Molecular insights into inflammation: the role of diet-derived compounds, aging and cardiovascular disease

Inflammation represents a key factor connecting aging, cardiovascular disease and gut health. Epigenetics regulation and mitochondrial homeostasis play a pivotal role in this interplay. A healthy, balanced diet has been hypothesized to counteract chronic inflammation supporting healthy aging. Thus, the aim of this doctoral thesis was to investigate the transcriptomic, epigenetic and mitochondrial mechanisms characterizing inflammation, focusing on the responses to nutritional bioactive molecules, aging and cardiovascular disease (CVD). The main research objective was to characterize the molecular effects of Mela Rosa Marchigiana callus extract (MRME) using an in vitro model of cellular senescence. Interestingly, transcriptomic analysis revealed that MRME downregulates the expression of inflammaging genes while genome wide DNA methylation analysis showed that this mechanism was independent of DNA methylation. Then, given that cell-free mitochondrial DNA has been suggested to have an inflammatory effect, and since inflammaging is one of the main factors underpinning the development of CVD, the second research objective was to quantify mitochondrial DNA copy number (mtDNAcn) in circulating cell-free DNA and extracellular vesicles (EVs) by comparing healthy subjects and patients with CVD in order to assess whether it is altered in the disease and whether it may serve as a predictive biomarker of CVD. Interestingly, comparing healthy controls with CVD patients the mtDNAcn carried by EVs was higher in case of CVD suggesting that it may have an active role in the disease with potential pro-inflammatory effect. Finally, this research activity also contributed to the characterization of the role of gut microbiota-derived metabolite Trimethylamine (TMA) in promoting gut inflammation with a particular focus on investigating its effect on cell-free DNA released by intestinal epithelial cells exposed to the compound. Interestingly, TMA increased the release of cell free mtDNA in the extracellular milleu. Overall, the finding of this research contributed to further elucidate the complex interplay between inflammation, diet, aging and CVD, highlining new mechanism and diet derived compounds that could be promising candidates to be further studied to counteract age-related diseases.