MSCs, derived from the mesoderm, are pluripotent stem cells endowed with the capacity for multidirectional differentiation, immunomodulatory properties, and self-renewal. They are widely available from diverse tissue sources (Wang et al., 2023). Notably, MSCs lack major histocompatibility complex II (MHC II) expression and exhibit low levels of costimulatory factors such as CD80, CD86, and CD40, resulting in low immunogenicity—a significant advantage for MSC-based therapies. MSC therapy holds immense potential for treating a broad spectrum of diseases and conditions, as it aims to harness transplanted MSCs to replace or repair damaged cells, tissues, or organs. While significant progress has been made in leveraging MSCs to slow aging, the field continues to face numerous challenges that require further exploration and resolution.

MSCs can contribute to slowing down aging through multiple mechanisms. On one hand, MSC transplantation can exert anti-aging effects via stem cell differentiation. For instance, intervertebral disc degenerative changes (IDD), which are closely associated with aging, can be mitigated by reducing senescent cells, thereby lowering levels of MMP13—a factor that promotes disc degeneration during aging (P et al., 2019). Human umbilical cord MSCs (HUCMSCs) have been shown to differentiate into nucleus pulposus cells (NPCs), replenishing NPC populations and enhancing the synthesis of extracellular matrix (ECM) by NPCs (Huang et al., 2023). However, the differentiation efficiency of MSCs is difficult to control within the complex in vivo environment. To address this, pre-differentiating MSCs into specific cell types prior to transplantation has been proposed to enhance lineage-specific differentiation. Nevertheless, this approach may limit the functional versatility of stem cells post-transplantation. Additionally, MSCs can exert anti-aging effects by stimulating endogenous tissue or cell regeneration. For example, bone marrow mesenchymal stem cells (BMSCs) transplanted into patients with acute myocardial infarction or chronic myocardial ischemia have been shown to remodel the extracellular matrix, promote neovascularization, and recruit endogenous stem cells (Siu et al., 2010). This mechanism highlights another potential strategy for stem cell transplantation in the context of aging.

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Fig. 1. Role of MSCs in anti-aging. MSCs function primarily through their secreted Exos. Exos first form mature exos in the MSCs through multiple stages, then are secreted from the MSCs through cytosis and cytotoxicity, and exert their effects on the recipient cells.

The production of exosomes (exos) is a complex process involving multiple stages, including the formation of early endosomes, maturation into late endosomes, and eventual development into functional small membrane vesicles. Initially regarded as cellular byproducts with limited biological significance, exos are now understood to play a critical role in intercellular communication, intracellular signaling, and immune regulation, as evidenced by recent studies (H Rashed et al., 2017; Yin et al., 2022). Exos exhibit dual functionality: they act as key mediators of intercellular communication through mechanisms such as antigen presentation, while also facilitating the removal of harmful molecules from cells or tissues, thereby enabling the identification of potential biomarkers (He et al., 2018). By virtue of these two roles, EVs assume significant role in stem cell therapy (Hu et al., 2022), immunomodulation (Anel et al., 2019), tumor metastasis (Luo et al., 2023), organogenesis (Asmussen et al., 2019), and normal development (Demonbreun and McNally, 2017).

Exosomes (Exos) derived from MSCs have been shown to overcome several limitations associated with stem cell therapy while preserving their fundamental biological properties. Extensive research has demonstrated that the direct intravenous administration of Evs can serve as a viable alternative to stem cell transplantation (Mianehsaz et al., 2019; Psaraki et al., 2022).This approach not only exhibits a pronounced inhibitory effect on tumor growth (Wang et al., 2020), but also effectively retards the aging process in organisms (Lin et al., 2019; Maqsood et al., 2020; Liu et al., 2021; Ahmadi and Rezaie, 2021). Furthermore, it addresses the safety concerns associated with current cell transplantation methods.

