Targeting SIRT1 via Exosomes Derived From Oleuropein‐Treated Cells: A Novel Approach to Rejuvenation Skin Through miRNA Modulation

Sirtuin1 (SIRT1) plays an important role in skin aging by regulating cellular processes such as oxidative stress response, inflammation modulation, Collagen and Elastin synthesis. This study aims to examine oleuropein's (OLE) effect on SIRT1 gene expression and to analyze SIRT1-related miRNAs in exosomes produced from Mesenchymal Stem cells (MSC) and Human Fetal Foreskin Fibroblast 2 (HFFF2) cells, along with these treated exosomes' impact on SIRT1 gene expression and the studied miRNAs in HFFF2 cells to decrease skin aging. A nontoxic concentration (400 μg/mL) of OLE was applied to the MSCs and HFFF2 cells. Then, Gradient Ultracentrifugation extracted their exosomes; cell-derived exosomes were confirmed by DLS assay and western Blot. Exosomes were applied at 50 μg/mL (exosome protein concentration) to HFFF2 cells. The expression of SIRT1 gene and related miRNAs relative to the control group were examined using qRT-PCR. This analysis was conducted on cells OLE-treated for SIRT1, on exosomes treatment with OLE for miRNAs, and on HFFF2 cells treated with cell-derived exosomes for both SIRT1 and miRNAs. SIRT1 expression was upregulated (p ≤ 0.05) in both OLE and cell-derived exosomes. Also, hsa-miR-29c-3p and hsa-miR-9-5p were downregulated (p ≤ 0.05), whereas hsa-miR-155-5p was upregulated (p ≤ 0.05) in exosomes OLE-treated and in HFFF2 cells treated with these exosomes. This study introduces a novel approach to skin rejuvenation by using manipulated exosomes OLE-treated, which enhance SIRT1 expression and suppress related miRNAs. This method potentially offers a more effective and less immunogenic alternative to direct OLE application due to the exosomes' ability to penetrate cells.