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Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age-associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C12FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C12FDG+ PBMCs that is commensurate with increases in age and senescence-related serum biomarkers. Interestingly, C12FDG+ PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C12FDG+ PBMCs and age-related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age-related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C12FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.

Recent studies have shed light on the dysregulated nature of cell senescence in many cancers, with implications for tumor immunity and prognosis. However, it is still unclear what role cellular senescence plays in stomach adenocarcinoma (STAD). To address this gap, we investigated the impact of cellular senescence on gastric cancer and its potential prognostic and therapeutic significance. The mRNA expression patterns, gene mutations, and clinical information of STAD were obtained from the cancer genome atlas (TCGA) and gene expression omnibus (GEO). Differentially expressed senescence-related genes were identified between gastric cancer tissues and normal tissues, then the prognostic value and functional roles of these genes in immunotherapy were systematically investigated by bioinformatics approaches. To authenticate the dysregulated genes identified within our prognostic signature, we conducted real-time quantitative PCR. Moreover, we verified gene expression patterns in both normal and tumor samples and performed in vitro experiments to modulate gene expression, assessing its impact on cell proliferation and invasion. Leveraging least absolute shrinkage and selection operator (LASSO) regression analysis, we successfully established a prognostic signature based on cell senescence-related genes. This signature categorized patients into high and low-risk groups, with the high-risk group exhibiting decreased overall survival likelihood compared to the low-risk group. Notably, these groups demonstrated distinct tumor microenvironment features and immune cell infiltration. Furthermore, patients in the high-risk group exhibited poorer responses to treatment compared to those in the low-risk group. To facilitate clinical application, we developed a nomogram for STAD prognosis prediction. By employing this cell senescence-related signature, we could accurately predict prognosis in STAD and tailor individualized therapeutic strategies, including chemotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Vascular aging (VA) is recognized as a pivotal factor in the development and progression of atherosclerosis (AS). Although various epidemiological and clinical research has demonstrated an intimate connection between aging and AS, the candidate mechanisms still require thorough examination. This review adopts an agingcentric perspective to deepen the comprehension of the intricate relationship between biological aging, vascular cell senescence, and AS. Various aging-related physiological factors influence the physical system's reactions, including oxygen radicals, inflammation, lipids, angiotensin II, mechanical forces, glucose levels, and insulin resistance. These factors cause endothelial dysfunction, barrier damage, sclerosis, and inflammation for VA and promote AS via distinct or shared pathways. Furthermore, the increase of senescent cells inside the vascular tissues, caused by genetic damage, dysregulation, secretome changes, and epigenetic modifications, might be the primary cause of VA. [ABSTRACT FROM AUTHOR]