MSC-Exos are known to contain a variety of microRNAs (miRNAs) associated with the aging process. Studies have shown that the expression of these miRNAs decreases with aging, leading to a reduction in the differentiation capacity of senescent MSCs and a disruption in the expression of secretory factors. Hisamatsu et al.(Hisamatsu et al., 2016) identified the downregulation of miR-17 and its paralogs, miR-106a and miR-106b (collectively referred to as miR-17/106), as a key factor contributing to the diminished differentiation potential and dysregulated secretory factor expression in senescent MSCs. Further research has corroborated the link between miR-17/106 and the age-related decline in the bone-forming ability of MSCs. For instance, transgenic mice overexpressing miR-17 exhibited enhanced bone tissue development and an extended lifespan (Du et al., 2014) highlighting the critical role of miR-17/106 in maintaining MSCs functionality and combating age-related degeneration.

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Fig. 2. MSCs can improve aging through genomic instability and telomere attrition. Genomic instability and telomere attrition can lead to aging, and the ability of MSCs to ameliorate these phenomena has been demonstrated in a variety of animal models, including mice and monkeys. In addition to MSCs, exos released from MSCs can also ameliorate genomic instability and thereby ameliorate senescence.

BMSCs and their derived exosomes (Exos) have demonstrated the ability to restore the functionality of senescent stem cells and fibroblasts. Additionally, EVs derived from BMSCs, along with the key DNA repair enzyme Ercc1, have been shown to extend lifespan and alleviate senescence in Ercc1−/− mice (Dorronsoro et al., 2021). In a study by Go et al., EVs obtained from MSCs were found to promote recovery in aged monkeys following cortical injury. This effect was attributed to enhanced myelin sheath formation, reduced DNA damage in oligodendrocytes, and increased density of mature oligodendrocytes post-injury (Go et al., 2021). Another study utilized a doxorubicin (DOXO)-inducible senescence model to explore the impact of stem cell treatment on telomere length and anti-aging effects in Dox-treated H9c2 cells. The findings highlighted the role of the vascular endothelial growth factor (VEGF)/Jagged-1/Notch-1/TGF-β1 signaling pathway in mediating these effects (Chen et al., 2018). Notably, telomere shortening is a significant prognostic marker in elderly patients with Idiopathic Pulmonary Fibrosis (IPF), a severe lung condition. The antifibrotic effects of TGF-β stimulation on bronchoalveolar epithelial cells (A549) and fibroblasts from IPF patients with varying telomere lengths were observed in response to membrane particles (MP) derived from human adipose tissue MSCs. These MPs exhibited senescence-protective properties by upregulating the anti-fibrotic marker TERT in epithelial cells, potentially aiding in the restoration of alveolar structure (Merino et al., 2021).

Inherited defects in DNA repair mechanisms exacerbate DNA damage accumulation, accelerating organ aging in one or multiple systems. While MSCs and their Exos demonstrate notable anti-aging potential, their precise role in the relationship between nuclear DNA damage and aging warrants further investigation and discussion.

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Fig. 3. MSCs can improve aging through epigenetic alterations and loss of proteostasis. Epigenetic alterations and loss of proteostasis can lead to aging, and this role for them has been demonstrated in a variety of aging models including, chronic renal failure in the elderly, aging-associated insulin resistance, and Alzheimer’s disease. MSCs treatment has ameliorated aging conditions to some degree in all cases.

