidant enzymes does not seem to have a significant impact on lifespan. More importantly, the study by Schriner et al.[52] suggests that changes in oxidative stress and the redox state in different cellular compartments, that is, the cytosol or mitochondria, might play different roles in the aging process. Additionally, the mitochondria are a major source of reactive oxygen species (ROS) and substantial evidence suggests that ROS could play important roles in altering cellular signaling pathways [5557], which could have a more significant impact on aging than the accumulation of oxidative damage.

Thioredoxin and biological functions

Thioredoxin (Trx) was first recognized in the early 1960s as the reductant for a variety of enzymes. Trx is a small protein (12 kDa) with two redox-active cysteine residues in the active center (Cys-Gly-Pro-Cys) and it has been shown to be reduced by Trx reductase in a NADPH-dependent reaction. In its dithiol form, Trx serves as the reductant for methionine sulfoxide (MetO) and PAPS (3′-phosphoadenosine-5′-phosphosulfate) in yeast and ribonucleotides in Escherichia coli[58, 59]. Isoforms of Trx have been found in E. coli, yeast and mammals. Two Trxs have been identified in humans, one cytosolic (TRX1) [60] and one mitochondrial (TRX2) [61]. A major role of Trx is as a hydrogen donor for enzymes involved in reductive reactions, for example, ribonucleotide reductase, which reduces ribonucleotides to deoxyribonucleotides for DNA synthesis; peroxiredoxin (Prx), which reduces peroxides [6264]; and MetO reductase, which reduces methionine sulfoxide in proteins and provides protection against oxidative stress [6567]. All Trxs catalyze the reduction of disulfides in proteins more efficiently (orders of magnitude faster) than Glutathione (GSH) or dithiothreitol [68]. Therefore, Trx plays an important role in maintaining a reduced environment in the cells through thiol-disulfide exchange reactions and protects cells and tissues from oxidative stress [69]. Trx also plays a major role in thiol-disulfide exchange reactions, which maintains cysteine residues in a reduced state in proteins [68]. Because the thiol-disulfide exchange reaction is rapid and readily reversible, this reaction is ideally suited to control protein function via the redox state. This is particularly important for several transcription factors, such as activator protein 1 (AP-1) and nuclear factor κB (NFκB), which contain cysteine residues [70]. The reduction of cysteine residues increases the DNA binding activity of these transcription factors [71, 72], which subsequently induces the expression of target genes. In addition, Trxs have essential roles in the development of mammals because knockout mice null for either Trx1 or Trx2 are embryonically lethal [73, 74]. Furthermore, Trx1 has anti-apoptotic effects by binding to apoptosis signal-regulating kinases (ASK) [75].

Transgenic mice overexpressing Trx1 by β-actin and endogenous promoters

In 1999, Yodoi and colleagues generated transgenic mice overexpressing Trx1 with a transgene containing the human TRX1 cDNA fused to the β–actin promoter (Tg(act-TRX1)+/0) [69]; they showed that these mice had an extended lifespan compared to their wild-type littermates [76, 77]. Our study demonstrated that young and adult mice overexpressing Trx1 had increased resistance to oxidative stress and reduced oxidative damage to proteins and lipids [78]. These results are very exciting for the following reasons: 1) the Tg(act-TRX1)+/0 mice are the second mouse model (the first one is mCAT mice) to support the oxidative stress theory of aging; and 2) these results could indicate the importance of redox state maintenance by Trx during aging. However, the survival study by Yodoi and colleagues has several possible deficits: 1) the study was conducted under conventional housing conditions, in which the infectious status of these mice could have potentially changed their normal aging process; and 2) the lifespan of the wild-type C57BL/6 mice in the colony was shorter than the C57BL/6 mice raised under barrier conditions, for example, the median lifespan was approximately 23 months of age, which is much shorter than the median lifespan of C57BL/6 mice in the aging colonies in San Antonio (29 to 30 months of age). To examine the effects of increased levels of Trx1 on oxidative stress in vivo and its long-term pathophysiological consequences under optimal housing conditions, we have conducted an aging study with Tg(act-TRX1)+/0 mice [78]. We observed a significant increase in the survival of male Tg(act-TRX1)+/0 mice compared to the wild-type mice only during the first half of their lifespan. For example, the transgenic mice had a 25% increase in their lifespan in the earlier part of life (75% survival) and a 13% increase in lifespan in the median part of life (50% survival). However, the transgenic mice showed only a 5.5% increase in lifespan in the later part of life (25% survival) and no increase thereafter (10% survival), which was associated with reduced Trx1 overexpression. To further confirm our initial observation, we conducted another survival study using males and females. The male Tg(act-TRX1)+/0 mice showed a significant increase in lifespan in the very early part of life (90% survival; both cohorts), and only the first male cohort showed a significant increase in lifespan in the early part of life (75% survival) compared to the wild-type mice. However, we found no difference in the lifespan at the median (50%) and the later part of life (25%, and 10% survival) between Tg(act-TRX1)+/0 and wild-type mice in two male cohorts. Although the Tg(act-TRX1)+/0 female mice seemed to have an extended lifespan in the earlier part of life (75% survival) compared to wild-type mice, none of the survival parameters were statistically significant [78]. These survival results are partially consistent with the previous study by Yodoi and colleagues that showed that the overexpression of Trx1 significantly increases median and maximum lifespans [76, 77]. Differences in results between this and previous studies could be due to different housing conditions of the mouse colony; the mice in our colony showed about a 20% longer (40 months) maximum longevity than mice maintained under conventional housing conditions (approximately 32 months) [77]. Therefore, our survival data did show that overexpression of Trx1 increased only the earlier part of lifespan in males, but no extension was observed in maximum lifespan, which is a question that remains to be answered, that is, why did Trx1 overexpression show an extension of lifespan only in the earlier part of life? These mice were generated with a β-actin promoter to drive the expression of the transgene, which could cause an age-related decrease in the overexpression of the transgene. We observed that the levels of overexpression significantly decreased with age, which was correlated with less reduction in protein oxidation levels [78].

