Abstract
Aging is an important risk factor in the occurrence of many chronic diseases. Senescence and exhaustion of adult stem cells are considered as a hallmark of aging in organisms. In this study, a senescent human amniotic mesenchymal stem cell (hAMSC) model subjected to oxidative stress was established in vitro using hydrogen peroxide. We investigated the effects of ganoderic acid D (GA-D), a natural triterpenoid compound produced from Ganoderma lucidum, on hAMSC senescence. GA-D significantly inhibited β-galactosidase (a senescence-associated marker) formation, in a dose-dependent manner, with doses ranging from 0.1 μM to 10 μM, without inducing cytotoxic side-effects. Furthermore, GA-D markedly inhibited the generation of reactive oxygen species (ROS) and the expression of p21 and p16 proteins, relieved the cell cycle arrest, and enhanced telomerase activity in senescent hAMSCs. Furthermore, GA-D upregulated the expression of phosphorylated protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK), peroxidase III (PRDX3), and nuclear factor-erythroid 2-related factor (NRF2) and promoted intranuclear transfer of NRF2 in senescent cells. The PERK inhibitor GSK2656157 and/or the NRF2 inhibitor ML385 suppressed the PERK/NRF2 signaling, which was activated by GA-D. They induced a rebound for the generation of ROS and β-galactosidase-positive cells and attenuated the differentiation capacity. These findings suggest that GA-D retards hAMSC senescence through activation of the PERK/NRF2 signaling pathway and may be a promising candidate for the discovery of antiaging agents.
Highlights
Aging is a major risk factor for most chronic diseases, such as metabolic, cardiovascular, and neurodegenerative diseases, and cancer [1]
HAMSCs strongly expressed vimentin but did not express cytokeratin 19 (Supplementary Figure 1). These results indicate that human amniotic mesenchymal stem cell (hAMSC) conform to mesenchymal stem cells (MSCs) accreditation, as recommended by the International Society for Cellular Therapy [30]
The expression of PRDX3 was inhibited when GSK2656157 or ML385 was employed (Figure 5(g)). These results suggest that ganoderic acid D (GA-D) might activate phosphorylated PERK (p-PERK) signaling to promote intranuclear transfer of nuclear factor-erythroid 2-related factor (NRF2) and prevent the senescence of hAMSCs
Summary
Aging is a major risk factor for most chronic diseases, such as metabolic, cardiovascular, and neurodegenerative diseases, and cancer [1]. Various studies have demonstrated that aging accelerates the initiation and/or clonal dominance of mutant stem cells in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline, which shows a causal relationship between the aging-associated accumulation of stem cell mutations and failure of tissue maintenance and cancer suppression [2]. In this regard, the senescence and exhaustion of adult stem cells are considered as a hallmark of aging in organisms. Stem cell senescence has received increased attention in recent years in the field of antiaging and regenerative medicine
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