Essential trace elements: From monitoring supply status to elucidating transfer across the blood-brain barrier

This dissertation investigates the role of trace elements (TEs) in human health and the aging process, focusing on essential elements like zinc (Zn), selenium (Se), copper (Cu), iodine (I), iron (Fe), and manganese (Mn). These TEs are crucial for maintaining physiological processes such as immune response, antioxidant activity, and cellular function, with their homeostasis being tightly regulated by the body. Disruptions in TE homeostasis —due to aging, dietary intake, or other factors— can lead to metabolic imbalances with potential health consequences, including neurodegenerative diseases. The thesis encompasses human intervention studies under the scope of long-term monitoring, biomarker research and postprandial serum variability and an in vitro blood-brain barrier (BBB) model to understand the dynamics of TEs across different life stages and conditions. In Chapter 2, throughout a dietary intervention study within the NutriAct project we monitored the mineral status of a middle-aged German population over two years. The primary findings revealed significant shifts in serum TE concentrations, particularly Zn, Se, and Mn, as a result of the implemented specific dietary patterns. Serum Zn concentrations significantly declined over time, whereas Se and Mn levels increased. This study suggests a direct link between dietary patterns and serum Zn, Se, and Mn profiles. Additionally, the rise in serum selenoprotein P (SELENOP) concentrations reaffirmed its utility as a suitable biomarker for Se status. Chapter 3 further investigates the NutriAct cohort, examining the association between thyroid hormone (TH) metabolism and intrahepatic lipids. Over the first 12 months of the intervention, a reduction in total and free triiodothyronine (T3) levels was observed, alongside a decrease in intrahepatic lipids. However, total and free thyroxine (T4) and thyroid-stimulating hormone (TSH) remained stable, indicating an euthyroid status within the representative population. This chapter highlights a potential link between peripheral T3 concentrations and liver fat, suggesting that lipid metabolism might be influenced by thyroid hormone variations independent of the hypothalamic-pituitary-thyroid (HPT) axis. In Chapter 4, postprandial serum TE variability and bioavailability were assessed in young and elderly participants within the BioMiEL study. Age-related differences in baseline serum concentrations of Zn, Se, and Cu were observed, with older participants displaying higher serum Cu and Se levels, but lower Zn levels, leading to an elevated Cu/Zn ratio. While postprandial changes in serum TE levels were generally limited, some variations in Cu, Se, and I were noted, which may reflect differences in TE metabolism between age groups. Zn, in particular, showed strong time-dependent fluctuations, indicating its sensitivity to postprandial changes. Contrary, the free Zn fraction in serum remained in general stable, indicating a compensatory mechanism which might be independent of postprandial total serum Zn variability. Chapter 5 addresses the Se status of vegans, a group at risk of Se deficiency due to dietary restrictions. Through targeted dietary interventions, including Se supplementation or the daily consumption of Brazil nut spread, significant improvements in serum Se levels and SELENOP concentrations were observed within two weeks. These findings emphasize the importance of dietary Se sources in improving Se status, especially in populations adhering to plant-based diets. In Chapter 6, a porcine brain capillary endothelial cell (PBCEC) model was employed to explore the Zn-modulated bidirectional Cu transfer across the BBB. The BBB cell culture system mimicked the in vivo conditions of Cu and Zn transport, with Cu being transferred from the blood side (apical) to the brain side (basolateral) during a 48-h incubation period. Co-incubation with Zn led to a reduced Cu/Zn ratio (<1) on the apical side, inhibiting or slowing Cu transfer across the BBB. This inhibition may be attributed to increased intracellular sequestration of Cu by metallothionein (MT), a protein upregulated by Zn availability. Such inhibition was not observed for the reverse Cu transfer, suggesting that BBB endothelial cells may help mitigate elevated Cu levels within the brain. Notably, Zn itself showed no significant transfer between compartments, suggesting minimal exchange across the BBB. Additionally, the integrity of the BBB remained unaffected by the different incubation conditions. This thesis emphasizes the importance of understanding TE dynamics in relation to dietary intake and aging. It highlights the potential of dietary interventions to improve TE status, particularly for vulnerable groups, such as vegans or the elderly, and underscores the need for further research into the interactions between multiple TEs and their impact on metabolic and neurodegenerative diseases. To fully assess TE status, it is crucial to employ robust methodologies, along with a comprehensive spectrum of TE status and biomarkers. This approach ensures a more accurate evaluation of TE homeostasis and better informs interventions aimed at mitigating age-related, diet-induced or combined deficiencies.