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

Abstract

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 DIO1 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.

Keywords: DNA damage; aging; deiodinase; liver; nucleotide excision repair; progeria; thyroid hormone.

Figure 1

Research question and experimental design. (A) Life span in mice with reduced somato-, lacto-, and/or thyrotropic signaling. The relationship between changes in percentage survival (x-axis) and log-hazard ratio effect size (y-axis) for median life span. Data were obtained from various life span cohorts (1) and separated by mutation. Mean values ± s.d.of the different cohorts are depicted for the various long-lived dwarf mutant mouse lines. (B) Schematic representation of the research question and experimental design.

Figure 2

Deiodinase activity in liver. Deiodinase 1 (DIO1) and 3 (DIO3) activity in livers of DNA repair-deficient (indicated in red) 4- and 14-week-old male Xpg^−/− mice (A, B), 26-week-old liver-specific male Alb-Xpg mice (C, D) and 26-week-old brain-specific male and female Emx-Xpg mice (E, F). n = 3–4 animals/group. Wild-type (Wt) littermate controls are indicated in blue. Error bars denote mean ± s.e. *P < 0.05, ***P < 0.001.

Figure 3

Deiodinase gene expression in liver. Dio1 and Dio3 gene expression in livers of 4- and 14-week-old male Xpg^−/− mice (A), 26-week-old liver-specific male Alb-Xpg mice (B), and 26-week-old brain-specific male and female Emx-Xpg mice (C). n = 3–4 animals/group. Error bars denote mean ± s.e. **P <0.01, ***P < 0.001.

Figure 4

Thyroid hormone concentrations in liver and plasma. Liver T3 and T4 concentrations in 4- and 14-week-old male and female Xpg^−/− mice (A, D), 26-week-old liver-specific male Alb-Xpg mice (B, E), and 26-week-old brain-specific male and female Emx-Xpg mice (C, F). Plasma T3 and T4 concentrations in 4- and 14-week-old male and female Xpg^−/− mice (G, J), 26-week-old liver-specific male Alb-Xpg mice (H, K), and 26-week-old male and female brain-specific Emx-Xpg mice (I, L). n = 3 animals/group. Error bars denote mean ± s.e. *P < 0.05.

Figure 5

Expression of thyroid hormone responsive genes and thyroid hormone-binding proteins in liver. Gene expression in livers of 4- and 14-week-old male Xpg^−/− mice (A, B), 26-week-old liver-specific male Alb-Xpg mice (C), and 26-week-old brain-specific male and female Emx-Xpg mice (D). n = 3–4 animals/group. The dotted line separates genes that are upregulated (left) or downregulated (right) in hypothyroidism. Alb, Tbg, and Ttr gene expression in livers of 4-week-old male Xpg^−/− mice (E), 14-week-old male Xpg^−/− mice (F), 26-week-old male Alb-Xpg mice (G) and 26-week-old male and female Emx-Xpg mice (H). n = 3–4 animals/group. Error bars denote mean ± s.e. *P < 0.05, **P < 0.01.

Figure 6

Alanine transferase and albumin concentrations in plasma. Alanine amino transferase (ALAT) concentration in plasma of 4- and 14-week-old male Xpg^−/− mice (A), and 26-week-old liver-specific male Alb-Xpg mice (B). Albumin concentration in plasma of 4- and 14-week-old male Xpg^−/− mice (C), and 26-week-old, liver-specific male Alb-Xpg mice (D). n = 2–3 animals/group. Error bars denote mean ± s.e. **P < 0.01.

Figure 7

Expression of senescence-associated factors in liver. P21, IL-6, Mmp12, and Timp1 expression in livers of 14-week-old male Xpg^−/− mice (A), 26-week-old liver-specific male Alb-Xpg mice (B), and 26-week-old brain-specific male and female Emx-Xpg mice (C). n = 3–4 animals/group. Error bars denote mean ± s.e. **P < 0.01, ***P < 0.001.