Skip to main content

Thioredoxin overexpression in both the cytosol and mitochondria accelerates age-related disease and shortens lifespan in male C57BL/6 mice

Abstract

To investigate the role of increased levels of thioredoxin (Trx) in both the cytosol (Trx1) and mitochondria (Trx2) on aging, we have conducted a study to examine survival and age-related diseases using male mice overexpressing Trx1 and Trx2 (TXNTg × TXN2Tg). Our study demonstrated that the upregulation of Trx in both the cytosol and mitochondria in male TXNTg × TXN2Tg C57BL/6 mice resulted in a significantly shorter lifespan compared to wild-type (WT) mice. Cross-sectional pathology data showed a slightly higher incidence of neoplastic diseases in TXNTg × TXN2Tg mice than WT mice. The incidence of lymphoma, a major neoplastic disease in C57BL/6 mice, was slightly higher in TXNTg × TXN2Tg mice than in WT mice, and more importantly, the severity of lymphoma was significantly higher in TXNTg × TXN2Tg mice compared to WT mice. Furthermore, the total number of histopathological changes in the whole body (disease burden) was significantly higher in TXNTg × TXN2Tg mice compared to WT mice. Therefore, our study suggests that overexpression of Trx in both the cytosol and mitochondria resulted in deleterious effects on aging and accelerated the development of age-related diseases, especially cancer, in male C57BL/6 mice.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

References

  • Abate C, Patel L, Rauscher FJ 3rd, Curran T (1990) Redox regulation of Fos and Jun DNA-binding activity in vitro. Science 249:1157–1161

    Article  CAS  Google Scholar 

  • Andersen PK, Borgan O, Gill RD, Keiding N (1993) Statistical models based on counting processes. Springer, New York

    Book  Google Scholar 

  • Arnér ESJ, Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267:6102–6109

    Article  Google Scholar 

  • Beauchamp C, Fridovich I (1971) Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem 44:276–287

    Article  CAS  Google Scholar 

  • Bronson RT, Lipman RD (1991) Reduction in rate of occurrence of age related lesions in dietary restricted laboratory mice. Growth Dev Aging 55:169–184

    PubMed  CAS  Google Scholar 

  • Brot N, Weissbach H (2000) Peptide methionine sulfoxide reductase: biochemistry and physiological role. Biopolymers 55:288–296

    Article  CAS  Google Scholar 

  • Brot N, Weissbach L, Werth J, Weissbach H (1981) Enzymatic reduction of protein-bound methionine sulfoxide. Proc Natl Acad Sci U S A 78:2155–2158

    Article  CAS  Google Scholar 

  • Chae HZ, Kang SW, Rhee SG (1999a) Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin. Methods Enzymol 300:219–226

    Article  CAS  Google Scholar 

  • Chae HZ, Kim HJ, Kang SW, Rhee SG (1999b) Characterization of three isoforms of mammalian peroxiredoxin that reduce peroxides in the presence of thioredoxin. Diabetes Res Clin Pract 45:101–112

    Article  CAS  Google Scholar 

  • Custudio M, Maria RL (2007) Diagnostics for choosing between log-rank and Wilcoxon tests. Dissertation, Western Michigan University

  • Galter D, Mihm S, Droge W (1994) Distinct effects of glutathione disulphide on the nuclear transcripton factor kB and the activator protein-1. Eur J Biochem 221:639–648

    Article  CAS  Google Scholar 

  • Go Y-M, Kang S-M, Roede JR, Orr M, Jones DP (2011) Increased inflammatory signaling and lethality of influenza H1N1 by nuclear thioredoxin-1. PLoS One 1:e18918

    Article  CAS  Google Scholar 

  • Hansen JM, Go YM, Jones DP (2006) Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu Rev Pharmacol Toxicol 46:215–234

    Article  CAS  Google Scholar 

  • Hoesel B, Schmid JA (2013) The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 12:86

    Article  CAS  Google Scholar 

  • Hsieh C-C, Papaconstantinou J (2006) Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. FASEB J 20:259–268

