Hiebert Paul, Martyts Anastasiya, Schwestermann Jonas, Janke Katharina, Hafner Jürg, Boukamp Petra, Mazza Edoardo, Werner Sabine
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich 8093, Switzerland.
Department of Mechanical and Process Engineering, Institute for Mechanical Systems, ETH Zurich, Zurich 8092, Switzerland.
Matrix Biol. 2022 Nov;113:39-60. doi: 10.1016/j.matbio.2022.09.002. Epub 2022 Sep 20.
Aging is associated with progressive skin fragility and a tendency to tear, which can lead to severe clinical complications. The transcription factor NRF2 is a key regulator of the cellular antioxidant response, and pharmacological NRF2 activation is a promising strategy for the prevention of age-related diseases. Using a combination of molecular and cellular biology, histology, imaging and biomechanical studies we show, however, that constitutive genetic activation of Nrf2 in fibroblasts of mice suppresses collagen and elastin expression, resulting in reduced skin strength as seen in aged mice. Mechanistically, the "aging matrisome" results in part from direct Nrf2-mediated overexpression of a network of microRNAs that target mRNAs of major skin collagens and other matrix components. Bioinformatics and functional studies revealed high NRF2 activity in aged human fibroblasts in 3D skin equivalents and human skin biopsies, highlighting the translational relevance of the functional mouse data. Together, these results identify activated NRF2 as a promoter of age-related molecular and biomechanical skin features.
衰老与皮肤渐进性脆弱及易撕裂倾向相关，这可能导致严重的临床并发症。转录因子NRF2是细胞抗氧化反应的关键调节因子，药理学上激活NRF2是预防与年龄相关疾病的一种有前景的策略。然而，通过结合分子与细胞生物学、组织学、成像及生物力学研究，我们发现，小鼠成纤维细胞中Nrf2的组成型基因激活会抑制胶原蛋白和弹性蛋白的表达，导致皮肤强度降低，如同在老年小鼠中所见。从机制上讲，“衰老基质组”部分源于Nrf2直接介导的一组微小RNA的过表达，这些微小RNA靶向主要皮肤胶原蛋白和其他基质成分的mRNA。生物信息学和功能研究揭示了在三维皮肤等效物和人体皮肤活检中，老年人类成纤维细胞具有高NRF2活性，突出了功能性小鼠数据的转化相关性。总之，这些结果确定激活的NRF2是与年龄相关的分子和生物力学皮肤特征的促进因素。