To test if continuous overexpression of Trx1 extends maximum lifespan, we generated an additional line of Trx1 transgenic mice (Trx1Tg) using a fragment of the human genome containing the TRX1 gene (a BAC clone (RP11-427 L11), Children’s Hospital Oakland Research Institute’s (CHORI) BACPAC Resources Center (BPRC), Oakland, CA.) with 8.3 kb and 12.3 kb of the 5′- and 3′-flanking sequences, respectively. We have confirmed that the transgenes in these mice were stably integrated and successfully passed to progeny following the Mendelian ratio for all lines of transgenic mice. We also confirmed that the levels of Trx1 were significantly higher (approximately 20% to 40%) in all the tissues we examined in the Trx1Tg mice, compared to their wild-type littermates, and were similar to the levels of overexpression in the young (4 to 6 months old) Tg(act-TRX1)+/0 mice. Furthermore, overexpression of Trx1 was maintained (up to 28 to 30 months old), that is, the levels of overexpressed Trx1 did not show any decrease or increase during aging. There were no compensatory changes in the levels of Trx2, glutaredoxin, glutathione or other major antioxidant enzymes. A survival study with Trx1Tg and wild-type mice was conducted and is currently ongoing. The current survival rate of Trx1Tg and wild-type mice is 29.8% and 27.6%, respectively. The earlier parts (75% survival) of lifespan in Trx1Tg and wild-type mice are 707 and 665 days, respectively. The difference (6.3%) is not significant (P > 0.05) as determined by the Generalized Wilcoxon test. Mortality rate after 700 days appears to be higher in the Trx1Tg than wild-type mice and no life-extension is currently observed. Therefore, continuous overexpression of Trx1 in mice showed similar effects observed in the Tg(act-TRX1)+/0 mice, that is, Trx1 overexpression showed some benefits for lifespan only in the earlier part of life.

A possible explanation for these results is that Trx1 could have deleterious effects in older animals because of its anti-apoptotic effect by inhibiting the Apoptosis Signal-Regulating Kinase-1 (ASK1) pathway [75, 79]. Our data showed that Tg(act-TRX1)+/0 mice had higher levels of the ASK1/Trx1 complex and reduced c-Jun N-terminal Kinase (JNK) activation [78]. The major cause of death in these mice was neoplastic disease, especially lymphoma, which is consistent with the end-of-life pathology data from C57BL/6 mice [80]. Interestingly, the end-of-life pathology data showed that Tg(act-TRX1)+/0 mice had higher incidences of total fatal tumors and fatal lymphoma compared to wild-type mice. This is not a surprising observation because Trx1 has anti-apoptotic action by inhibiting ASK, promoting cell proliferation, and is overexpressed in various cancers, including lymphoma [60, 81]. The possible role of Trx1 in tumor development was further confirmed by our study using the brain tumor model, which also showed that increased levels of TRX1 are correlated to increased cell proliferation and reduced cell death in tumors and tumor development (incidence and growth of tumors) [82].

Thus, our studies show that the overexpression of Trx1 in mice had some benefits in the earlier part of lifespan, but did not extend maximum lifespan, possibly due to the higher incidence of fatal tumors compared to wild-type mice. Experimental research on all animals was approved by the Institutional Animal Care and Use Committee (IACUC) of the Department of Veterans Affairs and the University of Texas Health Science Center at San Antonio.

Oxidative stress theory of aging – future directions of thioredoxins

Although the Free Radical or Oxidative Stress Theory of Aging is generally accepted as an important component of aging and age-related diseases, recent evidence using transgenic/knockout mice overexpressing or down-regulating antioxidant enzymes challenge the veracity of this theory since the animals showed no increase or decrease in lifespan. These results seriously call into question the role of oxidative damage/stress in the aging process in mammals. Thus, significant modifications to the theory are required if we are to understand the relationship between aging and the regulation of oxidative stress. Our laboratory made the interesting observation that the overexpression of Trx1 showed benefits only in the earlier part of life, with an increased incidence of tumors with age. These results led us to the following questions: 1) why did Trx1 overexpression show some beneficial effects on lifespan, while the overexpression of most other antioxidants failed to extend lifespan; and 2) why did Trx1 overexpression show an extension of lifespan only in the earlier part of life?

Several studies demonstrated that the cellular redox state plays an important role in the physiological responses to oxidative stress and aging. We demonstrated that lifespan extension in the earlier part of life in Tg(act-TRX1)+/0 mice is correlated to increased levels of the Trx1 redox state. The enhanced Trx1 redox state could play an important role in an organism’s ability to better respond to stress by altering the signaling pathways that are dependent on the cellular redox state [83]. The mRNA levels of IL-1β, one of the representative target genes in the NFkB pathway, were significantly lower in the liver tissue from Tg(act-TRX1)+/0 mice compared to wild-type mice. There is some indication that IL-1β could be involved in the wide-spread systemic inflammatory process. Substantial evidence suggests inflammation plays an important role in aging and, additionally, Tg(act-TRX1)+/0 mice showed significantly less incidence of inflammatory lesions in the lung (acidophilic macrophage pneumonia) compared to wild-type mice, which occurred mainly in the earlier part of life. Therefore, the reduction in systemic inflammation and suppression of acidophilic macrophage pneumonia, which is a non-neoplastic fatal disease commonly seen in C57BL/6 mice, could be possible contributing factors for the extension of lifespan in the earlier part of life in the Tg(act-TRX1)+/0 mice. These observations are further confirmed by our most recent study, in which we found that the overexpression of Trx1 can prevent the induction of pro-inflammatory cytokine TNFα in adipose tissue associated with high fat feeding [84]. This reduction of inflammation was associated with preserved glucose tolerance in this model, suggesting that Trx1 prevents insulin resistance through its anti-inflammatory effects. Together, these findings show that Trx1-mediated regulation of the inflammatory state may be a significant regulator of health under various age-related pathophysiological conditions.