Schematic diagram illustrating the senolytic role of D+Q in lumbar facet joint degeneration [Display omitted] Low back pain (LBP) is a pervasive issue, causing substantial economic burden and physical distress worldwide. Facet joint osteoarthritis (FJ OA) is believed to be a significant contributor to this problem. However, the precise role of chondrocyte senescence in FJ OA remains unclear, as does whether the clearance of chondrocyte senescence can alleviate the progression of FJ OA. The goal of this study was to understand the potential of Dasatinib (D) and Quercetin (Q) as a treatment to clear chondrocyte senescence during the progression of FJ OA. We used a preclinical bipedal standing mice model with the administration of Dasatinib (D) (5 mg/kg) and Quercetin (Q) (50 mg/kg) after 10 weeks of bipedal standing. Human degenerative lumbar facet joint (LFJ) samples were obtained to investigate the relationship between chondrocyte cellular senescence and LFJ osteoarthritis (OA). Subsequently, we established an in vitro model of excessive mechanical stress on chondrocytes and an in vivo bipedal standing mice model to induce LFJ OA. IHC (immunohistochemistry) staining in vivo and SA-β-gal staining, qRT-PCR and Western blot analysis were applied to test the senolytic effect of the combination of Dasatinib (D) and Quercetin (Q). IHC staining and X-ray microscope were also performed to examine the contribution of D+Q to the anabolism in cartilage and subchondral bone recoupling. Immunofluorescence and Western blot analysis in vitro and IHC staining in vivo were conducted to assess the impact of D+Q on the regulation of the NF-κB pathway activation during chondrocyte senescence. We observed that facet joint cartilage degeneration is associated with chondrocyte cellular senescence in both human and mouse degenerative samples. Following treatment with D+Q in vitro, cellular senescence was significantly reduced. Upon oral gavage administration of D+Q in the bipedal standing mice model, decreased cellular senescence and reversed chondrocyte anabolism were observed. Furthermore, administration of D+Q maintained subchondral bone remodeling homeostasis and potentially reversed the activation of the NF-κB pathway in chondrocytes of the lumbar facet joint. In summary, our investigation unveiled a significant correlation between chondrocyte senescence and LFJOA. Treatment with the senolytic combination of D+Q in FJ OA yielded a notable reduction in chondrocyte senescence, along with a decrease in the release of SASP factors. Additionally, it facilitated the promotion of cartilage anabolism, maintenance of subchondral bone coupling, and amelioration of NF-κB pathway activation. Our outcomes revealed that D+Q, the renowned combination used for senolytic treatment, alleviate the progression of LFJ OA. The utilization of D+Q as a senolytic demonstrates a novel and promising alternative for LFJ OA treatment. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the global population, characterised by red scaly patches that significantly affect patients' quality of life. Recent studies have suggested that cell senescence, a state in which cells cease to divide and secrete inflammatory mediators, plays a critical role in various chronic diseases, including psoriasis. However, the involvement and mechanisms of action of senescence-related genes in psoriasis remain unclear. Methods: This study aimed to identify senescence-related genes associated with psoriasis and explore their molecular mechanisms. RNA sequencing data from psoriasis and control samples were obtained from the GEO database. Differential expression analysis was performed using DESeq2 to identify differentially expressed genes (DEGs). The intersection of DEGs with cell senescence-related genes from the CellAge database was used to identify the candidate genes. Protein-protein interaction networks, Gene Ontology, and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to explore the functions and pathways of these genes. Machine learning algorithms, including Least Absolute Shrinkage and Selection Operator (LASSO) regression and Support vector machine-recursive feature elimination (SVE-RFE), were used to select feature genes that were validated by qRT-PCR. Additionally, an immune cell infiltration analysis was performed to understand the roles of these genes in the immune response to psoriasis. Results: This study identified 4,913 DEGs in psoriasis, of which 46 were related to cell senescence. Machine learning highlighted four key genes, CXCL1, ID4, CCND1, and IRF7, as significant. These genes were associated with immune cell infiltration and validated by qRT-PCR, suggesting their potential as therapeutic targets for psoriasis. Conclusions: This study identified and validated key senescence-related genes involved in psoriasis, providing insights into their molecular mechanisms and potential therapeutic targets and offering a foundation for developing targeted therapies for psoriasis. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a degenerative joint disease that leads to a substantial decline in the well-being of older individuals. Chondrocyte senescence and the resultant damage to cartilage tissue, induced by elevated levels of reactive oxygen species within the joint cavity, are significant causative factors in OA development. Cerium oxide nanoparticles (CeONPs) present a promising avenue for therapeutic investigation due to their exceptional antioxidant properties. However, the limited effectiveness of drugs in the joint cavity is often attributed to their rapid clearance by synovial fluid. Methods: Polyethylene glycol-packed CeONPs (PEG-CeONPs) were synthesized and subsequently modified with the cartilage-targeting peptide WYRGRLGK (WY-PEG-CeO). The antioxidant free radical activity and the mimetic enzyme activity of PEG-CeONPs and WY-PEG-CeO were detected. The impact of WY-PEG-CeO on chondrocytes oxidative stress, cellular senescence, and extracellular matrix degradation was assessed using in vitro assays. The cartilage targeting and protective effects were explored in animal models. Results: WY-PEG-CeO demonstrated significant efficacy in inhibiting oxidative stress, cellular senescence, and extracellular matrix degradation in OA chondrocytes. The underlying mechanism involves the inhibition of the PI3K/AKT and MAPK signaling pathways. Animal models further revealed that WY-PEG-CeO exhibited a prolonged residence time and enhanced penetration efficiency in cartilage tissue, leading to the attenuation of pathological changes in OA. Conclusions: These findings suggest that WY-PEG-CeO exerts therapeutic effects in OA by inhibiting oxidative stress and suppressing the over-activation of PI3K/AKT and MAPK signaling pathways. This investigation served as a fundamental step towards the advancement of CeONPs-based interventions, providing potential strategies for the treatment of OA. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) account for 0.01 to 2% of the total tumor mass; however, they play a key role in tumor progression, metastasis and resistance to current cancer therapies. The generation and maintenance of CSCs are usually linked to the epithelial–mesenchymal transition (EMT), a dynamic process involved in reprogramming cancer cells towards a more aggressive and motile phenotype with increased stemness potential. Cells that undergo an EMT process have shown to be more resistant to conventional chemo/radiotherapies. In this context, aldehyde dehydrogenase (ALDH) enzymes, known for their role in the cellular detoxification of aldehydes and enhancement of cell survival, are often upregulated in cancer cells, promoting their resistance to conventional cancer treatments. Indeed, high ALDH levels have become a hallmark biomarker of CSCs and are often used to isolate this sub-population from the more abundant cancer cell populations. Herein, we isolated human breast cancer epithelial cells with higher ALDH abundance (ALDHHigh) and compared them to those with low ALDH abundance (ALDHLow). ALDHHigh sub-populations exhibited more characteristic EMT biomarkers by adopting a more mesenchymal phenotype with increased stemness and enhanced migratory potential. Furthermore, ALDHHigh sub-populations displayed elevated senescent markers. Moreover, these cells also demonstrated higher levels of mitochondria DNA/mass, as well as greater mitochondrial and glycolytic metabolic function. Conversely, ALDHLow sub-populations showed a higher efficiency of mammosphere/colony formation and an increased proliferative capacity. Therefore, we demonstrated that these ALDH sub-populations have distinct characteristics, underscoring their role in EMT, the formation of tumors and the mechanisms of metastasis. [ABSTRACT FROM AUTHOR]

