Tumor cellular senescence, characterized by reversible cell cycle arrest following anti-cancer therapies, presents a complex paradigm in oncology. Given that senescent tumor cells may promote angiogenesis, tumorigenesis, and metastasis, selective killing senescent cells (SCs)-a strategy termed senotherapy-has emerged as a promising approach to improve cancer treatment. However, the clinical implementation of senotherapy faces significant hurdles, including lack of precise methods for SCs identification and the potential for adverse effects associated with highly cytotoxic senolytic agents. In this account, we elucidate recent advancement in developing novel approaches for the detection and selective elimination of SCs, encompassing prodrugs, nanoparticles, and other cutting-edge drug delivery systems such as PROTAC technology and CAR T cell therapy. Furthermore, we explore the paradoxical nature of SCs, which can induce growth arrest in adjacent neoplastic cells and recruit immunomodulatory cells that contribute to tumor suppression. Therefore, we utilize SCs membrane as vehicles to elicit antitumor immunity and potentially augment existing anti-cancer therapies. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of SCs detection, elimination or utilization.

Senescence is a key cellular response to ionizing radiation. Senescent cells experience irreversible growth arrest while remaining metabolically active and secrete a distinct set of proteins, collectively referred to as the senescence-associated secretory phenotype (SASP). These secreted factors influence neighboring non-irradiated cells through a mechanism known as the bystander effect. This study aimed to investigate and characterize the bystander effect in a melanoma cell model.

Murine melanoma B16F0 cells were exposed to X-irradiation (10 Gy), and senescence was induced 3 days later. Conditioned media from the senescent cells was collected and used to culture non-irradiated B16F0 cells. Proliferation, viability, clonogenic capacity, DNA damage foci formation, apoptosis, and senescence were assessed. The composition of the senescence-associated secretory phenotype was analyzed using mass spectrometry and bioinformatics tools.

Conditioned media from senescent cells induced by radiation reduced growth and promoted senescence in tumor cell cultures not exposed to ionizing radiation. Mass spectrometry analysis revealed greater protein diversity and abundance in conditioned media from senescent cells compared to that from non-irradiated cells. Additionally, conditioned media from senescent cells contained higher concentrations of proteins related to immune response, cellular aging, and responses to oxidative stress.

Cells undergoing radiation-induced senescence promote bystander senescence by secreting soluble factors involved in the induction and maintenance of senescence.

Although radiation-induced skin injuries are a concern in patients receiving radiation therapy, there are few effective treatments. The aim of this study was to evaluate the protective effects of extracorporeal shock wave therapy (ESWT) on irradiated fibroblasts and mouse skin.

In this in vitro study of human dermal fibroblasts, the experimental group was subjected to ESWT after irradiation (20 Gy). The control groups were only irradiated or only subjected to ESWT. At 24 or 48 hours after ESWT, cell viability, cell migration, and mRNA and protein expression were measured. In the in vivo study, the experimental group (7 mice) was treated with ESWT after irradiation (45 Gy). The control group (7 mice) was only irradiated. At 8 weeks after irradiation, dorsal skin was harvested for histopathologic examination and protein isolation.

In dermal fibroblasts, treatment with ESWT increased viability of irradiated cells compared with irradiated-only and untreated cells ( P = 0.005). ESWT increased cell migration 24 hours after irradiation ( P = 0.002) and decreased transforming growth factor-β (TGF-β) protein expression 48 hours after irradiation ( P = 0.024). In mice, ESWT decreased the level of radiation-related skin injury ( P = 0.006). Treatment of irradiated skin with ESWT decreased TGF-β1 ( P = 0.009) and phospho-Smad3 ( P = 0.009) protein expression, decreased myofibroblasts ( P = 0.047), and increased vessel density ( P < 0.001).

This study demonstrated that ESWT alleviated radiation-induced fibrosis by downregulating TGF-β1 expression, suggesting the potential of ESWT for the treatment of radiation-induced fibrosis.

Osteoarthritis (OA) is an age-related degenerative disease that affects bones and joints. The hallmark pathogenesis of OA is associated with chondrocyte senescence. Surfactant protein D (SP-D) is a member of the innate immune proteins family, which can inhibit the immune inflammatory response of chondrocytes. However, the effect of SP-D on chondrocyte senescence phenotype is poorly studied. The present study investigated the phenotypic regulation of OA chondrocyte senescence mediated by SP-D and explored the underlying molecular mechanism.