The next question is: why does Trx1 overexpression show an extension of lifespan only in the earlier part of life? As described above, we believe that the loss in life extension, or accelerated mortality, in old Trx1 transgenic mice could arise because the overexpression of the TRX1 gene could promote tumor growth, including lymphoma, a major fatal disease in C57BL/6 mice. Trx1 could promote the development of cancer in older animals because of its anti-apoptotic effect by inhibiting the ASK1 pathway and protecting against various stressors [75, 78, 79]. The Tg(act-TRX1)+/0 mice had higher levels of the ASK1/Trx1 complex, reduced JNK activation, reduced oxidative damage to lipids and proteins, and had a higher incidence of total fatal tumors and fatal lymphoma compared to wild-type mice. Since Trx1 is overexpressed in various cancers [81] and apoptosis plays important roles in carcinogenesis, overexpression of Trx1 could promote cancer growth by its anti-apoptotic action, protection against oxidative stress, and have deleterious effects in older animals.

Based on the data from Trx1 transgenic mice and other mice that have either up-regulated or down-regulated various antioxidant enzymes, it is clear that the role of oxidative stress in aging seems to be more complex than the oxidative stress theory describes. The effects of Trx1 overexpression (and oxidative stress) could be different between young and old mice. The protection against oxidative stress and changes in redox-sensitive signaling, for example, inflammatory signaling pathways, by Trx1 could be beneficial in young animals. However, our study has also indicated that reduced oxidative stress and changes in redox-sensitive signaling, for example, apoptosis signaling pathways, by Trx1 could play important roles in cancer growth, which has more deleterious effects in older animals.

Redox change in different cellular compartments is another important factor to be considered when studying the role of oxidative stress in aging. Since mitochondria generate most of the endogenous ROS, overexpressing Trx in mitochondria (Trx2) could show more significant effects on oxidative stress and longevity. Although Trx1 overexpression reduced the oxidative damage to proteins and lipids, DNA oxidation was not reduced by Trx1, which could be another reason why Trx transgenic mice had an increased incidence of cancer. This possibility could be supported by a recent study by Schriner et al.[52] which reported that the overexpression of catalase in mitochondria significantly extended lifespan and reduced the incidence of some cancers in mice, which is the only mouse model to support the oxidative stress theory of aging. In addition, Widder et al.[85] found beneficial roles of overexpressing Trx in the mitochondria (TghTrx2 mice) on the development of vascular dysfunction and hypertension, which are common age-related pathological changes in humans. Another study also showed the beneficial effects of Trx2 overexpression on endothelial functions and protection against atherosclerosis development [86]. Therefore, it is of interest to examine if overexpression of Trx2 could attenuate aging and/or age-related pathology in mice. Another important cellular compartment is the nucleus where an elegant study done by Go et al.[87] demonstrated that transgenic mice overexpressing Trx1 in the nucleus (NLS-hTrx1Tg) had an increased mortality by influenza H1N1, which was associated with increased inflammatory signaling. These results are contrary to the work with Trx1 (cytosolic) and Trx2 transgenic mice that showed protection against various stresses [86, 88]. This is additional evidence supporting the notion that compartmentalized redox regulation is a key component of redox signaling and cellular functions [87]. Therefore, the changes in redox state in different compartments of cells, that is, the mitochondria, cytosol and nucleus, could control the activity of redox-sensitive signaling in cells differently.

These results can potentially provide two interesting scenarios regarding Trx, cancer and aging: 1) overexpressing Trx in the mitochondria could play a more important role on lifespan than in the cytosol, which is similar to the results of the mCAT mice studies (overexpressing catalase in the mitochondria increased lifespan, but overexpressing catalase in the nucleus or the cytosol had no effect); and 2) down-regulating Trx in the cytosol could play important roles in suppressing cancer development, which may have beneficial effects in older animals. These paradoxical, but intriguing, scenarios could indicate that changes in the redox state in the cytosol and mitochondria attenuate lifespan through different mechanisms, for example, protection of the mitochondria against oxidative stress and reduced age-related pathology, such as cancer.

Based on these ideas, we are currently examining the effects of overexpressing Trx2 and/or down-regulating Trx1 on oxidative stress, redox status, redox-sensitive signaling, age-related diseases (especially cancer), and aging using Trx2 transgenic (Tg) and Trx1 knockout (KO) mice. Our ongoing study showed Trx2Tg mice that overexpress Trx2 in all tissues during aging showed less ROS production in mitochondria, less oxidative stress, and had a slight extension of lifespan in the earlier part of life. When we test the effects of reduced levels of thioredoxin in cytosol or mitochondria on aging, we may observe the reverse effects, that is, life-extension and reduction of cancer in the Trx1KO mice, while the Trx2KO mice showed little effects on lifespan but showed impaired mitochondrial function [89, 90]. We are also testing if overexpressing Trx2 along with down-regulating Trx1 could show additive anti-aging effects by using mice that up-regulate Trx in the mitochondria and down-regulate Trx in the cytosol (Trx2Tg x Trx1KO mice). The results from this study will allow us to determine if overexpression of Trx in the mitochondria and down-regulation of Trx in the cytosol throughout life play important roles in aging and age-related pathology through common or independent pathways.

