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Background: Sirtuins attract high attention considering their properties to reverse molecular hallmarks of aging and age-related disorders. Many secondary plant ingredients (SPI) are known for their sirtuin-activating activities as well as epigenetic regulation of telomers, autophagy, senolysis, DNA repair but also improvement of gut microbiota. Furthermore, prebiotics enhanced butyrate and was shown to interact with SIRT pathways. This study investigated the effects of a drink containing a mix of different SPIs in combination with galactooligosaccharides (G OS) and their effect on SIRT activation, markers of aging relevant mechanisms, and gut microbiota composition in correlation with subjective wellbeing and skin structure appearance. Methods: We analyzed gene expression, mtDNA amount, and microbial composition in response to a sirtuin- activating drink in humans compared to a control group consuming a placebo. Food frequency, beauty, and general health questionnaires were asked, and a set of mRNAs and miRNAs were assessed using qPCR analysis. The gut composition was analyzed using Illumnia sequencing. Results: SPI increased SIRT1 , SIRT3, and modulated cell cycle relevant miR16 and senescence regulating miR34 expression. Additionally, mtDNA amount was higher in the group consuming the active supplement indicating an improved mitochondrial activity. The combined effect of SPI and GOS lead to an increase of Actinobacteria , especially Bifidobacterium, but also Veillonellaceae which was not observed in the control group. Significant correlations between SIRT3 expression and the gut microbiota Bifidobacterium and Veillonellaceae were observed. Additionally, statistical analysis of subjects self-reporting indicated beneficial effects regarding beauty and wellbeing. Conclusion: Our results show that the combination of sirtuins inducing SPI and prebiotic GOS influences molecular pathways counteracting aging, senescence, inflammation, and enhanced groups of gut microbiota which are known to improve the innate and adaptive immune system. Keywords : secondary plant ingredients, prebiotic, Sirtuins, subjective wellbeing, Bifidobacterium

Introduction: Topical investigations have demonstrated that oxidative stress and inflammation play key roles in biological aging and determine incidence and course of age-related diseases. Lifestyle and environmental factors hugely impact epigenetic regulation and DNA stability with telomere attrition and epigenetic instability providing a potential record of the cumulative burden of endogenous and exogenous oxidative noxae. Certain physiologically active plant components exhibit antioxidative activities affecting epigenetic regulation of inflammation response and DNA repair. Methods: Against this background, the present study investigated green tea polyphenol epigallocatechin gallate (EGCG) in the context of telomere regulation in Caco-2 colorectal adenocarcinoma cells vs. ES-1 primary skin fibroblasts. Cell lines were treated with 20 and 200 µM EGCG for 36, 72 and 144 hours, respectively. Telomerase activity, relative telomere length as well as methylation status of hTERT and c-Myc from different culture conditions were assessed. Malondialdehyde (MDA) served as a surrogate marker of potential pro-oxidative effects of EGCG in a physiologically relevant tissue model. Results: EGCG incubation was associated with telomere shortening and decreased telomerase activity in Caco-2 cells, and relatively longer telomeres along with increased methylation of six 5'—C—phosphate—G—3' (CpG) sites in the promoter region of human Telomerase Reverse Transcriptase ( hTERT) in fibroblasts. At low concentrations, EGCG significantly decreased oxidative damage to lipids in Caco-2 cells and attenuated H 2 O 2 induced oxidation at higher concentrations. Conclusion: These results suggest differential EGCG-mediated telomeric modulation in cancer vs. primary cells and a specific antioxidant activity of EGCG against oxidative damage to lipids in abnormal cells. Keywords: Caco-2, epigallocatechin gallate, telomeres, hTERT, DNA methylation, telomerase, oxidative stress, malondialdehyde