DIETARY BIOACTIVES IN THE MODULATION OF METABOLIC, FUNCTIONAL AND AGING BIOMARKERS

Bioactive compounds and bioactive-rich foods play a crucial role in modulating key physiological pathways related to human health, including cardiometabolic regulation, intestinal function, and healthy aging. In particular, dietary (poly)phenols and xanthines have gained attention for their potential benefits on several metabolic and functional biomarkers. However, the mechanisms are not completely understood and the evidence in humans are still scarce. The present Ph.D. thesis investigates the role of dietary bioactives and bioactives-rich foods in modulating functional biomarkers of human health, with a focus on the mechanisms involving lipid metabolism, oxidative stress and inflammation, intestinal permeability, and telomere integrity. The research was structured into three main chapters, combining both in vitro and in vivo approaches. In Chapter 1, the mechanisms of action of selected bioactives, including (poly)phenols and xanthine-derived metabolites, were explored in different cellular models. In particular, 3T3-L1 adipocytes and Caco-2 intestinal epithelial cells were used to investigate processes such as lipid accumulation, glucose metabolism, and intestinal barrier integrity. Additionally, in 3T3-L1 adipocytes, a systematic review highlighted the modulatory role of dietary (poly)phenols on adipocyte metabolism, showing that different classes of (poly)phenols can influence key markers involved in lipid and glucose metabolism (e.g., AMPK, SIRT1). Experimental studies further revealed that quercetin-derived metabolites can reduce glucose-stimulated lipid accumulation, while blueberry and raspberry extracts protect intestinal barrier function under pro-inflammatory conditions by preserving tight junction integrity and reducing oxidative stress. Additionally, xanthine metabolites demonstrated protective effects on age-associated intestinal barrier dysfunction, suggesting their potential contribution to gut health during aging. Chapter 2 translated these mechanistic insights into the clinical setting, evaluating the effects of blueberry consumption, as source of dietary bioactives such (poly)phenols, in a human dietary intervention study. The human trial (the BLUMET study) assessed the impact of an 8-week blueberry intervention on biomarkers related to cardiometabolic health, oxidative stress, inflammation and intestinal permeability in individuals with metabolic syndrome. Preliminary findings suggest that blueberry intake may modulate some biomarkers of adipose tissue metabolism such as adiponectin and slightly reduce total cholesterol, supporting its potential role in the protection of human health. Conversely, no significant findings were documented for the rest of the biomarkers analyzed suggesting the need for further investigations. In Chapter 3, the focus was placed on telomere biology, a well-established hallmark of aging. The work was carried out as part of an Erasmus+ traineeship program at the University of Copenhagen (Denmark). The experiments investigated the role of xanthine and (poly)phenol metabolites in human samples (PBMCs) from the BLUMET study, as well as in cell culture models (THP-1). All activities were conducted under the supervision of Professor Peter Møller at the Department of Public Health, Section of Environmental Health, University of Copenhagen. In particular, cellular experiments, consisting in a dysmetabolism-induced monocytic cell line, demonstrated the potential of (poly)phenol metabolites to prevent telomere shortening suggesting their ability to modulate key pathways involved in cellular senescence. In addition, the findings from the BLUMET study suggested a possible protective effect of wild blueberry consumption on telomere length in individuals with metabolic syndrome, linking nutritional interventions to the preservation of genomic stability. In conclusion, this thesis contributes to the growing body of evidence supporting the beneficial role of dietary bioactives, in particular (poly)phenols, in modulating key markers of cardiometabolic health, gut function, and cellular aging. By integrating mechanistic, cellular, and clinical data, it highlights the importance of both individual metabolites and whole food matrices in modulating lipid metabolism, intestinal health, vascular function, and telomere maintenance. These findings underscore the need for future studies to elucidate the complex interactions between dietary bioactives and biological processes, with the ultimate purpose of defining nutritional strategies with the contribution of bioactive-rich foods able to enhance overall human health and well-being.