Based on our current preliminary data, we predict that overexpressing Trx2 will provide protection against oxidative stress in the mitochondria and delay aging, down-regulating Trx1 will provide protection against tumorigenesis by enhanced apoptosis or reduced cell proliferation to delay aging, and overexpression of Trx2 combined with down-regulation of Trx1 will show a greater anti-aging effect and reduction of pathology than overexpression of Trx2 or down-regulation of Trx1 would alone.

Conclusions

Although the Free Radical or Oxidative Stress Theory of Aging has been one of the most popular theories in aging research over the past several decades, the results generated from our lab and others have raised more questions about the oxidative stress theory than provided answers. These results seriously call into question the role of oxidative damage/stress in the aging process in mammals, requiring us to make significant modifications to the theory of oxidative stress in aging in order to understand the relationship between aging and the regulation of oxidative stress. The results generated from our lab (Trx1Tg, Trx1KO, Trx2Tg) and others (for example, mCAT mice, NLS-hTrx1Tg mice and TghTrx2 mice) could suggest that: 1) changes in oxidative stress and redox state in the cytosol, mitochondria or nucleus might play different roles in the aging process and in age-related diseases; 2) the role of oxidative stress and redox state could have different pathophysiological consequences in different tissues/cells, for example, mitotic vs. post-mitotic; 3) oxidative stress could have different pathophysiological impacts in young and old animals; and 4) the pathophysiological roles of oxidative stress and redox state could be controlled through changes in redox-sensitive signaling, which could have more diverse effects on pathophysiology than the accumulation of oxidative damage to various molecules. To critically test the role of oxidative stress on aging and age-related diseases, further study is required using animal models that regulate oxidative stress levels differently in each cellular compartment, each tissue/organ, and/or at different stages of life (young, middle, and old) to change redox sensitive signaling pathways.

Abbreviations

AP-1: 

Activator protein 1

ASK1: 

Apoptosis signal-regulating kinase 1

BPRC: 

BACPAC Resources Center

CHORI: 

Children’s Hospital Oakland Research Institute

CR: 

Calorie restriction

GPX: 

Glutathione peroxidase

GSH: 

Glutathione

KO: 

Knockout

MetO: 

methionine sulfoxid

MsrA: 

Methionine sulfoxidereductase A

NFκB: 

Nuclear factor κB

PAPS: 

3′-phosphoadenosine-5′-phosphosulfate

Prx: 

Peroxiredoxin

ROS: 

Reactive oxygen species

SOD: 

Superoxide dismutase

Tg: 

Transgenic

Trx: 

Thioredoxin

JNK: 

c-Jun N-terminal Kinase

IACUC: 

Institutional Animal Care and Use Committee.

Declarations

Acknowledgments

This research was supported by the VA Merit Review Grant 1 I01BX001023 from the Biomedical Laboratory Research and Development Service of the Veteran’s Affairs Office of Research and Development (YI), NIH Grant AG013319 (YI), The American Federation for Aging Research (AFAR) grant (YI), Grant from Glenn Foundation (YI), and NIA training grant T32 AG021890-05 for the study of the basic biology of aging (ABS) and Award.

Authors’ Affiliations

(1)
Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio
(2)
Department of Pathology, The University of Texas Health Science Center at San Antonio
(3)
Molecular Medicine, The University of Texas Health Science Center at San Antonio
(4)
Research Service, Audie L. Murphy VA Hospital South Texas Veterans Health Care System
(5)
Geriatric Research and Education Center, Audie L. Murphy VA Hospital South Texas Veterans Health Care System