In this study, an in vitro senescence chondrocyte model was generated by subjecting chondrocytes to IL-1β treatment. Furthermore, the expression of aging-related biomarkers and mitochondrial functions in SP-D overexpressing chondrocytes was observed. Co-immunoprecipitation was conducted to verify the association between SP-D and the identifed proteins within chondrocytes. Moreover, a rat OA model was established by destabilization of the medial meniscus surgery, and the effect of SP-D on reversing the aging phenotype of OA cartilage was investigated.

The results indicated that SP-D significantly decreased senescence and enhanced mitochondrial functions in senescent chondrocytes. The RNA-sequencing analysis revealed that the SIRT3/SOD2 pathway predominantly modulated the effect of SP-D on alleviating senescence. In addition, SP-D overexpression mitigated chondrocyte senescence, suppressed senescence-associated secretory phenotype (SASP) secretion and ameliorated mitochondrial damage. In the rat OA model, SP-D inhibited aging-related pathological changes by upregulating SIRT3/SOD2 pathway, thereby protecting the cartilage tissue integrity.

These findings indicate that SP-D modulates the inhibition of chondrocyte senescence by upregulating SIRT3/SOD2 pathway. These data indicate that targeting SP-D and the SIRT3/SOD2 pathway might be a promising therapeutic strategy for OA.

Current antiretroviral therapy (ART) for HIV infection reduces plasma viral loads to undetectable levels and has increased the life expectancy of people with HIV (PWH). However, this increased lifespan is accompanied by signs of accelerated aging and a higher prevalence of age-related comorbidities. Tat (Trans-Activator of Transcription) is a key protein for viral replication and pathogenesis. Tat is encoded by 2 exons, with the full-length Tat ranging from 86 to 101 aa (Tat101). Introducing a stop codon in position 73 generates a 1 exon, synthetic 72aa Tat (Tat72). Intracellular, full-length Tat activates the NF-κB pro-inflammatory pathway and increases antiapoptotic signals and ROS generation. These effects may initiate a cellular senescence program, characterized by cell cycle arrest, altered cell metabolism, and increased senescence-associated secretory phenotype (SASP) mediator release However, the precise role of HIV-Tat in inducing a cellular senescence program in CD4+ T-cells is currently unknown.

Jurkat Tetoff cell lines stably transfected with Tat72, Tat101, or an empty vector were used. Flow cytometry and RT-qPCR were used to address senescence biomarkers, and 105 mediators were assessed in cell supernatants with an antibody-based membrane array. Key results obtained in Jurkat-Tat cells were addressed in primary, resting CD4+ T-cells by transient electroporation of HIV-Tat-FLAG plasmid DNA.

In the Jurkat cell model, expression of Tat101 increased the levels of the senescence biomarkers BCL-2, CD87, and p21, and increased the release of sCD30, PDGF-AA, and sCD31, among other factors. Tat101 upregulated CD30 and CD31 co-expression in the Jurkat cell surface, distinguishing these cells from Tat72 and Tetoff Jurkats. The percentage of p21+, p16+, and γ-H2AX+ cells were higher in Tat-expressing CD4+ T-cells, detected as a FLAG+ population compared to their FLAG- (Tat negative) counterparts. Increased levels of sCD31 and sCD26 were also detected in electroporated CD4+ T-cell supernatants.

Intracellular, full-length HIV-Tat expression increases several senescence biomarkers in Jurkat and CD4+ T-cells, and SASP/Aging mediators in cell supernatants. Intracellular HIV-Tat may initiate a cellular senescence program, contributing to the premature aging phenotype observed in PWH.

Endometriosis significantly impacts women's health and fertility, with cell aging playing a crucial role in its development. This study utilized a multi-omic summary Mendelian randomization (SMR) analysis, integrating genome-wide association studies (GWAS), expression quantitative trait loci (eQTLs), methylation quantitative trait loci (mQTLs), and protein quantitative trait loci (pQTLs). The goal was to identify genes that exhibit causal associations between cell aging and endometriosis. Validation was conducted using the FinnGen R10 and UK Biobank cohorts. The SMR and HEIDI tests evaluated the genetic variants linked to both cell aging and endometriosis risk. Colocalization analysis revealed shared genetic variants, uncovering significant associations between the two conditions. A total of 196 CpG sites in 78 genes, alongside 18 eQTL-associated genes and 7 pQTL-associated proteins, were identified. Notably, the MAP3K5 gene displayed contrasting methylation patterns linked to endometriosis risk. In validation cohorts, the THRB gene and ENG protein were confirmed as risk factors. The findings suggest a causal mechanism where specific methylation patterns downregulate the MAP3K5 gene, heightening endometriosis risk, highlighting it and associated pathways as potential therapeutic targets.

