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Differences in Mouse Hepatic Thyroid Hormone Transporter Expression with Age and Hyperthyroidism
(2015)
Background: Clinical features of thyroid dysfunction vary with age, and an oligosymptomatic presentation of hyperthyroidism is frequently observed in the elderly. This suggests age modulation of thyroid hormone (TH) action, which may occur, for example, by alterations in TH production, metabolism and/or TH action in target organs. Objectives: In this paper, we address possible changes in TH transporter expression in liver tissues as a mechanism of age-dependent variation in TH action. Methods: Chronic hyperthyroidism was induced in 4- and 20-month-old C57BL6/NTac male mice (n = 8-10) by intraperitoneal injections of 1 µg/g body weight <smlcap>L</smlcap>-thyroxine (T<sub>4</sub>) every 48 h over 7 weeks. Control animals were injected with PBS. Total RNA was isolated from liver samples for analysis of the TH transporter and TH-responsive gene expression. TH concentrations were determined in mice sera. Results: Baseline serum free T<sub>4</sub> (fT<sub>4</sub>) concentrations were significantly higher in euthyroid young compared to old mice. T<sub>4</sub> treatment increased total T<sub>4</sub>, fT<sub>4</sub> and free triiodothyronine to comparable concentrations in young and old mice. In the euthyroid state, TH transporter expression was significantly higher in old than in young mice, except for Mct8 and Oatp1a1 expression levels. Hyperthyroidism resulted in upregulation of Mct10, Lat1 and Lat2 in liver tissue, while Oatp1a1, Oatp1b2 and Oatp1a4 expression was downregulated. This effect was preserved in old animals. Conclusion: Here, we show age-dependent differences in TH transporter mRNA expression in the euthyroid and hyperthyroid state of mice focusing on the liver as a classical TH target organ.
Age is the single biggest risk factor for most major human diseases. As such, understanding the intricate molecular changes that drive biological aging holds great promise in attempting to slow
the onset of systemic diseases and thereby increase the effective health-span in modern societies.
This thesis explores several computational approaches to capture and analyze the molecular biological alterations triggered by intrinsic and extrinsic aging using skin as a model tissue to deliver genes and pathways as potential targets for intervention strategies.
Publication 1 demonstrates the utility of multi-omics data integration strategies for aging research, leading to the identification of four latent aging phases in skin tissue through an integrated cluster analysis of gene expression and DNA methylation data. The four phases improved the detection of molecular aging signals and were shown to be associated with sunbathing habits of the test subjects. Deeper analysis revealed extensive non-linear alterations in various biological pathways particularly at the transition into the fourth aging phase, coinciding with menopause, with potentially wide-reaching functional implications. Publication 2 describes the development of a novel type of age clock, that provides a new level of interpretability by embedding biological pathway information in the architecture of an artificial neural network. The clock not only generates meaningful biological age estimates from gene expression data, but further allows simultaneous monitoring of the aging states of various biological processes through the activations of intermediate neurons. Analyses of the inner workings of the clock revealed a wide-spread impact of aging on the global pathway landscape. Simulation experiments using the transcriptomic clock recapitulated known functional aging gene associations and allowed deciphering of the pathways by which accelerated aging conditions such as chronic sun exposure and Hutchinson-Gilford progeria syndrome exert their effects. Publication 3 further explores the molecular alterations caused by the pro-aging effector UV irradiation in the skin. The multi-omics data analysis of repetitively irradiated skin revealed signs of the immediate acquisition of aging- and cancer-related epigenetic signatures and concurrent wide-spread transcriptional changes across various biological processes. Investigations into the varying resilience to irradiation between subjects revealed prognostic biomarker signatures capable of predicting individual UV tolerances, with accuracies far surpassing the traditional Fitzpatrick classification scheme. Further analysis of the transcripts and pathways associated with UV tolerance identified a form of melanin-independent DNA damage protection in individuals with higher innate UV resilience.
Together, the approaches and findings described in this thesis explore several new angles to advance our understanding of aging processes and external drivers of aging such as UV irradiation in the human skin and deliver new insight on target genes and pathways involved.