References

  1. Warner HR: Superoxide dismutase, aging, and degenerative disease. Free RadicBiol Med. 1994, 17: 249-258. 10.1016/0891-5849(94)90080-9.View ArticleGoogle Scholar
  2. Sohal RS, Weindruch R: Oxidative stress, caloric restriction, and aging. Science. 1996, 273: 59-63. 10.1126/science.273.5271.59.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Martin GM, Austad SN, Johnson TE: Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet. 1996, 13: 25-34. 10.1038/ng0596-25.View ArticlePubMedGoogle Scholar
  4. Sohal RS, Orr WC: Relationship between antioxidants, prooxidants, and the aging process. Ann NY AcadSci. 1992, 663: 74-84. 10.1111/j.1749-6632.1992.tb38651.x.View ArticleGoogle Scholar
  5. Bohr VA, Anson RM: DNA damage, mutation and fine structure DNA repair in aging. Mutation Res. 1995, 338: 25-34. 10.1016/0921-8734(95)00008-T.View ArticlePubMedGoogle Scholar
  6. Oliver CN, Ahn B, Moerman EJ, Goldstein S, Stadtman ER: Age-related changes in oxidized proteins. J BiolChem. 1987, 262: 5488-5491.Google Scholar
  7. Stadtman ER: Biochemical markers of aging. ExpGerontol. 1988, 23: 327-347.Google Scholar
  8. Stadtman ER: Protein oxidation and aging. Science. 1992, 257: 1220-1224. 10.1126/science.1355616.View ArticlePubMedGoogle Scholar
  9. Sohal RS, Dubey A: Mitochondrial oxidative damage, hydrogen peroxide release, and aging. Free RadicBiol Med. 1994, 16: 621-626. 10.1016/0891-5849(94)90062-0.View ArticleGoogle Scholar
  10. Zainal TA, Oberley TD, Allison DB, Szweda LI, Weindruch R: Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J. 2000, 14: 1825-1836. 10.1096/fj.99-0881com.View ArticlePubMedGoogle Scholar
  11. Enesco HE, Kruk P: Dietary restriction reduces fluorescent age pigment accumulation in mice. ExpGerontol. 1981, 16: 357-361.Google Scholar
  12. De AK, Chipalkatti S, Aiyar AS: Some biochemical parameters of ageing in relation to dietary protein. Mech Ageing Dev. 1983, 21: 37-48. 10.1016/0047-6374(83)90014-3.View ArticlePubMedGoogle Scholar
  13. Rao G, Xia E, Nadakavukaren MJ, Richardson A: Effect of dietary restriction on the age-dependent changes in the expression of antioxidant enzymes in rat liver. J Nutr. 1990, 120: 602-609.PubMedGoogle Scholar
  14. Chipalkatti S, De AK, Aiyar AS: Effect of diet restriction on some biochemical parameters related to aging in mice. J Nutr. 1983, 113: 944-950.PubMedGoogle Scholar
  15. Laganiere S, Yu BP: Anti-lipoperoxidation action of food restriction. Biochem Biophys Res Commun. 1987, 145: 1185-1191. 10.1016/0006-291X(87)91562-2.View ArticlePubMedGoogle Scholar
  16. Levin G, Cogan U, Mokady S: Food restriction and membrane fluidity. Mech Ageing Dev. 1992, 62: 137-141. 10.1016/0047-6374(92)90050-N.View ArticlePubMedGoogle Scholar
  17. Pieri C, Falasca M, Marcheselli F, Moroni F, Recchioni R, Marmocchi F, Lupidi G: Food restriction in female Wistar rats: V. Lipid peroxidation and antioxidant enzymes in liver. Arch GerontolGeriatr. 1992, 14: 93-99.Google Scholar
  18. Davis LJ, Tadolini B, Biagi PL, Walford RL, Licastro F: Effect of age and extent of dietary restriction on hepatic microsomal lipid peroxidation potential in mice. Mech Ageing Dev. 1993, 72: 155-163. 10.1016/0047-6374(93)90097-B.View ArticlePubMedGoogle Scholar
  19. Youngman LD, Park JK, Ames BN: Protein oxidation associated with aging is reduced by dietary restriction of protein or calories. ProcNatlAcadSci USA. 1992, 89: 9112-9116. 10.1073/pnas.89.19.9112.View ArticleGoogle Scholar
  20. Sohal RS, Ku H-H, Agarwal S, Forster MJ, Lal H: Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech Ageing Dev. 1994, 74: 121-133. 10.1016/0047-6374(94)90104-X.View ArticlePubMedGoogle Scholar
  21. Lass A, Sohal BH, Weindruch R, Forster MJ, Sohal RS: Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free RadicBiol Med. 1998, 25: 1089-1097. 10.1016/S0891-5849(98)00144-0.View ArticleGoogle Scholar
  22. Aksenova MV, Aksenov MY, Carney JM, Butterfield DA: Protein oxidation and enzyme activity decline in old brown Norway rats are reduced by dietary restriction. Mech Ageing Dev. 1998, 100: 157-168. 10.1016/S0047-6374(97)00133-4.View ArticlePubMedGoogle Scholar
  23. Dubey A, Forster MJ, Lal H, Sohal RS: Effect of age and caloric intake on protein oxidation in different brain regions and on behavioral functions of the mouse. Arch BiochemBiophys. 1996, 333: 189-197. 10.1006/abbi.1996.0380.View ArticleGoogle Scholar
  24. Chen LH, Snyder DL: Effects of age, dietary restriction and germ-free environment on glutathione-related enzymes in Loubund-Wistar rats. Arch Gerontol Geriatr. 1992, 14: 17-26. 10.1016/0167-4943(92)90003-M.View ArticlePubMedGoogle Scholar
  25. Sohal RS, Agarwal S, Candas M, Forster MJ, Lal H: Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev. 1994, 76: 215-224. 10.1016/0047-6374(94)91595-4.View ArticlePubMedGoogle Scholar
