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PLoS One. 2016 Mar 8;11(3):e0149941. doi: 10.1371/journal.pone.0149941. eCollection 2016.

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

Author information

1
Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
2
MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
3
Institute for Research on Cancer and Aging, Nice (IRCAN), UMR 7284 CNRS U1081 INSERM UNS, 28 avenue de Valombrose Faculté de Médecine, Nice, France.
4
Laboratory of Comparative Endocrinology, Biology Department, KULeuven, Leuven, Belgium.
5
Dept of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
6
Dept of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands.
7
Dept of Biomedical Sciences, Edison Biotechnology Institute, Ohio University, Athens, Ohio, United States of America.
8
Dept of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
9
Centre for Health Protection Research, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

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.

PMID:
26953569
PMCID:
PMC4783069
DOI:
10.1371/journal.pone.0149941
[Indexed for MEDLINE]
Free PMC Article

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