Cardiovascular and metabolic disorders present major causes of mortality in the ageing population. Polyphenols present in human diets possess cardiometabolic protective properties, however their underlying molecular mechanisms in humans are still not well identified. Even though preclinical and in vitro studies advocate that these bioactives can modulate gene expression, most studies were performed using targeted approaches. With the objective to decipher the molecular mechanisms underlying polyphenols cardiometabolic preventive properties in humans, we performed integrative multi-omic bioinformatic analyses of published studies which reported improvements of cardiometabolic risk factors following polyphenol intake, together with genomic analyses performed using untargeted approach. We identified 5 studies within our criteria and nearly 5000 differentially expressed genes, both mRNAs and miRNAs, in peripheral blood cells. Integrative bioinformatic analyses (e.g. pathway and gene network analyses, identification of transcription factors, correlation of gene expression profiles with those associated with diseases and drug intake) revealed that these genes are involved in the processes such as cell adhesion and mobility, immune system, metabolism, or cell signaling. We also identified 27 miRNAs known to regulate processes such as cell cytoskeleton, chemotaxis, cell signaling, or cell metabolism. Gene expression profiles negatively correlated with expression profiles of cardiovascular disease patients, while a positive correlation was observed with gene expression profiles following intake of drugs against cardiometabolic disorders. These analyses further advocate for health protective effects of these bioactives against age-associated diseases. In conclusion, polyphenols can exert multi-genomic modifications in humans and use of untargeted methods coupled with bioinformatic analyses represent the best approach to decipher molecular mechanisms underlying healthy-ageing effects of these bioactives.

Department of Biology Faculty of Sciences University Mohammed 1 60000 Oujda Morocco

Department of Food Science Czech University of Life Sciences 16500 Prague Czech Republic

Department of Medicine Democritus University of Thrace 68100 Alexandroupolis Dragana Greece

Faculty of Medical Sciences Goce Delcev University 2000 Stip North Macedonia

Institute for Adriatic Crops and Karst Reclamation 21000 Split Croatia

Institute for Biological Research Siniša Stanković National Institute of Republic of Serbia University of Belgrade 11060 Belgrade Serbia

Institute of Biology and Immunology of Reproduction Bulgarian Academy of Sciences 1113 Sofia Bulgaria

National Research Council 73100 Lecce Italy

Norwich Medical School University of East Anglia Norwich NR4 7TJ UK

Universitat Rovira i Virgili Departament de Bioquímica i Biotecnologia Nutrigenomics Research Group 43007 Tarragona Spain

Université Clermont Auvergne INRAE UNH F 63000 Clermont Ferrand France

Université Clermont Auvergne INRAE UNH F 63000 Clermont Ferrand France; Centre of Research Excellence in Nutrition and Metabolism Institute for Medical Research National Institute of Republic of Serbia University of Belgrade 11000 Belgrade Serbia

Université Clermont Auvergne INRAE UNH F 63000 Clermont Ferrand France; Department of Nutrition University of California Davis Davis CA 95616 United States

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