  26. Hamilton ML, Guo Z, Fuller CD, Van Remmen H, Ward WF, Austad SN, Troyer DA, Thompson I, Richardson A: A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA. Nucleic Acid Res. 2001, 29: 2117-2126. 10.1093/nar/29.10.2117.PubMed CentralView ArticlePubMedGoogle Scholar
  27. Honda Y, Honda S: The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression inCaenorhabditiselegans. FASEB J. 1999, 13: 1385-1391.PubMedGoogle Scholar
  28. Ishii N, Goto S, Hartman P: Protein oxidation during aging of the nematodeCaenorhabditiselegans. Free RadicBiol Med. 2002, 33: 1021-1025. 10.1016/S0891-5849(02)00857-2.View ArticleGoogle Scholar
  29. Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A: Genetic mouse models of extended lifespan. Exp Gerontol. 2003, 38: 1353-1364. 10.1016/j.exger.2003.10.019.View ArticlePubMedGoogle Scholar
  30. Murakami S, Salmon A, Miller RA: Multiplex stress resistance in cells from long-lived dwarf mice. FASEB J. 2003, 17: 1565-1566.PubMedGoogle Scholar
  31. Andziak B, O’Connor TP, Qi W, DeWaal EM, Pierce A, Chaudhuri AR, Van Remmen H, Buffenstein R: High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging Cell. 2006, 5: 463-471. 10.1111/j.1474-9726.2006.00237.x.View ArticlePubMedGoogle Scholar
  32. Seto NO, Hayashi S, Tener GM: Overexpression of Cu-Zn superoxide dismutase inDrosophiladoes not affect life-span. ProcNatlAcadSci USA. 1990, 87: 4270-4274. 10.1073/pnas.87.11.4270.View ArticleGoogle Scholar
  33. Reveillaud I, Niedzwiecki A, Bensch KG, Fleming JE: Expression of bovine superoxide dismutase inDrosophila melanogasteraugments resistance to oxidative stress. MolBiol Cell. 1991, 11: 632-640.Google Scholar
  34. Orr WC, Sohal RS: Effects of Cu-Zn superoxide dismutase overexpression on life span and resistance to oxidative stress in transgenic Drosophila melanogaster. Arch BiochemBiophys. 1993, 301: 34-40. 10.1006/abbi.1993.1111.View ArticleGoogle Scholar
  35. Orr WC, Arnold LA, Sohal RS: Relationship between catalase activity, life span and some parameters associated with antioxidant defenses in Drosophila melanogaster. Mech Age Dev. 1992, 63: 287-296. 10.1016/0047-6374(92)90006-Y.View ArticleGoogle Scholar
  36. Orr WC, Sohal RS: Extension of life span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science. 1994, 263: 1128-1130. 10.1126/science.8108730.View ArticlePubMedGoogle Scholar
  37. Sohal RS, Agarwal A, Agarwal S, Orr WC: Simultaneous overexpression of copper- and zinc-containing superoxide dismutase and catalase retards age-related oxidative damage and increases metabolic potential in Drosophila melanogaster. J BiolChem. 1995, 270: 15671-15674.Google Scholar
  38. Stearns SC, Kaiser M: The effects of enhanced expression of elongation factor EF1-alpha on lifespan inDrosophila melanogaster. Genetica. 1993, 91: 167-182. 10.1007/BF01435996.View ArticlePubMedGoogle Scholar
  39. Kaiser M, Gasser M, Ackermann R, Stearns SC: P-element inserts in transgenic flies: a cautionary tale. Heredity. 1996, 78: 1-11.View ArticleGoogle Scholar
  40. Orr WC, Mockett RJ, Benes JJ, Sohal RS: Effects of overexpression of copper-zinc and manganese superoxide dismutases, catalase, and thioredoxinreductase genes on longevity in Drosophila melanogaster. J BiolChem. 2003, 278: 26418-26422.Google Scholar
  41. Sun J, Tower J: FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adultDrosophila melanogasterflies. Mol Cell Biol. 1999, 19: 216-228.PubMed CentralView ArticlePubMedGoogle Scholar
  42. Sun J, Folk D, Bradley TJ, Tower J: Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics. 2002, 161: 661-672.PubMed CentralPubMedGoogle Scholar
  43. Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne G: Extension of Drosophilalifespan by overexpression of human SOD1 in motorneurons. Nat Genet. 1998, 19: 171-174. 10.1038/534.View ArticlePubMedGoogle Scholar
  44. Chavous DA, Wagner DJ, Bennett EJ, O’Connor CM: Overexpression and characterization of a protein L-isoaspartylmethyltransferase from Archaeoglobusfulgidis. FASEB J. 2000, 14: A1488-Google Scholar
  45. Chavous DA, Jackson FR, O’Connor CM: Extension of the Drosophilalifespan by overexpression of a protein repair methyltransferase. ProcNatlAcadSci USA. 2001, 98: 14814-14818. 10.1073/pnas.251446498.View ArticleGoogle Scholar
  46. Ruan H, Tang DX, Chen M-L, Joiner MA, Sun G, Brot N, Weissbach H, Heinemann SH, Iverson L, Wu C, Hoshi T: High-quality life extension by the enzyme peptide methionine sulfoxidereductase. ProcNatlAcadSci USA. 2002, 99: 2748-2753. 10.1073/pnas.032671199.View ArticleGoogle Scholar
  47. Epstein CJ, Avraham KB, Lovett M, Smith S, Elroy-Stein O, Rotman G, Bry C, Groner Y: Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. ProcNatlAcadSci USA. 1987, 84: 8044-8048. 10.1073/pnas.84.22.8044.View ArticleGoogle Scholar