Background: Gonadotropin-releasing hormone (GnRH) is commonly used in animal reproduction and production, but it was previously reported that GnRH decreases the embryo implantation rate during artificial insemination or embryo transfer in sheep. In addition to the finding that GnRH can target S100A4 to inhibit endometrial epithelial cells proliferation, it was also found that endometrial cells were in poor condition and experienced cell death in S100A4 knockout mice, but the mechanism is unclear. Methods: The protein PPP1CA, which interacts with S100A4, was detected by immunoprecipitation-mass spectrometry of overexpression and knockdown of S100A4 and PPP1CA. The effect of S100A4 and PPP1CA on cell senescence was detected by Galactosidase staining. To further reveal the mechanism effect of S100A4 and PPP1CA on cell senescence, transcriptome sequencing was conducted. Additionally, in vivo experiments were performed to assess PPP1CA protein expression in the endometrial tissue of S100A4 knockout mice. Results: S100A4 inhibited cell senescence by activating PPP1CA, while PPP1CA overexpression suppressed the activation of the IL-17 signaling pathway. Inhibition of the IL-17 signaling pathway inhibited the senescence of endometrial cells. Conclusion: S100A4 can target the PPP1CA/IL-17 signaling pathway and inhibit endometrial epithelial cell senescence. [ABSTRACT FROM AUTHOR]

Amniotic fluid exosomes (AF-Exos) from term labor (TL) cause amniotic membrane senescence and induce labor. However, the intrinsic mechanism through which this occurs remains unknown. Therefore, we performed microRNA (miRNA) microarray chip screening of AF-Exos obtained from TL and terms not in labor and discovered that the expression of miR-548az-5p was significantly upregulated in TL. This study aimed to explore the role of miR-548az-5p in AF-Exos-induced human amniotic epithelial cells (hAECs) senescence for labor initiation. Bioinformatics analysis revealed that Katanin catalytic subunit A1 like 1 (KATNAL1) is a potential miR-548az-5p target. In hAECs, the upregulation of miR-548az-5p suppressed KATNAL1 expression, disorganized microtubules, increased senescence-associated secretory phenotype-related biomarkers, and inhibited cell proliferation by cyclin D1 and cyclin-dependent kinase 6 (CDK6). This study identified that miR-548az-5p is involved in the senescence of amniotic epithelial cells by targeting KATNAL1 to induce labor. Notably, this study offers new perspectives on the mediation of cellular senescence using AF-Exos miRNAs, which results in labor. [ABSTRACT FROM AUTHOR]

Low back pain caused by intervertebral disc degeneration (IDD) has emerged as a significant global public health concern, with far-reaching consequences for patients' quality of life and healthcare systems. Although previous research have revealed that the mechanisms of intervertebral disc cell apoptosis, pyroptosis and necroptosis can aggravate IDD damage by mediating inflammation and promoting extracellular matrix degradation, but they cannot explain the connection between different cell death mechanisms and ion metabolism disorders. The latest study shows that cell death mechanisms such as cellular senescence, ferroptosis, and cuproptosis, and PANopotosis have similar roles in the progression of intervertebral disc degeneration, but not exactly the same damage mechanism. This paper summarizes the effects of various cell death patterns on the disease progression of IDD, related molecular mechanisms and signaling pathways, providing new perspectives and potential clinical intervention strategies for the prevention and treatment of IDD. [ABSTRACT FROM AUTHOR]

Cell senescence and metabolic reprogramming are significant features of diabetic kidney disease (DKD). However, the underlying mechanisms between cell senescence and metabolic reprogramming are poorly defined. Here, we report that retinoid X receptor α (RXRα), a key nuclear receptor transcription factor, regulates cell senescence and metabolic reprogramming in DKD. Through high-throughput sequencing, bioinformatic analysis and experimental validation, we confirmed the critical role of RXRα in promoting cell senescence and metabolic dysregulation in renal tubular epithelial cells (RTECs) induced by lipid overload. In vivo, in situ injection of AAV9- shRxra into the kidney reduced proteinuria, RTECs senescence and insulin resistance in DKD mice. In vitro , knockdown of RXRα markedly improved G2/M phase arrest and suppressed the expression of senescence-associated secretory phenotypes (SASPs). Protein-protein interaction (PPI) analysis and unbiased bioinformatics were employed to identify the direct interactions between RXRα and the mineralocorticoid receptor (MR), which were subsequently validated through coimmunoprecipitation. Gene network analysis revealed the collaborative regulatory role of RXRα and MR in RTECs senescence. In an accelerated aging mouse model, treatment with a MR antagonist has been shown to inhibite the RXRα/MR signaling, improve RTECs senescence, and reduce interstitial fibrosis and lipid deposition in the kidneys. These findings indicate that inhibition of RXRα/MR signaling could alleviate cell senescence during metabolic disorders. Thus, our study revealed that RXRα/MR signaling serves as a critical regulatory factor mediating the crosstalk between cell senescence and metabolic reprogramming, shedding light on a novel mechanism for targeting cell senescence and metabolic dysregulation in DKD. [ABSTRACT FROM AUTHOR]