Aging is closely linked to the global depletion of histones and tissue-specific alterations in their post-translational modifications. In a study by Zhang, MSC-Exos were shown to mitigate oxidative damage in H₂O₂-induced microglia (BV2) in vitro. Additionally, the conditioned medium of UCMSCs was found to counteract high glucose (HG)-induced extracellular matrix degradation in nucleus pulposus mesenchymal stem cells (NPMSCs). Specifically, MSCs-conditioned media (CM) treatment significantly reduced the levels of collagen II and aggrecan in NPMSCs, but these effects were reversed by the activation of phosphorylated p38 MAPK, restoring the extracellular matrix components (Qi et al., 2019). In another report (Cao et al., 2021), Cao et al. reported that miR-133b in MSC-derived extracellular vesicles (MSC-EVs) modulated connective tissue growth factor (CTGF), reducing TGF-2-induced renal cortical proximal tubular epithelial cell (HK1) damage, renal tubular epithelial-mesenchymal transition (EMT), and renal interstitial fibrosis in aged mice. SIRT1 (Sirtuin-1), a gene associated with premature aging, disease, and longevity, encodes a deacetylase enzyme that regulates various epigenetic modifications, influencing gene expression and chromatin structure. MSC-Exos significantly upregulated the expression of the SIRT1 gene in senescent mice (X. Zhang et al., 2023). Yu conducted a study (Yu et al., 2021) which demonstrated that the sustained release of miR-217 inhibitor from MSC-derived EVs played a role in reducing MSC-mediated neointimal hyperplasia following vascular injury. The overexpression of miR-217 resulted in the downregulation of Sirt-1 protein expression, leading to an increase in senescence, ROS expression, and EB malformation in transfected MSCs. Additionally, other studies (Sun et al., 2018) demonstrated that miR-2b targeted Sirtuin-1 in HK133 cells, resulting in increased Sirtuin-1 expression and a reduction in TGF-1-induced EMT and renal fibrosis. The investigation of the intricate relationship between aging-associated insulin resistance remains a prominent area of research. According to a study conducted by Su et al., it was discovered that the release of nanoscale exos miR-29b-3p from BMSCs in aged mice plays a regulatory role in insulin resistance through the activation of SIRT1. This finding suggests that targeting SIRT1 could potentially serve as a therapeutic approach for managing insulin resistance associated with aging (Su et al., 2019). In their study, Jiad et al. found that the activation of the cMet-AKT-GSK3 signaling pathway, along with the downregulation of hyperphosphorylated tau and the promotion of synaptic plasticity in the hippocampus of SAMP8 mice (a mouse model of Alzheimer’s disease with accelerated aging), led to the reversal of spinal loss. Furthermore, the utilization of SAMP8 mice to administer HUCMSCs that secreted hepatocyte growth factor (HGF) was found to modify the improvement of neurofibrillary tangles (NFT) (Jia et al., 2020a).

In vitro studies by Zhang et al. demonstrated that BMSCs could enhance the expression of genes associated with proliferation (PCNA and FGF-2) and anti-apoptosis (survivin and Bcl-2) in chondrocytes. The inhibition of CD73 led to reduced chondrocyte proliferation and increased apoptosis, suggesting that CD73/ecto-5′-nucleotidase plays a critical role in mediating these biological functions (Zhang et al., 2018). Similarly, Exos derived from olfactory mucosal mesenchymal stem cells (OM-MSCs-Exos) were shown to significantly improve cognitive function, reduce neuroinflammatory responses, alleviate endoplasmic reticulum (ER) stress, and decrease neuronal apoptosis in mouse models of Alzheimer’s disease. These effects are thought to be mediated through the involvement of LRP1(Hu et al., 2025).

The strong link between aging and epigenetic alterations, as well as the loss of proteostasis, has garnered considerable attention in the scientific community. Given the reversible nature of epigenetic modifications, these pathways represent promising targets for therapeutic interventions aimed at mitigating age-related decline. In this context, MSCs and Exos have emerged as pivotal tools in the development of anti-aging strategies, offering potential avenues for addressing the multifaceted challenges of aging.

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Fig. 4. MSCs can improve aging through disabled macroautophagy, mitochondrial dysfunction and chronic inflammation. Macroautophagy, mitochondrial dysfunction and chronic inflammation can lead to aging, among these, inflammation is a key feature that contributes to aging, and inflammation is specifically correlated with almost all aspects of other hallmarks of aging, with numerous age-related diseases associated with this hallmark and some improvement with both MSCs and Exos therapy.