    Article  CAS  Google Scholar 

  • Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, Kraut N, Beug H, Wirth T (2004) NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 114(4):569–581

    Article  CAS  Google Scholar 

  • Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A (2003) The delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to the extended longevity. J Gerontol 58A:291–296

    Article  Google Scholar 

  • Ikeno Y, Hubbard GB, Lee S, Richardson A, Strong R, Fernandez E, Diaz V, Nelson JF (2005) Housing density does not influence the longevity effect of calorie restriction. J Gerontol 12:1510–1517

    Article  Google Scholar 

  • Ikeno Y, Hubbard GB, Lee S, Cortez LA, Lew CM, Rodriguez M, Bartke A (2009) Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein (GHR/BP) knockout mice. J Gerontol 64A:522–529

    Article  CAS  Google Scholar 

  • Jiang S, Yan W (2017) Succinate in the cancer-immune cycle. Cancer Lett 390:45–47

    Article  CAS  Google Scholar 

  • Kim K, Kim IH, Lee KY, Rhee SG, Stadtman ER (1988) The isolation and purification of a specific “protector” protein which inhibits enzyme inactivation by a thiol/Fe (III)/O2 mixed-function oxidation system. J Biol Chem 263:4704–4711

    PubMed  CAS  Google Scholar 

  • Lawton KA, Berger A, Mitchell M, Milgram KE, Evans AM, Guo L, Hanson RW, Kalhan SC, Ryals JA, Milburn MV (2008) Analysis of the adult human plasma metabolome. Pharmacogenomics 9(4):383–397

    Article  CAS  Google Scholar 

  • Levine RL, Berlett BS, Moskovitz J, Mosoni L, Stadtman ER (1999) Methionine residues may protect proteins from critical oxidative damage. Mech Ageing Dev 107:323–332

    Article  CAS  Google Scholar 

  • Mahlke MA, Cortez LA, Ortiz MA, Rodriguez M, Uchida K, Shigenaga MK, Lee S, Zhang Y, Tominaga K, Hubbard GB, Ikeno Y (2011) The anti-tumor effects of CR are correlated with reduced oxidative stress in ENU-induced gliomas. Pathobiol Aging Age Relat Dis 1:7189

    Article  CAS  Google Scholar 

  • Mitsui A, Hamuro J, Nakamura H, Kondo N, Hirabayashi Y, Ishizaki-Koizumi S, Hirakawa T, Inoue T, Yodoi J (2002) Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxid Redox Signal 4(4):693–696

    Article  CAS  Google Scholar 

  • Nakamura H, Tamura S, Watanabe I, Iwasaki T, Yodoi J (2002) Enhanced resistancy of thioredoxin-transgenic mice against influenza virus-induced pneumonia. Immunol Lett 1:165–170

    Article  Google Scholar 

  • Patel DP, Krausz KW, Xie C, Beyoğlu D, Gonzalez FJ, Idle JR (2017) Metabolic profiling by gas chromatography-mass spectrometry of energy metabolism in high-fat diet-fed obese mice. PLoS One 12(5):e0177953

    Article  CAS  Google Scholar 

  • Pérez VI, Lew CM, Cortez LA, Webb CR, Rodriguez M, Liu Y, Qi W, Li Y, Chaudhuri A, Van Remmen H, Richardson A, Ikeno Y (2008) Thioredoxin 2 haploinsufficiency in mice results in impaired mitochondrial function and increased oxidative stress. Free Radic Biol Med 44(5):882–892

    Article  CAS  Google Scholar 

  • Pérez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, Richardson A (2009) The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8(1):73–75

    Article  CAS  Google Scholar 

  • 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 (2011) Thioredoxin 1 overexpression extends mainly the earlier part of life span in mice. J Gerontol 66(12):1286–1299

    Article  CAS  Google Scholar 

  • Philonenko P, Postovalov S (2015) A new two-sample test for choosing between log-rank and Wilcoxon tests with right-centered data. J Stat Comput Simul 85(14):2761–2770

    Article  Google Scholar 

  • Powis G, Mustacich D, Coon A (2000) The role of the redox protein thioredoxin in cell growth and cancer. Free Rad Biol Med 29:312–322