Cellular senescence is a response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation, and persistent DNA damage. In particular, radiation damage induces oxidative base damage and bond breaking in the DNA double-helix structure, which are treated by dedicated enzymatic repair pathways. In this review, we discuss the correlation between senescence and the accumulation of non-repaired single-strand breaks, as can occur during radiation therapy treatments. Recent in vitro cell irradiation experiments using high-energy photons have shown that single-strand breaks may be preferentially produced at the borders of the irradiated region, inducing senescence in competition with the apoptosis end-point typically induced by double-strand breaks. Such a particular response to radiation damage has been proposed as a possible cause of radiation-induced second primary cancer, as cells with an accumulation of non-repaired single-strand breaks might evade the senescent state at much later times. In addition, we highlight the peculiarities of strand-break repair pathways in relation to the base-excision pathway that repairs several different DNA oxidation defects. [ABSTRACT FROM AUTHOR]

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Obesity, a global health concern, results from an energy imbalance leading to lipid accumulation. In the present study, Cordyceps militaris extract (CM) and its primary component, cordycepin, were investigated to characterize their potential effects on adipogenesis and lipolysis. Treatment with CM or cordycepin reduced lipid droplets and increased hormone‐sensitive lipase activation in 3T3‐L1 cells. In a diabetic obese mouse model, CM and cordycepin lowered serum low‐density lipoprotein/very low‐density lipoprotein levels and reduced oxidative stress and cell senescence markers. Thus, cordycepin inhibits preadipocyte differentiation and promotes lipolysis, which may serve as a novel obesity treatment. Further studies, including clinical trials, are required to validate the clinical potential of cordycepin.

Cellular senescence is a response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation, and persistent DNA damage. In particular, radiation damage induces oxidative base damage and bond breaking in the DNA double-helix structure, which are treated by dedicated enzymatic repair pathways. In this review, we discuss the correlation between senescence and the accumulation of non-repaired single-strand breaks, as can occur during radiation therapy treatments. Recent in vitro cell irradiation experiments using high-energy photons have shown that single-strand breaks may be preferentially produced at the borders of the irradiated region, inducing senescence in competition with the apoptosis end-point typically induced by double-strand breaks. Such a particular response to radiation damage has been proposed as a possible cause of radiation-induced second primary cancer, as cells with an accumulation of non-repaired single-strand breaks might evade the senescent state at much later times. In addition, we highlight the peculiarities of strand-break repair pathways in relation to the base-excision pathway that repairs several different DNA oxidation defects.

Objective To investigate the effect of chronic psychological stress on testicular cell senescence in rats and the role of glucocorticoid receptor (GR) in the process. Methods Thirty-two male SD rats (4~6 weeks old, weighing 120~140 g) were randomly assigned into dimethyl sulfoxide (DMSO) group, mifepristone (RU486) group, chronic unpredictable mild stress (CUMS) group, and CUMS+RU486 group.DMSO of 0.5 ml/(kg·d) was injected subcutaneously into the rats of DMSO group.After the rats of the CUMS group were exposed to CUMS, mifepristone of 1 mg/(kg·d) was given to the rats of the RU486 group and CUMS+RU486 group.All the above 4 groups were inflicted for 42 consecutive days.After modeling, the psychological stress status of rats was evaluated with animal behavioral experiments.Computer-aided sperm analysis (CASA) system was used to detect sperm density.ELISA was employed to measure the serum levels of corticosterone (CORT), sex hormones and inflammation factors.The contents of malondialdehyde (MDA), H2O2, NAD+/NADH and ATP in the testicular tissues were tested with corresponding reagent kits.Western blotting was utilized to detect protein levels of β-gal, p16, and GR in testicular tissue, and transmission electron microscopy was used to observe mitochondrial structure of spermatogenic cells. Results Compared with the DMSO group, the sperm density, serum levels of testosterone (T), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were decreased while those of CORT and estradiol (E2) were increased in the CUMS group (all P < 0.001).Serum pro-inflammatory factors IL-6 and TNF-α concentrations were increased while anti-inflammatory factor IL-10 concentration was decreased in the CUMS group than the DMSO group (all P < 0.05).And, ATP content and NAD+/NADH ratio were decreased while MDA and H2O2 levels were elevated in testicular tissues in the CUMS group (all P < 0.05).Moreover, the protein levels of testicular cell aging markers β-gal, p16 and GR were significantly enhanced in the CUMS group (all P < 0.01), accompanied by swelling and vacuolization of mitochondrial structures in spermatogenic cells.RU486 treatment effectively improved sperm density and increased CORT level and down-regulated the testicular β-gal, p16 and GR protein level (all P < 0.05). Conclusion Chronic psychological stress induces testicular damage in rats, presenting declines in sperm density and CORT level, which is possibly associated with GR-mediated cell senescence.

