Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice
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 agi...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Bioscientifica
2023-11-01
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| Series: | European Thyroid Journal |
| Subjects: | |
| Online Access: | https://etj.bioscientifica.com/view/journals/etj/12/6/ETJ-22-0231.xml |
| _version_ | 1827631817874735104 |
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| author | Sander Barnhoorn Marcel E Meima Robin P Peeters Veerle M Darras Selmar Leeuwenburgh Jan H J Hoeijmakers Wilbert P Vermeij W Edward Visser |
| author_facet | Sander Barnhoorn Marcel E Meima Robin P Peeters Veerle M Darras Selmar Leeuwenburgh Jan H J Hoeijmakers Wilbert P Vermeij W Edward Visser |
| author_sort | Sander Barnhoorn |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T14:27:23Z |
| format | Article |
| id | doaj.art-f7af7f3f184c4cbe9795ae267498776b |
| institution | Directory Open Access Journal |
| issn | 2235-0802 |
| language | English |
| last_indexed | 2024-03-09T14:27:23Z |
| publishDate | 2023-11-01 |
| publisher | Bioscientifica |
| record_format | Article |
| series | European Thyroid Journal |
| spelling | doaj.art-f7af7f3f184c4cbe9795ae267498776b2023-11-28T06:56:41ZengBioscientificaEuropean Thyroid Journal2235-08022023-11-01126110https://doi.org/10.1530/ETJ-22-0231Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in miceSander Barnhoorn0Marcel E Meima1Robin P Peeters2Veerle M Darras3Selmar Leeuwenburgh4Jan H J Hoeijmakers5Wilbert P Vermeij6W Edward Visser7Department of Molecular Genetics, Erasmus Medical Center, Rotterdam, The NetherlandsDepartment of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The NetherlandsDepartment of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The NetherlandsLaboratory of Comparative Endocrinology, Biology Department, KU Leuven, Leuven, BelgiumDepartment of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The NetherlandsDepartment of Molecular Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Oncode Institute, Utrecht, The Netherlands; Institute for Genome Stability in Ageing and Disease, CECAD Research Centre, Cologne, Germany Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Oncode Institute, Utrecht, The NetherlandsDepartment of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The NetherlandsBackground: 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.https://etj.bioscientifica.com/view/journals/etj/12/6/ETJ-22-0231.xmlthyroid hormonedeiodinaseagingprogeriadna damagenucleotide excision repairliver |
| spellingShingle | Sander Barnhoorn Marcel E Meima Robin P Peeters Veerle M Darras Selmar Leeuwenburgh Jan H J Hoeijmakers Wilbert P Vermeij W Edward Visser Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice European Thyroid Journal thyroid hormone deiodinase aging progeria dna damage nucleotide excision repair liver |
| title | Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice |
| title_full | Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice |
| title_fullStr | Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice |
| title_full_unstemmed | Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice |
| title_short | Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice |
| title_sort | decreased hepatic thyroid hormone signaling in systemic and liver specific but not brain specific accelerated aging due to dna repair deficiency in mice |
| topic | thyroid hormone deiodinase aging progeria dna damage nucleotide excision repair liver |
| url | https://etj.bioscientifica.com/view/journals/etj/12/6/ETJ-22-0231.xml |
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