TY - JOUR
T1 - Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging
AU - Visser, Edward
AU - Bombardieri, Cintia
AU - Zevenbergen, Chantal
AU - Barnhoorn, Sander
AU - Ottaviani, Alexandre
AU - van der Pluijm, Ingrid
AU - Brandt, Renata
AU - Kaptein, E
AU - van Heerebeek, Ramona
AU - van Toor, Hans
AU - Garinis, G
AU - Peeters, Robin
AU - Medici, Marco
AU - van Ham, W
AU - Vermeij, Wilbert
AU - Waard, Monique
AU - de Krijger, Ronald
AU - Boelen, A
AU - Kwakkel, J
AU - Kopchick, JJ
AU - List, EO
AU - Melis, JPM
AU - Darras, VM
AU - Dolle, MET
AU - van der Horst, Bert
AU - Hoeijmakers, Jan
AU - Visser, Theo
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 (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.
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 (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.
U2 - 10.1371/journal.pone.0149941
DO - 10.1371/journal.pone.0149941
M3 - Article
VL - 11
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 3
ER -