Journal Article

Ganoderic acid D prevents oxidative stress‐induced senescence by targeting 14‐3‐3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells

Zhang, Jia‐Rong, Xu, Yan, Luo, Yi, Xiao, Jian‐Hui, Zhu, Xin‐Xin, Yuan, Huan

2022

Overview

Stem cell senescence is an important cause of aging. Delaying senescence may present a novel way to combat aging and age‐associated diseases. This study provided a mechanistic insight into the protective effect of ganoderic acid D (GA‐D) against human amniotic mesenchymal stem cell (hAMSCs) senescence. GA‐D, a Ganoderma lucidum‐derived triterpenoid, markedly prevented hAMSCs senescence via activating the Ca2+ calmodulin (CaM)/CaM‐dependent protein kinase II (CaMKII)/nuclear erythroid 2‐related factor 2 (Nrf2) axis, and 14‐3‐3ε was identified as a target of GA‐D. 14‐3‐3ε‐encoding gene (YWHAE) knockdown in hAMSCs reversed the activation of the CaM/CaMKII/Nrf2 signals to attenuate the GA‐D anti‐aging effect and increase senescence‐associated β‐galactosidase (SA‐β‐gal), p16 and p21 expression levels, including reactive oxygen species (ROS) production, thereby promoting cell cycle arrest and decreasing differentiation potential. YWHAE overexpression maintained or slightly enhanced the GA‐D anti‐aging effect. GA‐D prevented d‐galactose‐caused aging in mice by significantly increasing the total antioxidant capacity, as well as superoxide dismutase and glutathione peroxidase activity, and reducing the formation of malondialdehyde, advanced glycation end products, and receptor of advanced glycation end products. Consistent with the protective mechanism of GA‐D against hAMSCs senescence, GA‐D delayed the senescence of bone‐marrow mesenchymal stem cells in this aging model in vivo, reduced SA‐β‐gal and ROS production, alleviated cell cycle arrest, and enhanced cell viability and differentiation via regulating 14‐3‐3ε and CaM/CaMKII/Nrf2 axis. Therefore, GA‐D retards hAMSCs senescence by targeting 14‐3‐3ε to activate the CaM/CaMKII/Nrf2 signaling pathway. Furthermore, the in vivo GA‐D anti‐aging effect may involve the regulation of stem cell senescence via the same signal axis. GA‐D prevents MSC senescence via regulating 14‐3‐3e to activate the CaM/CaMKII/Nrf2 pathway; GA‐D prevents d‐gal‐caused aging in mice by enhancing antioxidative defense and retards the BMSCs senescence in d‐gal‐caused aging mice; GA‐D may be a potential anti‐aging agent.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: 14-3-3 Proteins - metabolism / 14‐3‐3ε / Advanced glycosylation end products / Aging / aging mouse model / Alzheimer's disease / Animals / Antioxidants - pharmacology / anti‐aging / Apoptosis / Bone marrow / bone‐marrow mesenchymal stem cells / Ca2+/calmodulin-dependent protein kinase II / Calcium-binding protein / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism / Calmodulin / CaM/CaMKII/Nrf2 signaling / Cancer / Cell cycle / Cell differentiation / Cell Proliferation / Cell viability / Cellular Senescence - genetics / Galactose / Ganoderic acid / ganoderic acid D / Glutathione peroxidase / Glycation End Products, Advanced - metabolism / Glycosylation / Homeostasis / human amniotic mesenchymal stem cells / Humans / Kinases / Mesenchymal stem cells / Mesenchymal Stem Cells - metabolism / Mice / Neurogenesis / NF-E2-Related Factor 2 - metabolism / Organisms / Oxidative Stress / Proteins / Reactive oxygen species / Reactive Oxygen Species - metabolism / Senescence / Signal Transduction / Stem cell transplantation / Stem cells / Superoxide dismutase / Triterpenes - pharmacology