BACKGROUND: Bone marrow mesenchymal stem cells in patients with osteoporosis show significant senescence and decreased activity and osteogenic differentiation. miR-212-3p inhibits osteogenic differentiation of human bone marrow mesenchymal stem cells. However, its regulation of senescence of bone marrow mesenchymal stem cells and its mechanism remain unclear. OBJECTIVE: To investigate the effect of miR-212-3p on senescence of bone marrow mesenchymal stem cells by targeting mitogen-activated protein kinase 3 (MAPK3) and its mechanism. METHODS: Rat bone marrow mesenchymal stem cells were isolated and cultured in vitro, and the third generation was collected for the following experiments: (1) Cultured in two groups: The control group was added with complete culture medium, and the model group was added with complete culture medium containing H2O2. After 72 hours of culture, β-galactosidase activity, miR-212-3p and MAPK3 mRNA expression, as well as MAPK3, p16, and p21 protein expression were detected. (2) Cultured in three groups: control group, inhibitor control group, and miR-212-3p inhibitor group. After transfection for 24 hours, miR-212-3p, mRNA and protein expression of MAPK3 were detected. (3) Dual luciferase reporter gene combined with qRT-PCR and western blot assay were used to verify the targeting regulation of miR-212-3p and MAPK3. (4) Cultured in different groups: control inhibitor group, miR-212-3p inhibitor group, miR212-3p inhibitor+interference control group, and miR-212-3p inhibitor+MAPK3 interference group. After transfection for 24 hours, MAPK protein and mRNA expression levels in cells were detected. They were divided into control group, H2O2 group, H2O2+ control inhibitor group, H2O2+miR-212-3p inhibitor group, H2O2+miR-212-3p inhibitor+interference control group, and H2O2+miR-212-3p inhibitor+MAPK3 interference group. Cells were transfected for 24 hours and then cultured with H2O2 for 72 hours. Aging-related β-galactosidase activity and p16 and p21 protein expression were detected. RESULTS AND CONCLUSION: (1) Compared with the control group, β-galactosidase activity, miR-212-3p mRNA expression and p16, p21 protein expression were increased in the model group (P < 0.05), while MAPK3 mRNA and protein expression levels were decreased (P < 0.05). (2) Compared with the control group, the mRNA expression of miR-212-3p was decreased (P < 0.05), and the mRNA and protein expression levels of MAPK3 were increased (P < 0.05) in miR212-3p inhibitor group. (3) Double luciferase reporter gene experiment confirmed that MAPK3 was the downstream target gene of miR-212-3p. (4) Compared with the control inhibitor group, the mRNA and protein expression levels of MAPK3 were increased in miR-212-3p inhibitor group (P < 0.05). Compared with the miR-212-3p inhibitor group, the mRNA and protein expression levels of MAPK3 in the miR-212-3p inhibitor+MAPK3 interference group were decreased (P < 0.05). Compared with H2O2+control inhibitor group, β-galactosidase activity in H2O2+miR-212-3p inhibitor group was decreased (P < 0.05). Compared with H2O2+miR212-3p inhibitor group, β-galactosidase activity in H2O2+miR-212-3p inhibitor+MAPK3 interference group was higher than that in H2O2+miR-212-3p inhibitor group (P < 0.05). Compared with the H2O2+control inhibitor group, the protein expression levels of p16 and p21 in the H2O2+miR-212-3p inhibitor group were decreased (P < 0.05). Compared with H2O2+miR-212-3p inhibitor group, the protein expression levels of p16 and p21 in H2O2+miR-212-3p inhibitor+MAPK3 interference group were increased (P < 0.05). (5) To conclude, downregulation of miR-212-3p inhibits the senescence of rat bone marrow mesenchymal stem cells, and its mechanism of action may be achieved by targeting up-regulation of MAPK3 expression. [ABSTRACT FROM AUTHOR]

Autophagy, a cellular degradation process involving the formation and clearance of autophagosomes, is mediated by autophagic proteins, such as microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (p62), and modulated by 3-methyladenine (3-MA) as well as chloroquine (CQ). Senescence, characterised by permanent cell cycle arrest, is marked by proteins such as cyclin-dependent kinase inhibitor 1 (p21) and tumour protein 53 (p53). This study aims to investigate the relationship between cell senescence and renal function in diabetic kidney disease (DKD) and the effect of autophagy on high-glucose-induced cell senescence. We categorised 46 patients with DKD diagnosed by renal biopsy into classes I, IIa, IIb, III and IV and used four normal kidney specimens from patients with renal trauma as controls. We evaluated pathological changes, LC3 and p21. We used streptozotocin-induced DKD models in rats and 35 mM glucose-cultured human proximal tubular epithelial cells (HK-2) with or without 3-MA and CQ. We assessed p53, p21, LC3 and p62. We observed autophagosomes and detected senescence-associated galactosidase (SA-β-gal) activity. In patients with DKD, p21 and LC3 expression levels increased over time and correlated positively with blood creatinine and proteinuria. In DKD rats and HK-2 cells, p21, p53, LC3 and p62 expression levels were higher than in the controls, as were SA-β-gal-positive cells, renal tubular autophagosomes and co-expression of p21 and LC3. The 3-MA reduced p16, p21 and p53 expression compared with the high glucose group, whereas CQ had the opposite effect. These results suggest that renal tubular cell senescence is associated with the progression of DKD. Additionally, autophagic flux may play a role in mediating high-glucose-induced senescence in renal tubular cells. [ABSTRACT FROM AUTHOR]