MiR-199a-5p, produced by MSCs, has been shown to inhibit autophagy and enhance the therapeutic efficacy of MSCs-based treatments for idiopathic pulmonary fibrosis in elderly patients by modulating the Sirt1/AMPK signaling pathway (Shi et al., 2021). Cellular senescence is a critical factor influencing liver regeneration, contributing to a higher incidence of severe complications following liver surgery in the elderly. Recent studies have highlighted the potential of MSC-Exos in addressing this issue, primarily through their association with Atg4B-mediated mitophagy, a key protein in autophagy regulation. This mechanism helps restore mitochondrial integrity and function in aging hepatocytes, thereby promoting their proliferation. Additionally, the enrichment of DEAD-Box helicase 5 (DDX5) in UCMSCs-EVs and its interaction with transcription factor E2F1 facilitate the nuclear translocation of DDX5, activating Atg4B expression (J. Zhang et al., 2023). Further research by Zhang demonstrated that MSCs-Exos reduce oxidative stress and exhibit anti-apoptotic effects in the brains of SAMP8 senescent mice (X. Zhang et al., 2023). Similarly, Chen’s study revealed that overexpression of Bmi1 in MSCs confers anti-aging and anti-osteoporosis effects by mitigating oxidative stress and deactivating the p16/p19 signaling pathway (Chen et al., 2019). Beclin-1, a crucial positive regulator of mammalian autophagy, may also be upregulated by MSCs to activate autophagy signaling, thereby ameliorating Parkinson’s disease (Heris et al., 2022). These findings underscore the multifaceted role of MSCs and Exos in modulating autophagy, mitochondrial function, and oxidative stress, offering promising therapeutic strategies for age-related diseases.

Mitochondria have been recognized as key drivers of both chronic inflammation and cell death. The progressive decline in mitochondrial function during senescence significantly contributes to the development of the senescence phenotype, initiating inflammation and cell death through multiple interconnected pathways (J et al., 2019). Adipose-derived MSCs (ADMSCs) have demonstrated the ability to enhance mitochondrial autophagy, leading to the reduction of intracellular reactive oxygen species (ROS) and the improvement of mitochondrial quality. As a result, these MSCs act as regulators of cellular metabolic homeostasis, ultimately delaying the aging process (Lv et al., 2021; Maremanda et al., 2019). The administration of UCMSCs has been shown to counteract age-related muscle loss, likely due to their ability to reduce oxidative stress, apoptosis, and inflammation, while promoting AMPK/PGC1α-signaling-mediated mitochondrial biogenesis (Piao et al., 2022). In Zhang et al.’s study (Y. Zhang et al., 2023), MSC-Exos were found to effectively mitigate vascular smooth muscle cell (VSMC) senescence induced by Ang II. This protective effect was achieved through the downregulation of mitochondrial fission, mediated by miR-19b-3p regulation of the MST4/ERK/Drp1 signaling pathway. Additionally, the study highlighted the detrimental effects of cisplatin on neuronal mitochondria. Counteracting this mitochondrial damage using a small molecule, pifithrin-μ, which inhibits p53 accumulation in mitochondria, may help prevent the formation of tau deposits in the brains of aged mice. These findings underscore the critical role of mitochondrial function in aging and the potential of MSC-based therapies to mitigate age-related cellular damage.

In Deng’s study (Deng et al., 2020), the aging of dermal fibroblasts was primarily induced by ultraviolet B (UVB) radiation. The researchers evaluated the anti-aging effects of MSC-EVs on dermal fibroblasts exposed to UVB-induced photoaging. Treatment with MSC-EVs led to increased expression of glutathione peroxidase 1 (GPX-1) and extracellular matrix protein collagen type 1 (Col-1), reduced expression of matrix metalloproteinase-1 (MMP-1), improved intracellular reactive oxygen species (ROS) levels, and alleviated UVB-induced photoaging. This investigation aligns with the findings of Khalid et al.(Khalid et al., 2023), who noted that aging and degenerative changes in the intervertebral disc (IVD) occur earlier than in other connective tissues. Their study demonstrated a reduction in oxidative stress in intervertebral disc degeneration (IVDD), alongside significant improvements in matrix production and cartilage regeneration. Reactive oxygen species (ROS), such as hydroxyl radicals (OH⁻), superoxide ions (O_₂⁻), hypochlorite ions (OCl⁻), and hydrogen peroxide (H_₂O_₂), are highly reactive and unstable molecules that contribute to cellular damage. Inflammation is a well-established mechanism driving the aging process, and the dysregulation of macrophages, which play a pivotal role in initiating and modulating inflammatory responses, is a key factor in this phenomenon. These studies collectively highlight the potential of MSCs-EVs in mitigating oxidative stress, inflammation, and tissue degeneration associated with aging.

