Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging

W Edward Visser; Cíntia R Bombardieri; Chantal Zevenbergen; Sander Barnhoorn; Alexandre Ottaviani; Ingrid van der Pluijm; Renata Brandt; Ellen Kaptein; Ramona van Heerebeek; Hans van Toor; George A Garinis; Robin P Peeters; Marco Medici; Willy van Ham; Wilbert P Vermeij; Monique C de Waard; Ronald R de Krijger; Anita Boelen; Joan Kwakkel; John J Kopchick; Edward O List; Joost P M Melis; Veerle M Darras; Martijn E T Dollé; Gijsbertus T J van der Horst; Jan H J Hoeijmakers; Theo J Visser

doi:10.1371/journal.pone.0149941

Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging

W Edward Visser, Cíntia R Bombardieri, Chantal Zevenbergen, Sander Barnhoorn, Alexandre Ottaviani, Ingrid van der Pluijm, Renata Brandt, Ellen Kaptein, Ramona van Heerebeek, Hans van Toor, George A Garinis, Robin P Peeters, Marco Medici, Willy van Ham, Wilbert P Vermeij, Monique C de Waard, Ronald R de Krijger, Anita Boelen, Joan Kwakkel, John J KopchickEdward O List, Joost P M Melis, Veerle M Darras, Martijn E T Dollé, Gijsbertus T J van der Horst, Jan H J Hoeijmakers, Theo J Visser

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

Abstract

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging.

Original language	English
Article number	e0149941
Pages (from-to)	e0149941
Journal	PloS one
Volume	11
Issue number	3
DOIs	https://doi.org/10.1371/journal.pone.0149941
Publication status	Published - 2016
Externally published	Yes

Keywords

Aging/genetics
Animals
DNA Damage
Hypothyroidism/genetics
Iodide Peroxidase/genetics
Liver/metabolism
Mice
Mice, Knockout
Organ Specificity
Thyroid Hormones/genetics

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10.1371/journal.pone.0149941

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Visser, W. E., Bombardieri, C. R., Zevenbergen, C., Barnhoorn, S., Ottaviani, A., van der Pluijm, I., Brandt, R., Kaptein, E., van Heerebeek, R., van Toor, H., Garinis, G. A., Peeters, R. P., Medici, M., van Ham, W., Vermeij, W. P., de Waard, M. C., de Krijger, R. R., Boelen, A., Kwakkel, J., ... Visser, T. J. (2016). Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging. PloS one, 11(3), e0149941. Article e0149941. https://doi.org/10.1371/journal.pone.0149941

@article{49ac04b381aa4089ac93c0aca2090db8,

title = "Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging",

abstract = "DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging. ",

keywords = "Aging/genetics, Animals, DNA Damage, Hypothyroidism/genetics, Iodide Peroxidase/genetics, Liver/metabolism, Mice, Mice, Knockout, Organ Specificity, Thyroid Hormones/genetics",

author = "Visser, {W Edward} and Bombardieri, {C{\'i}ntia R} and Chantal Zevenbergen and Sander Barnhoorn and Alexandre Ottaviani and {van der Pluijm}, Ingrid and Renata Brandt and Ellen Kaptein and {van Heerebeek}, Ramona and {van Toor}, Hans and Garinis, {George A} and Peeters, {Robin P} and Marco Medici and {van Ham}, Willy and Vermeij, {Wilbert P} and {de Waard}, {Monique C} and {de Krijger}, {Ronald R} and Anita Boelen and Joan Kwakkel and Kopchick, {John J} and List, {Edward O} and Melis, {Joost P M} and Darras, {Veerle M} and Doll{\'e}, {Martijn E T} and {van der Horst}, {Gijsbertus T J} and Hoeijmakers, {Jan H J} and Visser, {Theo J}",

note = "Publisher Copyright: {\textcopyright} 2016 Visser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2016",

doi = "10.1371/journal.pone.0149941",

language = "English",

volume = "11",

pages = "e0149941",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "3",

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Visser, WE, Bombardieri, CR, Zevenbergen, C, Barnhoorn, S, Ottaviani, A, van der Pluijm, I, Brandt, R, Kaptein, E, van Heerebeek, R, van Toor, H, Garinis, GA, Peeters, RP, Medici, M, van Ham, W, Vermeij, WP, de Waard, MC, de Krijger, RR, Boelen, A, Kwakkel, J, Kopchick, JJ, List, EO, Melis, JPM, Darras, VM, Dollé, MET, van der Horst, GTJ, Hoeijmakers, JHJ & Visser, TJ 2016, 'Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging', PloS one, vol. 11, no. 3, e0149941, pp. e0149941. https://doi.org/10.1371/journal.pone.0149941

TY - JOUR

T1 - Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging

AU - Visser, W Edward

AU - Bombardieri, Cíntia R

AU - Zevenbergen, Chantal

AU - Barnhoorn, Sander

AU - Ottaviani, Alexandre

AU - van der Pluijm, Ingrid

AU - Brandt, Renata

AU - Kaptein, Ellen

AU - van Heerebeek, Ramona

AU - van Toor, Hans

AU - Garinis, George A

AU - Peeters, Robin P

AU - Medici, Marco

AU - van Ham, Willy

AU - Vermeij, Wilbert P

AU - de Waard, Monique C

AU - de Krijger, Ronald R

AU - Boelen, Anita

AU - Kwakkel, Joan

AU - Kopchick, John J

AU - List, Edward O

AU - Melis, Joost P M

AU - Darras, Veerle M

AU - Dollé, Martijn E T

AU - van der Horst, Gijsbertus T J

AU - Hoeijmakers, Jan H J

AU - Visser, Theo J

N1 - Publisher Copyright: © 2016 Visser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2016

Y1 - 2016

N2 - DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging.

AB - DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging.

KW - Aging/genetics

KW - Animals

KW - DNA Damage

KW - Hypothyroidism/genetics

KW - Iodide Peroxidase/genetics

KW - Liver/metabolism

KW - Mice

KW - Mice, Knockout

KW - Organ Specificity

KW - Thyroid Hormones/genetics

UR - https://www.mendeley.com/catalogue/c2ebda3f-df58-37e0-9d51-95dab88c37b0/

U2 - 10.1371/journal.pone.0149941

DO - 10.1371/journal.pone.0149941

M3 - Article

C2 - 26953569

SN - 1932-6203

VL - 11

SP - e0149941

JO - PloS one

JF - PloS one

IS - 3

M1 - e0149941

ER -

Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging

Abstract

Keywords

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