There is still considerable controversy surrounding the impact of mastication on obesity. The aim of this study was to identify the interplay between the masticatory muscles, teeth, and general muscular fitness and how they contribute to body adiposity in a general German population. This cross-sectional study included 616 participants (300 male, 316 female, age 31–93 years) from the population-based Study of Health in Pomerania. The cross-sectional areas of the masseter, medial and lateral pterygoid muscles were measured using magnetic resonance imaging (MRI), muscular fitness assessed by hand grip strength (HGS) and body fat distribution was measured by bioelectrical impedance analysis (BIA) and MRI. The overall prevalence of obesity was high in our cohort. The cross-sectional area of the masseter muscles was positively associated with the number of teeth, body mass index (BMI) and HGS, and negatively associated with the BIA-assessed body fat when adjusted for age, sex, teeth, and BMI. Especially the correlation was strong (p < 0.001). Analogous relationships were observed between the masseter, HGS and MRI-assessed subcutaneous fat. These associations were most pronounced with masseter, but also significant with both pterygoid muscles. Though the masticatory muscles were affected by the number of teeth, teeth had no impact on the relations between masseter muscle and adiposity. Physical fitness and masticatory performance are associated with body shape, controlled and directed by the relevant muscles.
Aging is a risk factor for stroke. Animal models of stroke have been widely used to study the pathophysiology of ischemic stroke, which in turn helped to develop numerous therapeutic strategies. Despite the considerable success of therapeutic strategies in animal models of ischemic stroke, almost all of them have been proved to be unsuccessful in the clinical trials. One of explanation is that data obtained from young animals may not fully resemble the effects of ischemic stroke in aged animals or elder patients, causing the discrepancy between animal experiments and clinical trials. To investigate these differences with regard to age, pathway specific gene arrays were used to identify and isolate differentially expressed genes in periinfarct following focal cerebral ischemia. The results from this study showed a persistent up-regulation of pro-apoptotic and inflammatory-related genes up to 14 days post stroke, a 50% reduction in the number of transcriptionally active stem cell-related genes and a decreased expression of genes with anti-oxidative capacity in aged rats. Also, it was observed that at day 3 post-stroke, the contralateral, healthy hemisphere of young rats is much more active at transcriptional level than that of the aged rats, especially at the level of stem cell- and hypoxia signaling associated genes. Next, protein levels between young and aged post-stroke rats in periinfarct were compared using proteomic tools. Among others, AnxA3 was identified as differentially regulated protein, but the expression of AnxA3 has no significant changes in periinfarct between these two age groups at day 3 and 14. Different from periinfarct, a strong upregulation of AnxA3 at day 3 in young rats plus a strengthened increase of AnxA3 at day 14 in aged rats using immunohistochemical quantification indicated a delayed microglial accumulation in infarct core of aged rats, suggesting that quick activation of microglia in infarct core of young rats might be beneficial for recovery. Colocalization with established microglial marker demonstrated that AnxA3 as a novel microglial marker is implicated in the microglial responses to the focal cerebral ischemia. In addition, it was found that AnxA3 positive microglial cells incorporated more proliferating cell marker BrdU. Third, the expression, localization and function of several transport proteins were investigated in young rats following focal ischemic stroke. P-gp staining was detected in endothelial cells of desintegrated capillaries and by day 14 in newly generated blood vessels. There was no significant difference, however, in the Mdr1a mRNA amount in the periinfarct region compared to the contralateral site. For Bcrp, a significant mRNA up-regulation was observed from day 3 to 14. This up-regulation was followed by the protein as confirmed by quantitative immunohistochemistry. Oatp2, located in the vascular endothelium, was also up-regulated at day 14. For Mrp5, an up-regulation was observed in neurons in the periinfarct region (day 14). In conclusion, reduced transcriptional activity in the healthy, contralateral sensorimotor cortex in conjunction with an early up-regulation of proapoptotic genes and a decreased expression of genes with anti-oxidative capacity in the ipsilateral sensorimotor cortex of aged rats, plus the delayed up-regulation of AnxA3 positive microglial cells in infarct core may contribute to diminished recovery in post-stroke old rats. In addition, it was demonstrated in this study that after stroke the transport proteins were up-regulated with a maximum at day 14, a time point that coincides with behavioral recuperation. The study further suggests Bcrp as a pronounced marker for the regenerative process and a possible functional role of Mrp5 in surviving neurons. This study provided several evidences for the different responses of young and aged rats using a focal ischemic stroke model. Understanding the effect of age is crucial for the development of relevant therapeutic drugs.