In a study by Gorgun et al., evidence was provided that MSCs-Exos preconditioned with hypoxic inflammatory cytokines effectively mitigated mitochondrial dysfunction in macrophages. This was achieved by reducing lipid peroxidation and inhibiting mitochondrial complex I activity, oxygen consumption, and ATP synthesis associated with age-related injury (Gorgun et al., 2022; Motawea et al., 2020). Given the increased susceptibility of elderly diabetic patients to cardiovascular events, securing a reliable source of MSCs, such as HUCMSCs is critical for addressing the significant health risks they face. In a study conducted by Xiong et al.(Xiong et al., 2021), the administration of miR-21-enriched exosomes derived from human placental MSCs (hPMSC-Exo) demonstrated multiple beneficial effects in elderly diabetic rats. These included alleviating endothelial dysfunction, reducing systolic blood pressure, and exhibiting antioxidant properties. Additionally, miR-21 in hPMSC-Exos was found to mitigate oxidative stress damage, decrease the expression of senescence-associated proteins, and attenuate senescence in Q and CD2 T cells through the PTEN/PI3K-Nrf2 signaling pathway. Furthermore, HUCMSCs were induced into neural stem cells (NSCs) through the addition of growth factors and neuromodulatory protein 1β (NRG1β) during NSC differentiation. This process may regulate the p53/GPX4/SLC7A11 pathway, reducing ferroptosis levels in cells and thereby slowing the progression of ischemic stroke (Zhai et al., 2022).

In elderly rats subjected to permanent distal middle cerebral artery occlusion (MCAO), the administration of small EVs derived from human BMSCs effectively facilitated neuronal recovery and promoted remodeling of the peri-infarct brain region. BMSC-EVs have shown potential in treating Alzheimer’s disease by delivering miR-29c-3p to neurons, which suppresses BACE1 expression and activates the Wnt/β-catenin pathway. This mechanism reduces neuroinflammation and delays disease progression (Sha et al., 2021). Additionally, MSC-derived exosomes (MSC-Exos) have been demonstrated to promote doxorubicin (DO)-mediated bone regeneration in aged rats. This effect is achieved by enhancing the proliferation and osteogenic capacity of BMSCs, with further improvements potentially attributed to immunomodulatory mechanisms (Jia et al., 2020b). In a study conducted by Khalid et al.(Gorgun et al., 2022), the synergistic effect of Sox9 and TGFβ1 was observed to significantly enhance cartilage formation, regeneration, and matrix synthesis in human umbilical cord mesenchymal stem cells (hUCMSCs). This combination also effectively reduced inflammation in intervertebral disc degeneration (IVDD), thereby alleviating degenerative conditions. In the research conducted by Go et al.(Go et al., 2020), the therapeutic potential of MSC-EVs in treating cortical injury was initially explored in aged rhesus monkeys (Macaca mulatta). The findings revealed that neuroinflammation, initially localized to the lesion site, could spread to other brain regions during the chronic phase of inflammation. According to a study conducted by Gorgun et al.(Walberer et al., 2014), MSCs-Exos preconditioned with hypoxic inflammatory cytokines were shown to reduce the expression of TNF-α, iNOS, and NADase CD38, thereby mitigating age-related inflammation. This discovery is particularly relevant given the increasing prevalence of total joint replacement surgeries among elderly individuals, where wear particles from prosthetic implants often trigger chronic inflammation and osteolysis. Kushioka et al. investigated the therapeutic effects of interleukin-4 overproducing mesenchymal stem cells (IL4-MSCs) on chronic inflammation in elderly mice. The results demonstrated that IL4-MSCs significantly reduced osteoclast activity, increased the M2/M1 macrophage ratio, and enhanced alkaline phosphatase (ALP)-positive areas and bone mineral density (BMD) values, highlighting their potential in addressing age-related inflammatory conditions.(Kushioka et al., 2023). In another study by Motawea et al.(Xiong et al., 2021), HUCMSCs were identified as a reliable source of MSCs. When administered to aged diabetic rats, HUCMSCs effectively lowered systolic blood pressure, improved endothelial dysfunction, and exhibited strong anti-inflammatory properties, thereby alleviating symptoms associated with aged diabetes. Exosomes derived from human embryonic mesenchymal stem cells (HEMSCs) have been shown to enhance sulfated glycosaminoglycan (s-GAG) synthesis, which is otherwise inhibited by IL-1β, while also suppressing IL-1β-induced nitric oxide and MMP13 production. These exosomes modulate inflammatory responses and nociceptive behaviors, playing a significant role in the healing of condylar cartilage and subchondral bone in a rat model of temporomandibular joint osteoarthritis (Zhang et al., 2019). Similarly, HUCMSCs have demonstrated the ability to modulate the articular cavity microenvironment in a rat knee osteochondral defect model. This modulation is primarily achieved by promoting macrophage polarization toward the M2 phenotype and inhibiting inflammatory responses, thereby acting as a potential promoter of osteochondral regeneration (Jiang et al., 2021).