Senescence-associated secretory phenotype (SASP) is an important feature of cellular senescence and plays an important role in regulating the disease microenvironment. At present, the role of SASP in intervening bone metabolism and inducing bone loss is very limited. Therefore, this paper discusses the regulatory mechanism of SASP in osteoporosis models and summarizes its regulatory characteristics: SASP is fully expressed in senescent bone cells and transmits aging effects to mesenchymal stem cells in an autocrine/paracrine manner, thereby interfering with osteogenic differentiation. SASP activates immune cells and promotes their aging, thus inducing the formation of inflammatory tissue microenvironment and aggravating bone loss. Mitochondrial homeostasis, pathologic hyperglycemia, and obesity-induced fat accumulation all promote SASP expression, thus disrupting microenvironmental homeostasis and transmitting aging effects to bone tissue. To sum up, understanding the role of SASP in osteoporosis lays a solid foundation for us to develop anti-SASP therapy for osteoporosis in the future.

Abstract Background Pulmonary fibrosis (PF) is an aging-related progressive lung disorder. The aged lung undergoes functional and structural changes termed immunosenescence and inflammaging, which facilitate the occurrence of fibrosis. Interleukin-10 (IL-10) is a potent anti-inflammatory and immunoregulatory cytokine, yet it remains unclear how IL-10 deficiency-induced immunosenescence participates in the development of PF. Methods Firstly we evaluated the susceptibility to fibrosis and IL-10 expression in aged mice. Then 13-month-old wild-type (WT) and IL-10 knockout (KO) mice were subjected to bleomycin(BLM) and analyzed senescence-related markers by PCR, western blot and immunohistochemistry staining of p16, p21, p53, as well as DHE and SA-β-gal staining. We further compared 18-month-old WT mice with 13-month-old IL-10KO mice to assess aging-associated cell senescence and inflamation infiltration in both lung and BALF. Moreover, proliferation and apoptosis of alveolar type 2 cells(AT2) were evaluated by FCM, immunofluorescence, TUNEL staining, and TEM analysis. Recombinant IL-10 (rIL-10) was also administered intratracheally to evaluate its therapeutic potential and related mechanism. For the in vitro experiments, 10-week-old naïve pramily lung fibroblasts(PLFs) were treated with the culture medium of 13-month PLFs derived from WT, IL-10KO, or IL-10KO + rIL-10 respectively, and examined the secretion of senescence-associated secretory phenotype (SASP) factors and related pathways. Results The aged mice displayed increased susceptibility to fibrosis and decreased IL-10 expression. The 13-month-old IL-10KO mice exhibited significant exacerbation of cell senescence compared to their contemporary WT mice, and even more severe epithelial-mesenchymal transition (EMT) than that of 18 month WT mice. These IL-10 deficient mice showed heightened inflammatory responses and accelerated PF progression. Intratracheal administration of rIL-10 reduced lung CD45 + cell infiltration by 15%, including a 6% reduction in granulocytes and a 10% reduction in macrophages, and increased the proportion of AT2 cells by approximately 8%. Additionally, rIL-10 significantly decreased α-SMA and collagen deposition, and reduced the expression of senescence proteins p16 and p21 by 50% in these mice. In vitro analysis revealed that conditioned media from IL-10 deficient mice promoted SASP secretion and upregulated senescence genes in naïve lung fibroblasts, which was mitigated by rIL-10 treatment. Mechanistically, rIL-10 inhibited TGF-β-Smad2/3 and PTEN/PI3K/AKT/ERK pathways, thereby suppressing senescence and fibrosis-related proteins. Conclusions IL-10 deficiency in aged mice leads to accelerated cell senescence and exacerbated fibrosis, with IL-10KO-PLFs displaying increased SASP secretion. Recombinant IL-10 treatment effectively mitigates these effects, suggesting its potential as a therapeutic target for PF. Graphical Abstract

Abstract Background Premature ovarian insufficiency (POI) is a condition characterized by a substantial decline or loss of ovarian function in women before the age of 40. However, the pathogenesis of POI remains to be further elucidated, and specific targeted drugs which could delay or reverse ovarian reserve decline are urgently needed. Abnormal DNA damage repair (DDR) and cell senescence in granulosa cells are pathogenic mechanisms of POI. Ubiquitin-specific protease 14 (USP14) is a key enzyme that regulates the deubiquitylation of DDR-related proteins, but whether USP14 participates in the pathogenesis of POI remains unclear. Methods We measured USP14 mRNA expression in granulosa cells from biochemical POI (bPOI) patients. In KGN cells, we used IU1 and siRNA-USP14 to specifically inhibit USP14 and constructed a cell line stably overexpressing USP14 to examine its effects on DDR function and cellular senescence in granulosa cells. Next, we explored the therapeutic potential of IU1 in POI mouse models induced by D-galactose. Results USP14 expression in the granulosa cells of bPOI patients was significantly upregulated. In KGN cells, IU1 treatment and siUSP14 transfection decreased etoposide-induced DNA damage levels, promoted DDR function, and inhibited cell senescence. USP14 overexpression increased DNA damage, impaired DDR function, and promoted cell senescence. Moreover, IU1 treatment and siUSP14 transfection increased nonhomologous end joining (NHEJ), upregulated RNF168, Ku70, and DDB1, and increased ubiquitinated DDB1 levels in KGN cells. Conversely, USP14 overexpression had the opposite effects. Intraperitoneal IU1 injection alleviated etoposide-induced DNA damage in granulosa cells, ameliorated the D-galactose-induced POI phenotype, promoted DDR, and inhibited cell senescence in ovarian granulosa cells in vivo. Conclusions Upregulated USP14 in ovarian granulosa cells may play a role in POI pathogenesis, and targeting USP14 may be a potential POI treatment strategy. Our study provides new insights into the pathogenesis of POI and a novel POI treatment strategy.