  48. Mikawa S, Kinouchi H, Kamii H, Gobbel GT, Carlson E, Epstein CJ, Chan PH: Attenuation of acute and chronic damage following traumatic brain injury in copper, zinc-superoxide dismutase transgenic mice. J Neurosurg. 1996, 85: 885-891. 10.3171/jns.1996.85.5.0885.View ArticlePubMedGoogle Scholar
  49. Murakami K, Kondo T, Epstein CJ, Chan PH: Overexpression of CuZn-superoxide dismutase reduces hippocampal injury after global ischemia in transgenic mice. Stroke. 1997, 28: 1797-1804. 10.1161/01.STR.28.9.1797.View ArticlePubMedGoogle Scholar
  50. Huang T-T, Carlson EJ, Gillespie AM, Shi Y, Epstein CJ: Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J Gerontol. 2000, 55: B5-B9.View ArticleGoogle Scholar
  51. Pérez V, Van Remmen H, Bokov A, Epstein C, Vijg J, Richardson A: The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell. 2009, 8: 73-75. 10.1111/j.1474-9726.2008.00449.x.PubMed CentralView ArticlePubMedGoogle Scholar
  52. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS: Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005, 308: 1909-1911. 10.1126/science.1106653.View ArticlePubMedGoogle Scholar
  53. Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang T-T, Nelson J, Strong R, Richardson AL: Lifelong reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics. 2003, 16: 29-37. 10.1152/physiolgenomics.00122.2003.View ArticlePubMedGoogle Scholar
  54. Elchuri S, Oberley TD, Qi W, Eisenstein RS, Roberts LJ, Van Remmen H, Epstein CJ, Huang T-T: Cu/ZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene. 2005, 24: 367-380. 10.1038/sj.onc.1208207.View ArticlePubMedGoogle Scholar
  55. Hensley K, Robinson KA, Gabbita SP, Salsman S, Floyd RA: Reactive oxygen species, cell signaling, and cell injury. Free Rad Bio Med. 2000, 28: 1456-1462. 10.1016/S0891-5849(00)00252-5.View ArticleGoogle Scholar
  56. Thannickal VJ, Fanburg BL: Reactive oxygen species in cell signaling. Am J Physiol Lung Cell MolPhysiol. 2000, 279: L1005-L1028.Google Scholar
  57. Hancock JT, Desikan R, Neill SJ: Role of reactive oxygen species in cell signalling pathways. BiochemSoc Trans. 2001, 29: 345-350. 10.1042/BST0290345.View ArticleGoogle Scholar
  58. Asahi T, Bandurski RS, Wilson LG: Yeast sulfate-reducing system. II. Enzymatic reduction of protein disulfide. J BiolChem. 1961, 236: 1830-1835.Google Scholar
  59. Black S, Harte EM, Hudson B, Wartofsky L: A specific enzymatic reduction of L(−) methionine sulfoxide and a related nonspecific reduction of disulfides. J BiolChem. 1960, 235: 2910-2916.Google Scholar
  60. Tagaya Y, Maeda Y, Mitsui A, Kondo N, Matsui H, Hamuro J, Brown N, Arai K-I, Yokota T, Wakasugi H, Yodoi J: ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J. 1989, 8: 757-764.PubMed CentralPubMedGoogle Scholar
  61. Spyrou G, Enmark E, Miranda-Vizuete A, Gustafsson J-A: Cloning and expression of a novel mammalian thioredoxin. J BiolChem. 1997, 272: 2936-2941.Google Scholar
  62. Chae HZ, Kim HJ, Kang SW, Rhee SG: Characterization of three isoforms of mammalian peroxiredoxin that reduce peroxides in the presence of thioredoxin. Diabetes Res Clin Pract. 1999, 45: 101-112. 10.1016/S0168-8227(99)00037-6.View ArticlePubMedGoogle Scholar
  63. Chae HZ, Kang SW, Rhee SG: Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin. Methods Enzymol. 1999, 300: 219-226.View ArticlePubMedGoogle Scholar
  64. Kim K, Kim IH, Lee KY, Rhee SG, Stadtman ER: The isolation and purification of a specific “protector” protein which inhibits enzyme inactivation by a thiol/Fe(III)/O2 mixed-function oxidation system. J BiolChem. 1988, 263: 4704-4711.Google Scholar
  65. Brot N, Weissbach L, Werth J, Weissbach H: Enzymatic reduction of protein-bound methionine sulfoxide. ProcNatlAcadSci USA. 1981, 78: 2155-2158. 10.1073/pnas.78.4.2155.View ArticleGoogle Scholar
  66. Brot N, Weissbach H: Peptide methionine sulfoxidereductase: biochemistry and physiological role. Biopolymers. 2000, 55: 288-296. 10.1002/1097-0282(2000)55:4<288::AID-BIP1002>3.0.CO;2-M.View ArticlePubMedGoogle Scholar
  67. Levine RL, Berlett BS, Moskovitz J, Mosoni L, Stadtman ER: Methionine residues may protect proteins from critical oxidative damage. Mech Ageing Dev. 1999, 107: 323-332. 10.1016/S0047-6374(98)00152-3.View ArticlePubMedGoogle Scholar
  68. Arnér ESJ, Holmgren A: Physiological functions of thioredoxin and thioredoxinreductase. Eur J Biochem. 2000, 267: 6102-6109. 10.1046/j.1432-1327.2000.01701.x.View ArticlePubMedGoogle Scholar
  69. Takagi Y, Mitsui A, Nishiyama A, Nozaki K, Sono H, Gon Y, Hashimoto N, Yodoi J: Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage. Proc Natl Acad Sci USA. 1999, 96: 4131-4136. 10.1073/pnas.96.7.4131.PubMed CentralView ArticlePubMedGoogle Scholar
  70. Abate C, Patel L, Rauscher FJ, Curran T: Redox regulation of Fos and Jun DNA-binding activityin vitro. Science. 1990, 249: 1157-1161. 10.1126/science.2118682.View ArticlePubMedGoogle Scholar
  71. Toledano MB, Leonard WJ: Modulation of transcription factor NF-KB binding activity by oxidation-reductionin vitro. Proc Natl Acad Sci USA. 1991, 88: 4328-4332. 10.1073/pnas.88.10.4328.PubMed CentralView ArticlePubMedGoogle Scholar
