Cellular senescence was originally observed in cultured fibroblasts following limited replications . It was subsequently noted as a response to DNA damage, telomere attrition, mitochondrial dysfunction, and oncogenic, hyperglycemic, and oxidative stresses [4,5,6]. Cellular senescence plays an important role in parturition and embryo development [7,8]. It may influence the fate of tumorigenesis through senescence-associated secretory phenotype (SASP). It was reported that acute senescent cells induce immortalized prostate cells to undergo senescence via SASP but have no effect on metastatic prostate cancer cells . Replicative, developmental, and stress-induced premature cell senescence share common cellular phenotypic changes including an increased expression of p16 and p21, cell cycle and proliferation arrest, senescence-associated (SA) heterochromatin foci, SA-β galactosidase (β gal), and SASP, as well as cellular morphological changes . Phenotypic changes of senescent cells are mediated by multiple signaling pathways leading to complex transcriptional reprogramming [11,12].
Hyperglycemia due to type 2 diabetes (T2D) and pre-diabetic metabolic syndrome and obesity has emerged as a key extracellular stress signal to induce cellular senescence as well as cell death . As T2D is increasing with aging and contributes to age-related chronic diseases , hyperglycemia has become a leading age stress factor. Hyperglycemia induces cellular senescence through metabolism shift, reactive oxygen species (ROS) generation, mitochondrial dysfunction, and aberrant gene expressions.
Replicative and stress (hyperglycemia and oxidative stress)-induced mesenchymal stromal cell senescence has been extensively investigated as it is critical for MSC-based cell therapy. Mesenchymal stromal cells (MSCs) are isolated and characterized according to a set of criteria [14,15]. Current isolation procedures generate heterogeneous nonclonal stromal cell populations with different multipotent and differentiation potentials . MSCs possess immunosuppressive and anti-inflammatory properties [17,18]. As MSCs can be obtained and cultured with ease, they are popular sources for cell-based therapy of a variety of human diseases. More than 700 clinical trials have been registered . However, MSC-based cell therapy faces challenging problems. Replicative senescence of cultured MSCs limits the cell expansion and its availability for cell therapy. Moreover, stress-induced premature senescence in vitro and in vivo reduces the efficacy of transplanted MSCs in tissue regeneration and treatment of autoimmune and inflammatory diseases. New strategies are actively being employed to develop new drugs to combat cellular senescence. The candidate drugs are either senolytic, which kill and remove senescent cells, or senomorphic, which modify senescent cell phenotypes to attenuate their tissue-damaging effects [19,20,21]. Senomorphic agents comprise a wide range of compounds with different targets aiming at reducing SASP and senescent markers without causing cell apoptosis . Recent studies indicate that tryptophan metabolites produced via the tryptophan hydroxylase (TPH) pathway defend against replicative and hyperglycemia or oxidative stress-induced cell senescence. 5-methoxytryptophan (5-MTP) was reported to rescue bone marrow mesenchymal stromal cells (BM-MSCs) from high glucose (HG)-induced senescence , while melatonin protects MSC from replicative and stress-induced senescence . Melatonin and 5-MTP represent a new class of senomorphic compounds which may be useful in protecting MSC against senescence and age-related diseases.
2. Hyperglycemia Induces Cellular Senescence
High blood glucose levels (hyperglycemia) contribute to diabetic microvascular, renal, retinal and neural complications by multiple mechanisms including mitochondrial dysfunction and ROS generation [24,25]. Results from in vivo and in vitro experiments have shown that hyperglycemia induces cellular damage, apoptosis, and necrosis through ROS generation and mitochondrial dysfunction [24,25]. In addition, hyperglycemia was reported to induce renal tubular cell and retinal endothelial cell senescence in streptozotocin-induced diabetic mice [26,27] and HG in cultured media was reported to induce senescence of diverse cell types including MSCs [28,29,30]. Senescent cells cause further tissue damage through secretion of pro-inflammatory cytokines and proteolytic enzymes [1,31].
2.1. HG-Induced Cellular Senescence Is Attributed to Mitochondrial Dysfunction and ROS Generation
The exact mechanisms by which HG induces senescence are not entirely clear. Mitochondrial dysfunction and ROS generation are considered to be major players. HG induces mitochondrial ROS generation by enhancing mitochondrial metabolism via tricarboxylic acid (TCA) cycle and oxidative phosphorylation . ROS generation is closely related to mitochondrial morphological changes. It was reported that HG-treated rat liver cells undergo mitochondrial fission, which was required for ROS generation . ROS, in turn, cause mitochondrial fission , creating a vicious cycle (Figure 1). It was also reported that HG increases ROS through activation of NADPH oxidase [34,35], but its relevance to cell senescence is unclear and remains to be investigated. ROS overproduction is considered to be a major cause of cell damage and lethality. However, at sublethal concentrations, H2O2 induces cellular senescence as a way of protecting cells from ROS-induced death [36,37]. ROS represent a common mediator via which diverse stress signals induce cellular senescence. For example, Ras overexpression in fibroblasts induce cellular senescence by elevation of ROS generation .
Figure 1. Simplified scheme illustrating the mechanism by which high glucose (HG) induces cellular senescence. HG enhances tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which results in reactive oxygen species (ROS) generation. HG induces mitochondrial fission, which is accompanied by ROS accumulation. ROS, in turn, induces mitochondrial fission as indicated by a two-head arrow. Sublethal ROS (H2O2) induces oxidative DNA damage and senescent phenotypic changes.
ROS induces cellular senescence by oxidative damage to DNA, leading to telomere attrition and altered expression of p53, p16, and p21 [38,39]. However, increased ROS generation cannot explain all the phenotypic manifestations. Mitochondrial structural changes and functional defects contribute significantly to stress-induced senescence . Changes in mitochondrial dynamics [41,42], metabolism, and signaling molecules such as AMPK [43,44,45] are considered to mediate senescence independent of ROS.
2.2. HG Induces MSC Senescence
MSCs in bone marrow reside in hypoxic microenvironment. They depend on glycolysis as energy source and thus express relatively low levels of oxidative phosphorylation (OXPHOS) proteins . MSCs cultured in nutrient-rich normoxic conditions shifts the metabolism to OXPHOS . MSC metabolism is altered during osteoblastic vs. chondrogenic differentiation. Osteoblastic differentiation requires OXPHOS, while chondrogenic differentiation uses aerobic glycolysis in energy generation . When MSCs are incubated with HG medium, excessive intracellular glucose shifts metabolism from aerobic glycolysis to TCA cycle and OXPHOS. Consequently, a high level of ROS is leaked from the electron transport chain which induces MSC senescence [49,50]. Effects of HG on MSC mitochondrial biogenesis and metabolism have not been described. However, it is likely HG-induced mitochondrial structural and metabolic changes contribute to MSC senescence. MSC senescence puts a limit to MSC expansion, which hampers its use in cell therapy. Furthermore, it impairs MSC function which reduces its support for hematopoiesis and immunosuppressive properties .
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This entry is adapted from 10.3390/ijms22020697