Stafa Klodjan, Rella Antonella, Eagle Whitby, Dong Kelly, Morris Kelsey, Layman Dawn, Corallo Krystle, Trivero Jacqueline, Maidhof Robert, Goyarts Earl, Pernodet Nadine
Research and Development, The Estée Lauder Companies, Melville, NY, United States.
Estée Lauder Research Laboratories, Melville, NY, United States.
Front Physiol. 2024 Feb 29;15:1291344. doi: 10.3389/fphys.2024.1291344. eCollection 2024.
The skin is the largest organ of the human body and fulfills protective, immune, and metabolic functions. Skin function and barrier integrity are actively regulated through circadian rhythm-associated genes and epigenetic mechanisms including DNA methylation/demethylation, histone acetylation/deacetylation, and microRNAs. MicroRNA-146a-5p (miR-146a) has been associated with immune activation and skin inflammation; however, the role of miR-146a in regulating skin aging is an open question. This study investigated the role of miR-146a in fibroblasts obtained from different donors in the context of aging, and a potential association of this miRNA with circadian rhythm. Normal human dermal fibroblasts (NHDFs) from 19y, 27y, 40y, and 62y old donors were used to analyze for miR-146a expression. Expression of miR-146a was downregulated with the hsa-mirVana miR-146a inhibitor, and upregulated with an extract from Adansonia digitata. Effects on markers of skin aging, including cell proliferation, production of Collagen-1 and inflammatory cytokines were assessed. We show that the expression of miR-146a decreases with age in dermal fibroblasts and inhibition of miR-146a in 19y and 62y old NHDFs induced significant changes in essential clock genes indicating an association with circadian rhythm control. Furthermore, downregulation of miR-146a results in a reduction of cellular proliferation, Collagen-1 production, as well as an increase in DNA damage and pro-inflammatory markers. Activation of miR-146a with the Adansonia digitata extract reduced the deleterious effects seen during miR-146a inhibition and increased miR-146a transport through exosome transfer. miR-146a interacts with multiple biological pathways related to skin aging, including circadian rhythm machinery, cell-to-cell communication, cell damage repair, cell proliferation, and collagen production and represents a promising target to fight skin aging. Adansonia digitata extract can promote miR-146a expression and therefore support skin cells' health.
皮肤是人体最大的器官，具有保护、免疫和代谢功能。皮肤功能和屏障完整性通过昼夜节律相关基因和表观遗传机制（包括DNA甲基化/去甲基化、组蛋白乙酰化/去乙酰化以及微小RNA）得到积极调节。微小RNA-146a-5p（miR-146a）与免疫激活和皮肤炎症相关；然而，miR-146a在调节皮肤衰老中的作用仍是一个悬而未决的问题。本研究调查了miR-146a在不同供体来源的成纤维细胞衰老过程中的作用，以及这种微小RNA与昼夜节律的潜在关联。使用来自19岁、27岁、40岁和62岁供体的正常人皮肤成纤维细胞（NHDFs）分析miR-146a的表达。用hsa-mirVana miR-146a抑制剂下调miR-146a的表达，并用猴面包树提取物上调其表达。评估了对皮肤衰老标志物的影响，包括细胞增殖、胶原蛋白-1的产生和炎性细胞因子。我们发现，在皮肤成纤维细胞中，miR-146a的表达随年龄增长而降低，在19岁和62岁的NHDFs中抑制miR-146a会导致关键生物钟基因发生显著变化，表明其与昼夜节律控制有关。此外，miR-146a的下调会导致细胞增殖减少、胶原蛋白-1产生减少，以及DNA损伤和促炎标志物增加。用猴面包树提取物激活miR-146a可减少miR-146a抑制期间出现的有害影响，并通过外泌体转运增加miR-146a的运输。miR-146a与多个与皮肤衰老相关的生物学途径相互作用，包括昼夜节律机制、细胞间通讯、细胞损伤修复、细胞增殖和胶原蛋白产生，是对抗皮肤衰老的一个有前景的靶点。猴面包树提取物可促进miR-146a的表达，从而维持皮肤细胞的健康。
