764 Targeting dermal fibroblast senescence with senomorphic and epigenetic properties of haritaki fruit extract: Effects on SASP and miR over-expression in senescent fibroblasts’ extracellular vesicles

Abstract

Skin aging is the consequence of two biological process: intrinsic genetically programmed factors and extrinsic environmental factors. At the cellular level, accumulation of senescent cells (SC) is also involved in skin aging. SC stop to proliferate but remain metabolically active. The secretome of SC (Senescence Associated Secretory Phenotype: SASP), is a cocktail of mediators like CSF3, CXCL1, IL8, IL1b, IL6, MMP-1 and -3, involved in skin aging. Extracellular vesicles (EV) have also been reported to act as cytokines during intercellular communication. They transport proteins, mRNAs and miRNAs, over short or long distances. miRNAs are a class of short, single-stranded, noncoding RNA molecules. As epigenetic modulators, miRNAs affect the protein levels of the target mRNAs without modifying the gene sequences. Several miRs are known to be involved in senescence and skin aging. The aim of our study was to evaluate, the effect of Haritaki fruit extract (HF extract) on SASP and senescence associated miRs contained in EV. Our results showed that, 14 days after ionizing radiation (7.5 Gy), human dermal fibroblasts presented a senescent phenotype: flattened and irregular shape, senescence associated ß-galactosidase activity, SASP expression (RT-PCR) and miR 24a-3p, miR 186-5p, miR 30a-3p and miR 29a-3p overexpression in EV (RT-PCR). Our results also showed that incubation of senescent fibroblasts with HF extract strongly decreased SASP mRNA level and miR 34a-5p, miR 24a-3p, miR 186-5p, miR 30a-3p and miR 29a-3p over-expression in EV. Taken together these results demonstrated that Haritaki fruit extract is a strong senomorphic agent with epigenetic effect, suggesting that it may be useful for the development of new anti-aging dermo-cosmetic products.