    Article  CAS  Google Scholar 

  • Rankin EB, Giaccia AJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15(4):678–685

    Article  CAS  Google Scholar 

  • Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 17:2569–2606

    Article  Google Scholar 

  • 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 (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–1911

    Article  CAS  Google Scholar 

  • Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    Article  CAS  Google Scholar 

  • Semenza GL (2009) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29(5):625–634

    Article  CAS  Google Scholar 

  • Spyrou G, Enmark E, Miranda-Vizuete A, Gustafsson J-A (1997) Cloning and expression of a novel mammalian thioredoxin. J Biol Chem 272:2936–2941

    Article  CAS  Google Scholar 

  • Sun Y, Elwell JH, Oberley LW (1988) A simultaneous visualization of the antioxidant enzymes glutathione peroxidase and catalase on polyacrylamide gels. Free Radic Res Commun 5:67–75

    Article  CAS  Google Scholar 

  • Surh YJ, Kundu JK, Na HK, Lee JS (2005) Redox-sensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals. J Nutr 132:2993S–3001S

    Article  Google Scholar 

  • Tagaya Y, Maeda Y, Mitsui A, Kondo N, Matsui H, Hamuro J, Brown N, Arai K-I, Yokota T, Wakasugi H, Yodoi J (1989) 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 8:757–764

    Article  CAS  Google Scholar 

  • Takagi Y, Mitsui A, Nishiyama A, Nozaki K, Sono H, Gon Y, Hashimoto N, Yodoi J (1999) Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage. Proc Natl Acad Sci U S A 96:4131–4136

    Article  CAS  Google Scholar 

  • Toledano MB, Leonard WJ (1991) Modulation of transcription factor NF-KB binding activity by oxidation-reduction in vitro. Proc Natl Acad Sci U S A 88:4328–4332

    Article  CAS  Google Scholar 

  • Wang C, Li Q, Redden DT, Weindruch R, Allison DB (2004) Statistical methods for testing effects on “maximum lifespan”. Mech Ageing Dev 125:629–632

    Article  Google Scholar 

  • Welsh SJ, Bellamy WT, Briehl MM, Powis G (2002) The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1α protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 62:5089–5095

    PubMed  CAS  Google Scholar 

  • Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardson A (1998) Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 273:28510–28515

    Article  CAS  Google Scholar 

  • Wong RSY (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87

    Article  CAS  Google Scholar 

  • Xia Y, Shen S, Verma IM (2014) NF-κB, an active player in human cancers. Cancer Immunol Res 2(9):823–830

    Article  CAS  Google Scholar 

  • Yoshihara E, Masaki S, Matsuo Y, Chen Z, Tian H, Yodoi J (2013) Thioredoxin/Txnip: redoxisome, as a redox switch for the pathogenesis of diseases. Front Immunol 4:514

    Google Scholar 

  • Zhang H, Luo Y, Zhang W, He Y, Dai S, Zhang R, Huang Y, Bernatchez P, Giordano FJ, Shadel G, Sessa WC, Min W (2007) Endothelial-specific expression of mitochondrial thioredoxin improves endothelial cell function and reduces atherosclerotic lesions. Am J Pathol 1:1108–1120

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the Pathology Core in the San Antonio Nathan Shock Center (P30-AG013319) for the pathological analyses.

Funding

This research was supported by the VA Merit Review grant from the Department of Veteran Affairs (Y.I.), the NIH grant AG13319 (Y.I.), the American Federation for Aging Research (AFAR) grant (Y.I.), and a grant from the Glenn Foundation (Y.I.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yuji Ikeno.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cunningham, G.M., Flores, L.C., Roman, M.G. et al. Thioredoxin overexpression in both the cytosol and mitochondria accelerates age-related disease and shortens lifespan in male C57BL/6 mice. GeroScience 40, 453–468 (2018). https://doi.org/10.1007/s11357-018-0039-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-018-0039-6

Keywords

  • Thioredoxin
  • Transgenic mouse
  • Oxidative stress
  • Cancer
  • Aging