430 Targeting SASP exosomes to limit senescence-associated premature skin aging

Abstract

There are increasing evidences that persistent senescent cells accumulating in tissues significantly participate to the gradual functional decline associated with aging. Senescent cells phenotype is characterized by an irreversible cell cycle arrest, an altered morphology and a modified metabolism and secretome. The SASP (senescence-associated secretory phenotype) encompass a large array of mediators (inflammatory cytokines, chemokines, proteases, reactive oxygen species…) that are believed to accelerate aging. Some non-coding RNAs (microRNAs or long noncoding RNAs) were recently identified as members of the SASP, and were shown to promote senescence induction and maintenance. Thus, we focused on exosomes, small vectorized extracellular vesicles that transport these noncoding RNAs (and other SASP constituents) and likely play a critical role in the long-distance propagation of SASP negative effects. Replicative senescence (RS) and stress-induced premature senescence (SIPS) were induced in human dermal fibroblasts (HDF) by repeated passage (P28) or exposure to hydrogen peroxide. Senescent phenotype and secretory profiles (nuclear markers, ß-galactosidase activity, cytokines, MMP-1…) were carefully characterized. In line with previous reports, we found that RS and SIPS fibroblasts produce much more exosomes than normal HDF. Several cargo microRNAs were identified by real-time quantitative PCR (miR-21, miR-23, miR-29 and miR-34). Exposure of normal HDF to isolated exosomes obtained from senescent HDF leads to metabolic changes, and chiefly collagen synthesis decline. This was not seen with exosomes from normal HDF. A vegetable extract enriched with wogonin, an identified inhibitor of SASP, could reduce exosomes production (other SASP constituents were also affected). The metabolic impact of senescent cells-derived exosomes was limited by the extract.