The loss of macroautophagy, mitochondrial dysfunction, and chronic inflammation are key drivers of cellular and molecular aging, as well as the onset of age-related diseases. Targeting these mechanisms offers a promising strategy for mitigating the aging process, with MSCs and Exos emerging as highly promising therapeutic tools in the field of anti-aging research.

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Fig. 5. MSCs can improve aging through cellular senescence. Cellular senescence is a biological process that manifests itself particularly in certain diseases, especially age-related diseases. Mesenchymal stem cell therapy plays a crucial role in slowing down cellular senescence.

Cellular senescence is a biological process that can lead to detrimental effects, whether in the short-term or long-term. A study (Jin et al., 2021) conducted by researchers revealed that BMSCs-Exos containing lncRNA MEG-3 can alleviate osteoarthritis by promoting the synthesis of type II collagen and inhibiting cellular senescence and apoptosis, thereby preserving the chondrocyte phenotype. Additionally, another investigation (Liao et al., 2021) demonstrated that UCMSC-Exos could prevent senescence in mouse primary tubular epithelial cells (PTEC) by downregulating the expression of senescence markers and senescence-associated secretory phenotype (SASP) factors. Conversely, the expression of miR-199a-5p derived from MSCs has been shown to induce senescence in patients with pulmonary fibrosis through modulation of the Sirt1/AMPK signaling pathway (Lei et al., 2021). Conversely, a reduction in miR-199a-5p levels has been shown to reverse cellular senescence and enhance the therapeutic efficacy of MSCs in treating pulmonary fibrosis (Levine and Kroemer, 2019). Additionally, EVs derived from human placental MSCs can repair capillary dilation, subsequently activating tumor protein P53 and cell cycle-dependent kinase inhibitor 1A (P21) to inhibit cellular senescence (Kou et al., 2022). BMSCs have demonstrated the ability to counteract proliferation inhibition by mitigating DNA damage and oxidative stress, while also reducing cellular senescence and restoring radiation-induced bone loss through activation of the Wnt/β-catenin signaling pathway (Zuo et al., 2019). Furthermore, MSCs-Exos facilitate the downregulation of SIRT1, leading to a gradual increase in acetylated p53 expression over time. This induces the expression of p53 and its downstream molecule p21, ultimately halting the cell cycle and promoting cellular senescence (Matsuoka et al., 2021). These findings underscore the multifaceted role of MSC-derived therapies in modulating cellular senescence and their potential applications in treating age-related conditions (Matsuoka et al., 2021). MSC-EVs effectively enhance the restoration of senescent endothelial cells (ECs) and accelerate wound healing in aged and diabetic animals by promoting angiogenesis. The regulation of functional recovery and wound healing by MSC-EVs is critically dependent on the involvement of miR-146a and Src. The pro-angiogenic and wound-healing effects of miR-146a can be partially enhanced through the dephosphorylation of Src (X et al., 2021). In Kim’s research (Kim et al., 2021), cellular senescence was investigated in mouse and human models of renal stenosis (STK). However, further research is needed to clarify the precise role of cellular senescence in ischemic and renal artery stenosis (RAS)-induced renal injury. Following MSCs treatment, a reduction in renal cell cycle arrest and senescence activity was observed in RAS. In the context of non-healing wounds, human dermal fibroblasts (HDFs) are prone to aging, leading to impaired migration, proliferation, and secretory function.