Objective In the process of proliferation and division, normal human cells reach the mortality stage M1 and mortality stage M2, which makes the cells stop division and apoptosis. This irreversible physiological process is also an inherent anti-tumor mechanism. The limited ability of cell proliferation limits its role in basic research, clinical application, bioengineering and other fields. The development of immortalized cell lines with stable, continuous proliferation and normal structure and function has become a hot and difficult point in the research of cell biology.Immortalized cells are important sources for the production of engineered blood cells.This review discusses the molecular research process of immortalization technology which is widely used at present and describes the technology of immortalized cell de-immortalization.

Abstract Background BCR-ABL is a constitutively active tyrosine kinase that stimulates multiple downstream signaling pathways to promote the survival and proliferation of chronic myeloid leukemia (CML) cells. The clinical application of specific BCR-ABL tyrosine kinase inhibitors (TKIs) has led to significantly improved prognosis and overall survival in CML patients compared to previous treatment regimens. However, direct targeting of BCR-ABL does not eradicate CML cells expressing T315I-mutated BCR-ABL. Our previous study revealed that inhibiting CREB binding protein (CBP) is efficacious in activating β-catenin/p300 signaling, promoting cell differentiation and inducing p53/p21-dependent senescence regardless of BCR-ABL mutation status. We hypothesize that the specific inhibition of CBP may represent a novel strategy to promote β-catenin/p300-mediated differentiation and suppress cancer cell proliferation for treating CML patients. Methods The anticancer efficacy of PBA2, a novel CBP inhibitor, in CML cells expressing wild-type or T315I-mutated BCR-ABL was investigated in vitro and in vivo. Cell differentiation was determined by the nitroblue tetrazolium (NBT) reduction assay. The extent of cellular senescence was assessed by senescence-associated β-galactosidase (SA-β-Gal) activity. Cytotoxicity was measured by MTS assay. RNA interference was performed to evaluate the cell proliferation effects of CBP knockdown. The interaction of β-catenin and CBP/p300 was examined by co-immunoprecipitation assay. Results PBA2 exhibited significantly higher anticancer effects than imatinib in CML cells harboring either wild-type or T315I-mutated BCR-ABL both in vitro and in vivo. Mechanistically, PBA2 reduced CBP expression and promoted β-catenin-p300 interaction to induce cell differentiation and senescence. Conclusion Our data supported the rational treatment of CML by inhibiting the β-catenin/CBP pathway regardless of BCR-ABL mutation status.

ABSTRACT Periodontal ligament stem cells (PDLSCs) are key cells that suppress periodontal damage during both the progression and recovery stages of periodontitis. Although substantial evidence has demonstrated that incubation under an inflammatory condition may accelerate senescence of PDLSCs, whether cellular senescence in response to inflammatory incubation contributes to cell dysfunction remain unexplored. In this study, we first observed inflammation‐caused PDLSC senescence in periodontitis based on comparisons of matched patients, and this cellular senescence was demonstrated in healthy cells that were subjected to inflammatory conditions. We subsequently designed further experiments to investigate the possible mechanism underlying inflammation‐induced PDLSC senescence with a particular focus on the role of long noncoding RNAs (lncRNAs). LncRNA microarray analysis and functional gain/loss studies revealed SLC30A4‐AS1 as a regulator of inflammation‐mediated PDLSC senescence. By full‐length transcriptome sequencing, we found that SLC30A4‐AS1 interacted with SRSF3 to affect the alternative splicing (AS) of TP53BP1 and alter the expression of TP53BP1‐204. Further functional studies showed that decreased expression of TP53BP1‐204 reversed PDLSC senescence, and SLC30A4‐AS1 overexpression‐induced PDLSC senescence was abolished by TP53BP1‐204 knockdown. Our data suggest for the first time that SLC30A4‐AS1 plays a key role in regulating PDLSC senescence in inflammatory environments by modulating the AS of TP53BP1. [ABSTRACT FROM AUTHOR]

