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

Edward Visser, Cintia Bombardieri, Chantal Zevenbergen, Sander Barnhoorn, Alexandre Ottaviani, Ingrid van der Pluijm, Renata Brandt, E Kaptein, Ramona van Heerebeek, Hans van Toor, G Garinis, Robin Peeters, Marco Medici, W van Ham, Wilbert Vermeij, Monique Waard, Ronald de Krijger, A Boelen, J Kwakkel, JJ KopchickEO List, JPM Melis, VM Darras, MET Dolle, Bert van der Horst, Jan Hoeijmakers, Theo Visser

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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 (Csb(m/m)/Xpa(-/-)) or intermediate (Ercc1(-/Delta-7)) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csb(m/m)/Xpa(-/-) livers. Similar findings are noticed in Ercc1(-/Delta-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 languageUndefined/Unknown
JournalPLoS One (print)
Issue number3
Publication statusPublished - 2016

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