Molecular mechanisms of age-dependent thyroid hormone action on target tissues

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Age is an important determinant of the clinical presentation of thyroid dysfunction and health consequences of disturbed thyroid hormone (TH) action are particularly relevant in an aging population. The molecular mechanisms that account for age-dependent changes in TH action are not fully understood. In the first funding period we have studied age-impact on organ response and TH signaling in conditions of TH excess and deprivation in young, adult and old male rodents. We found, that age modulates phenotypes of hyper- and hypothyroidism such as energy homeostasis and behaviour, while e.g. heart rate and cardiac hypertrophy was not affected. Gene expression analysis showed distinct organ-related changes in TH transporters and intracellular TH signaling in response to age and T4/T3-serum status. In the clinical setting we have established a prospective patient cohort (TSAGE cohort) and have obtained preliminary evidence for age-dependent changes in human T4-T0 serum status in endogenous hyper- and hypothyroidism. In the second funding period we plan to 1) complete characterization of age-impact on organ thyroid status and T4-T0 serum status in our animal models, 2) identify causes for observed age-modulation of organ response and address reasons for absent age impact, 3) study TH-related heart disease in a murine model in a collaboration to address a potentially fatal complication of hyperthyroidism in an old organism and 4) continue with clinical studies (ongoing TSAGE cohort and additional recruited cohorts) to define age-specific serum TH status and to identify novel markers of hyper- and hypothyroidism in young and old patients.