Mitophagy plays a crucial role in maintaining the homeostasis of intervertebral disc (IVD). Early Growth Response 1 (EGR1), a conservative transcription factor, is commonly upregulated under oxidative stress conditions and participates in regulating cellular senescence, apoptosis, and inflammatory responses. However, the specific role of EGR1 in nucleus pulposus (NP) cell senescence and mitophagy remains unclear. In this study, through bioinformatics analysis and validation using human tissue specimens, we found that EGR1 is significantly upregulated in IVD degeneration (IDD). Further experimental results demonstrate that knockdown of EGR1 inhibits TBHP-induced NP cell senescence and mitochondrial dysfunction while promoting the activation of mitophagy. The protective effect of EGR1 knockdown on NP cell senescence and mitochondrion disappears upon inhibition of mitophagy with mdivi1. Mechanistic studies reveal that EGR1 suppresses NP cell senescence and mitochondrial dysfunction by modulating the PINK1-Parkin dependent mitophagy pathway. Additionally, EGR1 knockdown delays acupuncture-induced IDD in rats. In conclusion, our study demonstrates that under TBHP-induced oxidative stress, EGR1 knockdown mitigates NP cell senescence and mitochondrial dysfunction through the PINK1-Parkin dependent mitophagy pathway, thereby alleviating IDD. [Display omitted] • Knocking down EGR1 inhibits TBHP-induced nucleus pulposus cell senescence. • Knocking down EGR1 promotes mitophagy. • Knocking down EGR1 inhibits nucleus pulposus cell senescence by activating PINK1-Parkin-regulated mitophagy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood. In this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects. We pretreated HT-22 cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, β-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin. Our data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection. Icariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases. [Display omitted] • Ceramide could induce neuronal senescence and Alzheimer's disease-related pathologies. • Icariin demonstrates a protective effect against ceramide-induced neuronal senescence. • Icariin mediated neuroprotective effects by directly targeting P53. • Icariin may serve as a promising therapeutic approach for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Telomeres cap the ends of chromosomes. The length of telomeres is highly related to chronological age. As people age, their telomeres become shorter. Shorter telomeres put people at a greater risk of premature disease and death. A healthy lifestyle tends to preserve telomeres, whereas unhealthy practices cause increased biological aging and shorter telomeres. This study investigated the extent to which regular strength training is related to the length of telomeres in 4814 US men and women who were representative of the US adult population. Participants gave blood, and the length of telomeres in their blood cells was precisely measured. Participants also reported how often they engaged in exercises to strengthen their muscles. The findings showed that adults who strength trained regularly had significantly longer telomeres and therefore less biological aging than adults who did not strength train, even after taking into account many factors, including their age, sex, race, income, household size, smoking, body size, and participation in physical activities other than strength training. Telomere length is an index of cellular aging. Healthy lifestyles are associated with reduced oxidative stress and longer telomeres, whereas unhealthy behaviors are related to shorter telomeres and greater biological aging. This investigation was designed to determine if strength training accounted for differences in telomere length in a random sample of 4814 US adults. Data from the National Health and Nutrition Examination Survey (NHANES) were employed to answer the research questions using a cross-sectional design. Time spent strength training was calculated by multiplying days of strength training per week by minutes per session. Participation in other forms of physical activity was also calculated based on reported involvement in 47 other activities. Weighted multiple regression and partial correlation were used to calculate the mean differences in telomere length across levels of strength training, adjusting for differences in potential confounders. With the demographic covariates controlled, strength training and telomere length were linearly related (F = 14.7, p = 0.0006). Likewise, after adjusting for all the covariates, the linear association remained strong and significant (F = 14.7, p = 0.0006). In this national sample, 90 min per week of strength training was associated with 3.9 years less biological aging, on average. Regular strength training was strongly related to longer telomeres and less biological aging in 4814 US adults. [ABSTRACT FROM AUTHOR]

Dysfunctional mitochondria producing excessive ROS are the main factors that cause ovarian aging. Immp2l deficiency causes mitochondrial dysfunction and excessive ROS production, leading to ovarian aging, which is attributed to granulosa cell senescence. The pathway controlling mitochondrial proteostasis and mitochondrial homeostasis of the UPRmt and mitophagy are closely related with the ROS and cell senescence. Our results suggest that Immp2l knockout led to granulosa cell senescence, and enocyanin treatment alleviated Immp2l deficiency-induced granulosa cell senescence, which was accompanied by improvements in mitochondrial function and reduced ROS levels. Interestingly, redox-related protein modifications, including S-glutathionylation and S-nitrosylation, were markedly increased in Immp2l-knockout granulosa cells, and were markedly reduced by enocyanin treatment. Furthermore, STAT1 was significantly increased in Immp2l-knockout granulosa cells and reduced by enocyanin treatment. The co-IP results suggest that the expression of STAT1 was controlled by S-glutathionylation and S-nitrosylation, but not phosphorylation. The UPRmt was impaired in Immp2l-deficient granulosa cells, and unfolded and misfolded proteins aggregated in mitochondria. Then, the HIF1α/BNIP3-mediated mitophagy pathway was activated, but mitophagy was impaired due to the reduced fusion of mitophagosomes and lysosomes. The excessive aggregation of mitochondria increased ROS production, leading to senescence. Hence, Enocyanin treatment alleviated granulosa cell senescence through STAT1/ATF4-mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3-mediated mitophagy. [ABSTRACT FROM AUTHOR]