Research Progress On Chinese Medicine Intervention in Mesenchymal Stem Cell Aging

Keywords mesenchymal stem cells; aging; traditional Chinese medicine Mesenchymal stem cells (MSC) are pluripotent stem cells derived from mesoderm that can differentiate into a variety of cell types under appropriate conditions to replace damaged cells. Tissues and cells maintain normal functions and homeostasis of the body. However, MSCs themselves also undergo senescence. Wagner et al. [1] systematically reported the aging phenomenon of MSCs for the first time, pointing out that MSCs will undergo replicative senescence during in vitro passage, which is manifested as flat and wide cell morphology, decreased proliferation and migration capabilities, cell cycle arrest, and β-galactolipids. Increased glycosidase activity, etc.

NEW TRADITIONAL CHINESE MEDICINE CISTANCHE HERBAL SUPPLEMENTS FOR LONGEVITY

MSC aging not only significantly affects their own regenerative function, but also leads to a reduction in stem cell reserves, thereby reducing the body's ability to repair damaged tissue and accelerating the human aging process. Therefore, in-depth research on the aging mechanism of MSC is of great clinical significance.

Current research [2] shows that the MSC aging mechanism involves multiple signaling pathways. Traditional Chinese medicine has the characteristics of multi-component and multi-target, and may play a role in enhancing autophagy, antioxidant, anti-inflammation, maintaining telomere length, etc. by regulating relevant signaling pathways, thereby effectively alleviating MSC aging [3]. at present
Most of the research focuses on the active ingredients of traditional Chinese medicines, most of which are kidney-tonifying, blood-activating and qi-tonifying traditional Chinese medicines, which mainly maintain cell function and delay aging by enhancing autophagy, antioxidant, anti-inflammatory and other effects and regulating related signaling pathways. This article aims to summarize the mechanism of traditional Chinese medicine interfering with MSC aging in order to provide a basis for the development of new anti-aging treatment strategies.

1 MSC aging mechanism and involved signaling pathways

Current studies [2] show that the MSC aging mechanism involves telomere shortening, DNA damage, epigenetic disorders, microenvironmental disorders, oxidative stress, protein homeostasis disorders, and nutrient sensing disorders. As the number of divisions increases, MSC telomeres will shorten to a critical length, hindering DNA replication and inducing aging. At the same time, long-term proliferating MSCs will lose the ability to recognize and repair DNA damage, exacerbating the aging process [4].
Epigenetic regulation, such as histone modification, DNA methylation, chromatin reorganization, and RNase modification, affects gene expression and promotes cell aging [5]. Senescent cells secrete senescence-associated secretory phenotypes (SASP), such as inflammatory factors, chemokines, growth factors, and matrix metalloproteinases (MMPs), leading to chronic inflammation, affecting the cell microenvironment, and accelerating MSC aging [6]. Reactive oxygen species (ROS) produced by oxidative stress damage can cause DNA damage and mitochondrial dysfunction, directly leading to or accelerating MSC aging [7]. Protein homeostasis disorders, especially autophagy and ubiquitination dysfunction, are key factors leading to MSC aging [8-9]. Hyperglycemia and high-fat environments accelerate MSC aging through nutrient sensing disorders [10-11]. These mechanisms are intertwined and jointly promote the aging process of MSC.

The above-mentioned cell aging mechanisms involve multiple signaling pathways. The p53/p21 and p16 pathways inhibit the activity of cell cycle-dependent kinases, thereby blocking the cell cycle. Both are often used as biological markers of aging. The sirtuin 1 (SIＲT1) pathway inhibits the p53/p21 and p16 pathways, increases telomerase activity and telomere length, and reduces DNA damage, thereby delaying MSC aging [12]. Another family member, SIＲT6, participates in epigenetic regulation through deacetylation, maintains genome stability, and prevents MSC decline [13]. The mammalian target of rapamycin (mTOR) pathway is regulated by the upstream factor protein kinase B (Akt). Intervention of the PI3K/Akt/mTOR pathway can activate autophagy and improve cell aging [8]. High glucose environment can activate the mTOR pathway and induce cell senescence [10]. The AMP-activated protein kinase (AMPK) pathway not only regulates oxidative stress response and delays MSC aging by promoting mitochondrial fusion and reducing mitochondrial fission [14], but also inhibits the mTOR pathway to activate autophagy and inhibit MSC aging [15].

Silencing the ligand IHH in the Hedgehog signaling pathway can reduce the SASP secretion of MSCs and inhibit aging [16]. The insulin/insulin-like growth factor (IIS) pathway affects telomerase activity and promotes MSC aging through insulin and insulin-like growth factor (IGF) and its receptor (IGFR) signaling [17]. Inhibition of the Wnt/β-Catenin pathway can reduce ROS generation and reverse the p53-mediated aging phenotype [18], while overactivation promotes ROS generation and accelerates MSC aging [19]. In addition, the decline of the Wnt pathway is often accompanied by chromatin remodeling and abnormal histone modification, which in turn affects the function of MSCs [13]. Reduced transcriptional activity of nuclear factor erythroid 2-related factor 2 (NＲF2) can lead to the accumulation of chronic oxidative stress and promote MSC aging; activation of the NＲF2 pathway can reverse aging and restore cell viability [7]. p38MAPK in the mitogen-activated protein kinase (MAPK) pathway can activate the p53/p21 pathway and accelerate MSC aging, while melatonin can inhibit the p53/p38 MAPK pathway and reverse MSC aging [20]. Activation of the nuclear factor-κB (NFκB) pathway can increase SASP secretion and promote DNA damage, accelerating MSC aging [6]; however, some studies [21] have found that its activation can improve the expression of the telomere-related gene TINF2 and delay MSC aging. The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway can be activated under estrogen deficiency conditions, promoting SASP secretion and exacerbating MSC aging [22], but STAT3 overexpression can protect mitochondrial function, reduce ROS levels, and enhance the anti-aging ability of cells [23]. The expression of Yes-associated protein (YAP) and transcription coactivator with PDZ binding motif (TAZ) in the Hippo pathway decreases in aged MSCs. Enhanced YAP activity helps repair DNA damage and slow down cell replicative aging; conversely, inhibiting YAP expression restores mitochondrial dysfunction and improves MSC aging [24]. The MSC aging mechanism and the signaling pathways involved are shown in Figure 1.