In Liu’s study (Liu et al., 2022a), MSCs-CM pretreated with interferon (IFN) and tumor necrosis factor (TNF) (referred to as IT MSC-CM) was found to be enriched with growth factors associated with wound healing. In vitro experiments demonstrated that pretreated MSC-CM was more effective than standard MSC-CM in enhancing the migration, proliferation, and activation of HDFs. Chemotherapy drugs, such as doxorubicin (DOXO), are widely used in cancer treatment but can induce cellular senescence in heart cells, leading to significant cardiotoxicity as a side effect.

In a study conducted by Xia et al., stem cell treatment in rat embryonic myoblasts (H9c2) reduced the expression of senescence-related genes, p53 and p16, and identified the miR-34a-SIRT1 protein axis as a potential mediator of the anti-aging effects of MSCs (Xia and Hou, 2018).

The decline in intercellular communication during aging can significantly disrupt hormone regulation and homeostasis. While the senescence-associated secretory phenotype (SASP) extensively addresses this phenomenon, it is primarily driven by cell-intrinsic factors (Deng et al., 2021; Miller et al., 2020). This review compares MSCs and exosomes (exos), which exhibit either pro-senescence or life-extending properties, with systemic factors transported through the bloodstream. Furthermore, it explores the functioning of various intercellular communication networks and assesses the role of extracellular matrix degradation in the aging process.

In Liu’s study (Liu et al., 2022b), the transplantation of HUCMSCs effectively restored estradiol (E2) and follicle-stimulating hormone (FSH) levels in both aging mice and chemotherapy-induced mice. Additionally, hUCMSC treatment increased the number of primordial follicles, developing follicles, and preovulatory follicles in the ovaries of mice. It also promoted the repair of oviducts and uterine tissues by regenerating oviductal cilia and reconstructing uterine glands and endometrial structures. In the study conducted by Li et al. (Li et al., 2023; Grady et al., 2019), the effects of hUCMSC-derived exosomes (hUCMSC-Exos) on a natural ovarian aging (NOA) mouse model were investigated. The results demonstrated that hUCMSC-Exos could regulate follicle number and hormone levels by inhibiting apoptosis, achieved through the suppression of PTEN expression by miR-21-5p. In Kim’s study (Kim and Lee, 2022), treatment with human placental-derived mesenchymal stem cells (hPD-MSCs) significantly increased serum levels of insulin-like growth factor-I (IGFI), a known promoter of healthy lifespan. Additionally, hPD-MSC stimulation elevated levels of 3-hydroxybutyrate, glycolic acid, and taurine, which are associated with improved health and longevity. In the study conducted by Kim (Kim et al., 2020), intravenous administration of human placenta-derived mesenchymal stem cells (hPDMSCs) was shown to enhance ovarian function in older women. This improvement was mediated by miR-145-5p and the BMP-SMAD signaling pathways, highlighting the therapeutic potential of hPDMSCs in addressing age-related ovarian dysfunction. MiR-140-5p in synovial mesenchymal stem cell (SMSCs)-Exos plays a crucial role in inhibiting the matrix metalloproteinase (MMP) family, thereby disrupting the dynamic equilibrium of the extracellular matrix and slowing the progression of osteoarthritis (OA). Conversely, exosomes isolated from synovial fluid have been shown to stimulate the release of inflammatory cytokines and MMPs, highlighting the dual role of exosomes in modulating ECM homeostasis and inflammation in OA (Tao et al., 2017).