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.
Highlights
Aging is a complex and still poorly understood process damage to macromolecules is considered to be an important contributing factor
To determine if thyroid hormone (TH) signaling is altered during aging in our mouse mutants, we assessed thyroid state in livers of extremely aging (XAA; abbreviation for Csbm/m/Xpa-/- KO mice), moderately aging (MAA; abbreviation for Ercc1-/Δ-7 KO mice) and naturally old WT mice
We quantified Dio1 and Thrsp mRNA levels, highly sensitive markers of hepatic thyroid state. Expression of both genes was significantly (~3 to 30-fold) decreased in livers of 18-day old XAA mice and 16-week old moderately accelerated aging (MAA) mice compared to agematched controls, strongly suggesting that livers of these progeroid mutants are in a hypothyroid state (Fig 1A and 1B)
Summary
Aging is a complex and still poorly understood process damage to macromolecules is considered to be an important contributing factor. A major route of DNA repair is nucleotide excision repair (NER), a multi-step “cut-and-patch” repair mechanism which is responsible for removing a remarkable diversity of helix-distorting lesions caused by exogenous factors or endogenous metabolism, integrating environmental and intrinsic contributions to the aging process. Important insights into the link between DNA damage and aging have come from studies using rapidly aging mice with defects in transcription-coupled NER (TC-NER) as models for human progeroid syndromes [2,3,4]. In the absence of TC-NER, the vital process of transcription is hampered by persisting DNA lesions, causing accelerated cell death and premature aging. Since progeroid mutants display varying extents of accelerated aging in different tissues, presumably reflecting tissue-dependent induction of DNA damage, expression of repair and/or damage response genes they are termed ‘segmental’ progeroid syndromes. TC-NER deficient patients and corresponding mouse mutants are valuable models that manifest many genuine aspects of normal aging in an accelerated manner [5,6,7]
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