  72. Galter D, Mihm S, Droge W: Distinct effects of glutathione disulphide on the nuclear transcripton factor kB and the activator protein-1. Eur J Biochem. 1994, 221: 639-648. 10.1111/j.1432-1033.1994.tb18776.x.View ArticlePubMedGoogle Scholar
  73. Matsui M, Oshima M, Oshima H, Takaku K, Maruyama T, Yodoi J: Early embryonic lethality caused by targeted disruption of the mouse thioredoxin gene. DevBiol. 1996, 178: 179-185.Google Scholar
  74. Nonn L, Williams RR, Erickson RP, Powis G: The absence of mitochondrial thioredoxin 2 causes massive apoptosis, exencephaly, and embryonic lethality in homozygous mice. Mol Cell Biol. 2003, 23: 916-922. 10.1128/MCB.23.3.916-922.2003.PubMed CentralView ArticlePubMedGoogle Scholar
  75. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H: Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998, 17: 2569-2606.View ArticleGoogle Scholar
  76. Mitsui A, Hamuro J, Nakamura H, Kondo N, Hirabayashi Y, Ishizaki-Koizumi S, Hirakawa T, Inoue T, Yodoi J: Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxid Redox Signal. 2002, 4: 693-10.1089/15230860260220201.View ArticlePubMedGoogle Scholar
  77. Nakamura H, Mitsui A, Yodoi J: Thioredoxin overexpression in transgenic mice. Methods Enzymol. 2002, 347: 436-440.View ArticlePubMedGoogle Scholar
  78. Pérez VI, Cortez LA, Lew CM, Rodriguez M, Webb CR, Van Remmen H, Chaudhuri A, Qi W, Lee S, Bokov A, Fok W, Jones D, Richardson A, Yodoi J, Tominaga K, Hubbard GB, Ikeno Y: Thioredoxin 1 overexpression extends mainly the earlier part of life span in mice. J Gerontol. 2011, 66: 1286-1299.View ArticleGoogle Scholar
  79. Hsieh CC, Papaconstantinou J: Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. FASEB J. 2006, 20: 259-268. 10.1096/fj.05-4376com.PubMed CentralView ArticlePubMedGoogle Scholar
  80. Ikeno Y, Hubbard GB, Lee S, Richardson A, Strong R, Fernandez E, Diaz V, Nelson JF: Housing density does not influence the longevity effect of calorie restriction. J Gerontol. 2005, 60A: 1510-1517.View ArticleGoogle Scholar
  81. Powis G, Mustacich D, Coon A: The role of the redox protein thioredoxin in cell growth and cancer. Free Rad Biol Med. 2000, 29: 312-322. 10.1016/S0891-5849(00)00313-0.View ArticlePubMedGoogle Scholar
  82. Mahlke M, Cortez LA, Ortiz MA, Rodriguez M, Uchida K, Shigenaga MK, Lee S, Zhang Y, Tominaga K, Hubbard GB, Ikeno Y: The anti-tumor effects of CR are correlated with reduced oxidative stress in ENU-induced gliomas. Pathobiol Aging Age-related Dis. 2011, 1: 7189-Google Scholar
  83. Hansen JM, Go YM, Jones DP: Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu Rev PharmacolToxicol. 2006, 46: 215-234. 10.1146/annurev.pharmtox.46.120604.141122.View ArticleGoogle Scholar
  84. Salmon AB, Flores LC, Li Y, Van Remmen H, Richarson A, Ikeno Y: Reduction of glucose intolerance with high fat feeding is associated with anti-inflammatory effects of thioredoxin 1 overexpression in mice. Pathobiol Aging Age-related Dis. 2012, 2: 17101-Google Scholar
  85. Widder JD, Fraccarollo D, Galuppo P, Hasnen JM, Jones DP, Ertl G, Bauersachs J: Attenuation of angiotensin II-induced vascular dysfunction and hypertension by overexpression ofthioredoxin-2. Hypertension. 2009, 54: 338-344. 10.1161/HYPERTENSIONAHA.108.127928.PubMed CentralView ArticlePubMedGoogle Scholar
  86. Zhang H, Luo Y, Zhang W, He Y, Dai S, Zhang R, Huang Y, Bernatchez P, Giordano FJ, Shadel G, Sessa WC, Min W: Endothelial-specific expression of mitochondrial thioredoxin improves endothelial cell function and reduces atherosclerotic lesions. Am J Pathol. 2007, 170: 1108-1120. 10.2353/ajpath.2007.060960.PubMed CentralView ArticlePubMedGoogle Scholar
  87. Go Y-M, Kang S-M, Roede JR, Orr M, Jones DP: Increased inflammatory signaling and lethality of influenza H1N1 by nuclear thioredoxin-1. PLoS One. 2011, 6: e18918-10.1371/journal.pone.0018918.PubMed CentralView ArticlePubMedGoogle Scholar
  88. Nakamura H, Tamura S, Watanabe I, Iwasaki T, Yodoi J: Enhanced resistancy of thioredoxin-transgenic mice against influenza virus-induced pneumonia. Immunol Lett. 2002, 82: 165-170. 10.1016/S0165-2478(02)00033-0.View ArticlePubMedGoogle Scholar
  89. Pérez V, Bokov A, Van Remmen H, Mele J, Ran Q, Ikeno Y, Richardson A: Is the oxidative stress theory of aging dead?. Biochem Biophys Acta. 2009, 1790: 1005-1014. 10.1016/j.bbagen.2009.06.003.PubMed CentralView ArticlePubMedGoogle Scholar
  90. Perez V, Lew CM, Cortez LA, Webb CR, Rodriguez M, Liu Y, Qi W, Li Y, Chaudhuri A, Van Remmen H, Richardson A, Ikeno Y: Thioredoxin 2 haploinsufficiency in mice results in impaired mitochondrial function and increased oxidative stress. FreeRad Biol Med. 2008, 44: 882-892.View ArticleGoogle Scholar

Copyright

© Flores et al.; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement