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Extracellular vesicles (EVs) and their miRNA cargo are intercellular communicators transmitting their pleiotropic messages between different cell types, tissues, and body fluids. Recently, they have been reported to contribute to skin homeostasis and were identified as members of the senescence-associated secretory phenotype of human dermal fibroblasts. However, the role of EV-miRNAs in paracrine signaling during skin aging is yet unclear. Here we provide evidence for the existence of small EVs in the human skin and dermal interstitial fluid using dermal open flow microperfusion and show that EVs and miRNAs are transferred from dermal fibroblasts to epidermal keratinocytes in 2D cell culture and in human skin equivalents. We further show that the transient presence of senescent fibroblast derived small EVs accelerates scratch closure of epidermal keratinocytes, whereas long-term incubation impairs keratinocyte differentiation in vitro. Finally, we identify vesicular miR-23a-3p, highly secreted by senescent fibroblasts, as one contributor of the EV-mediated effect on keratinocytes in in vitro wound healing assays. To summarize, our findings support the current view that EVs and their miRNA cargo are members of the senescence-associated secretory phenotype and, thus, regulators of human skin homeostasis during aging., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Solar lentigines are a common feature of sun-induced skin ageing. Little is known, however, about the genetic factors contributing to their development. In this genome-wide association study, we aimed to identify genetic loci associated with solar lentigines on the face in 502 middle-aged French women. Nine SNPs, gathered in two independent blocks on chromosome 6, exhibited a false discovery rate below 25% when looking for associations with the facial lentigine score. The first block, in the 6p22 region, corresponded to intergenic SNPs and also exhibited a significant association with forehead lentigines (P = 1.37 × 10(-8) ). The second block, within the 6p21 HLA region, was associated with decreased HLA-C expression according to several eQTL databases. Interestingly, these SNPs were also in high linkage disequilibrium with the HLA-C*0701 allele (r(2)  = 0.95). We replicated an association recently found by GWAS in the IRF4 gene. Finally, a complementary study on 44 selected candidate SNPs revealed novel associations in the MITF gene. Overall, our results point to several mechanisms involved in the severity of facial lentigines, including HLA/immunity and the melanogenesis pathway., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A genome-wide association study (GWAS) was conducted on 502 French middle-aged Caucasian women to identify genetic factors that may affect skin aging severity. A high-throughput Illumina Human Omni1-Quad beadchip was used. After single-nucleotide polymorphism (SNP) quality controls, 795,063 SNPs remained for analysis purposes. Possible stratification was first examined using the Eigenstrat method, and then the relationships between genotypes and four skin aging indicators (global photoaging, lentigines, wrinkles, and sagging) were investigated separately by linear regressions adjusted on age, smoking habits, lifetime sun exposure, hormonal status, and the two main Eigen vectors. One signal passed the Bonferroni threshold (P=1.53 × 10(-8)) and was significantly associated with global photoaging. It was also correlated with the wrinkling score and the sagging score. According to HapMap, this SNP, rs322458, was in linkage disequilibrium (LD) with intronic SNPs of the STXBP5L gene, which is expressed in the skin. In addition, it was also in LD with another SNP that increases the expression of the FBXO40 gene in the skin. These two genes, which were not previously described in the context of aging, may constitute good candidates for the investigation of molecular mechanisms of skin photoaging.

Skin aging is an ineluctable process leading to the progressive loss of tissue integrity and is characterized by various outcomes such as wrinkling and sagging. Researchers have identified impacting environmental factors (sun exposure, smoking, etc.) and several molecular mechanisms leading to skin aging. We have previously performed genome-wide association studies (GWAS) in 502 very-well characterized French women, looking for associations with four major outcomes of skin aging, namely, photoaging, solar lentigines, wrinkling, and sagging, and this has led to new insights into the molecular mechanisms of skin aging. Since individual SNP associations in GWAS explain only a small fraction of the genetic impact in complex polygenic phenotypes, we have made the integration of these genotypes into the reference Kegg biological pathways and looked for associations by the gene set enrichment analysis (GSEA) approach. 106 pathways were tested for association with the four outcomes of skin aging. This biological pathway analysis revealed new relevant pathways and genes, some likely specific of skin aging such as the WNT7B and PRKCA genes in the "melanogenesis" pathway and some likely involved in global aging such as the DDB1 gene in the "nucleotide excision repair" pathway, not picked up in the previously published GWAS. Overall, our results suggest that the four outcomes of skin aging possess specific molecular mechanisms such as the "proteasome" and "mTOR signaling pathway" but may also share common molecular mechanisms such as "nucleotide excision repair." [ABSTRACT FROM AUTHOR]