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

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 demo...

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Autores principales: Flores, Lisa C., Roman, Madeline G., Cunningham, Geneva M., Cheng, Christie, Dube, Sara, Allen, Colton, Van Remmen, Holly, Hubbard, Gene B., Saunders, Thomas L., Ikeno, Yuji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201794/
https://www.ncbi.nlm.nih.gov/pubmed/30370017
http://dx.doi.org/10.1080/20010001.2018.1533754
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author Flores, Lisa C.
Roman, Madeline G.
Cunningham, Geneva M.
Cheng, Christie
Dube, Sara
Allen, Colton
Van Remmen, Holly
Hubbard, Gene B.
Saunders, Thomas L.
Ikeno, Yuji
author_facet Flores, Lisa C.
Roman, Madeline G.
Cunningham, Geneva M.
Cheng, Christie
Dube, Sara
Allen, Colton
Van Remmen, Holly
Hubbard, Gene B.
Saunders, Thomas L.
Ikeno, Yuji
author_sort Flores, Lisa C.
collection PubMed
description 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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spelling pubmed-62017942018-10-26 Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice Flores, Lisa C. Roman, Madeline G. Cunningham, Geneva M. Cheng, Christie Dube, Sara Allen, Colton Van Remmen, Holly Hubbard, Gene B. Saunders, Thomas L. Ikeno, Yuji Pathobiol Aging Age Relat Dis Research Article 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. Taylor & Francis 2018-10-23 /pmc/articles/PMC6201794/ /pubmed/30370017 http://dx.doi.org/10.1080/20010001.2018.1533754 Text en © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Flores, Lisa C.
Roman, Madeline G.
Cunningham, Geneva M.
Cheng, Christie
Dube, Sara
Allen, Colton
Van Remmen, Holly
Hubbard, Gene B.
Saunders, Thomas L.
Ikeno, Yuji
Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice
title Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice
title_full Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice
title_fullStr Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice
title_full_unstemmed Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice
title_short Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice
title_sort continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male c57bl/6 mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201794/
https://www.ncbi.nlm.nih.gov/pubmed/30370017
http://dx.doi.org/10.1080/20010001.2018.1533754
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