European Thyroid Journal (Nov 2023)

Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice

  • Sander Barnhoorn,
  • Marcel E Meima,
  • Robin P Peeters,
  • Veerle M Darras,
  • Selmar Leeuwenburgh,
  • Jan H J Hoeijmakers,
  • Wilbert P Vermeij,
  • W Edward Visser

DOI
https://doi.org/10.1530/ETJ-22-0231
Journal volume & issue
Vol. 12, no. 6
pp. 1 – 10

Abstract

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Background: Thyroid hormone signaling is essential for development, metabolism, and response to stress but declines during aging, the cause of which is unknown. DNA damage accumulating with time is a main cause of aging, driving many age-related diseases. Previous studies in normal and premature aging mice, due to defective DNA repair, indicated reduced hepatic thyroid hormone signaling accompanied by decreased type 1 deiodinase (DIO1) and increased DIO3 activities. We investigated whether aging-related changes in deiodinase activity are driven by systemic signals or represent cell- or organ-autonomous changes. Methods: We quantified liver and plasma thyroid hormone concentrations, deiodinase activities and expression of T3-responsive genes in mice with a global, liver-specific and for comparison brain-specific inactivation of Xpg, one of the endonucleases critically involved in multiple DNA repair pathways. Results: Both in global and liver-specific Xpg knockout mice, hepatic DIO1 activity was decreased. Interestingly, hepatic DIO3 activity was increased in global, but not in liver-specific Xpg mutants. Selective Xpg deficiency and premature aging in the brain did not affect liver or systemic thyroid signaling. Concomitant with DIO 1 inhibition, Xpg−/− and Alb-Xpg mice displayed reduced thyroid hormone-related gene expression changes, correlating with markers of liver damage and cellular senescence. Conclusions: Our findings suggest that DIO1 activity during aging is predominantly modified in a tissue-autonomous manner driven by organ/cell-intrinsic accumulating DNA damage. The increase in hepatic DIO3 activity during aging largely depends on systemic signals, possibly reflecting the presence of circulating cells rather than activity in hepatocytes.

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