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.
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: W Edward
authors.initials: WE
authors.lastname: Visser
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Cíntia R
authors.initials: CR
authors.lastname: Bombardieri
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Zevenbergen
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Barnhoorn
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.|Institute for Research on Cancer and Aging, Nice (IRCAN), UMR 7284 CNRS U1081 INSERM UNS, 28 avenue de Valombrose Faculté de Médecine, Nice, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ottaviani
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Renata
authors.initials: R
authors.lastname: Brandt
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Kaptein
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ramona
authors.initials: R
authors.lastname: van Heerebeek
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Toor
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Medici
authors.affiliation: Laboratory of Comparative Endocrinology, Biology Department, KULeuven, Leuven, Belgium.
authors.forename: Willy
authors.initials: W
authors.lastname: van Ham
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Wilbert P
authors.initials: WP
authors.lastname: Vermeij
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.affiliation: Dept of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.affiliation: Dept of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anita
authors.initials: A
authors.lastname: Boelen
authors.affiliation: Dept of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Joan
authors.initials: J
authors.lastname: Kwakkel
authors.affiliation: Dept of Biomedical Sciences, Edison Biotechnology Institute, Ohio University, Athens, Ohio, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.affiliation: Dept of Biomedical Sciences, Edison Biotechnology Institute, Ohio University, Athens, Ohio, United States of America.
authors.forename: Edward O
authors.initials: EO
authors.lastname: List
authors.affiliation: Dept of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Joost P M
authors.initials: JP
authors.lastname: Melis
authors.affiliation: Laboratory of Comparative Endocrinology, Biology Department, KULeuven, Leuven, Belgium.
authors.forename: Veerle M
authors.initials: VM
authors.lastname: Darras
authors.affiliation: Centre for Health Protection Research, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Martijn E T
authors.initials: ME
authors.lastname: Dollé
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.affiliation: MGC Dept of Genetics, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004249:DNA Damage; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*
chemical_list: D013963:Thyroid Hormones; D007453:Iodide Peroxidase