Replicative senescence presents a significant challenge in mesenchymal stem cell (MSC) expansion due to high reactive oxygen species (ROS) levels generated during culture. Elevated ROS levels lead to oxidative stress, cellular damage, and senescence, limiting the biomedical applications of MSCs. In this study, a supramolecular thermo-reversible hydrogel composed of the natural polyphenolic compound gallic acid (GA) and polyvinyl alcohol (PVA) was designed to scavenge ROS and mitigate MSC senescence. The PVA-GA hydrogel, stabilized by strong hydrogen bonding forces, exhibited an elastic modulus comparable to that of human soft tissue and facilitated the sustained release of GA over 14 days. It enhanced MSC survival, protected against oxidative stress, reduced intracellular ROS levels, diminished mitochondrial damage, and decreased cellular senescence. The hydrogel maintained the multilineage differentiation potential and typical phenotype of MSCs. Additionally, it preserved vascular endothelial growth factor (VEGF) secretion from MSCs under oxidative stress and enhanced their pro-angiogenic effect. The conditioned medium derived from MSCs in the hydrogel group promoted migration and tube formation of human umbilical vein endothelial cells (HUVECs). These findings suggest that the PVA-GA hydrogel holds significant promise for the biomedical applications of MSCs, potentially addressing the challenges posed by oxidative stress and cellular senescence.

Background: Radiotherapy is a key treatment for cancer, effectively controlling local tumor growth through DNA damage that induces senescence or apoptosis in cancer cells. However, radiotherapy can trigger complex cellular reactions, such as cell senescence, which is characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory factors known as the senescent-associated secretory phenotype (SASP). Methods: This study investigates the regulatory role of ALDH1A3, a key enzyme implicated in cancer cell metabolism and radiotherapy resistance, in the induction of senescence and SASP. Using in vitro models, we demonstrate that ALDH1A3 knockdown accelerates cellular senescent-like phenotype while regulating the SASP through the cGAS-STING immune response pathway. Results: Our results indicate that while ALDH1A3 knockdown promotes senescence, it reduces the secretion of pro-inflammatory factors via inhibition of the cGAS-STING pathway, potentially mitigating SASP-related tumor progression. Conclusions: These findings provide insights into the molecular mechanisms underlying prostate cancer cell senescence and suggest that ALDH1A3 could be a potential therapeutic target to enhance the efficacy of radiotherapy while controlling the adverse effects of SASP.

Epithelioid hemangioendothelioma (EHE) is a difficult to treat vascular sarcoma defined by TAZ- CAMTA1 or YAP-TFE3 fusion proteins. Human cell lines needed to further understand the pathogenesis of EHE have been lacking. Herein, we describe a method to generate EHE extended primary cell cultures. An integrated multi -omic and functional approach was used to characterize these cultures. The cell cultures, relatively homogenous by single cell RNA-Seq, demonstrated established characteristics of EHE including increased proliferation, anchorage independent growth, as well as the overall gene expression profile and secondary genetic alterations seen in EHE. Whole genome sequencing (WGS) identified links to epigenetic modifying complexes, metabolic processes, and pointed to the importance of the extracellular matrix (ECM) in these tumors. Bulk RNA-Seq demonstrated upregulation of pathways including PI3K-Akt signaling, ECM/ECM receptor interaction, and the Hippo signaling pathway. Development of these extended primary cell cultures allowed for single-cell profiling which demonstrated different cell compartments within the cultures. Furthermore, the cultures served as a therapeutic platform to test the efficacy of TEAD inhibitors in vitro . Overall, the development of EHE primary cell cultures will aid in the mechanistic understanding of this sarcoma and serve as a model system to test new therapeutic approaches.

As aging progresses, the structures and functions of immune organs such as the thymus and spleen deteriorate, leading to impaired immune function and immune senescence. This study investigated the potential of umbilical cord mesenchymal stem cells (UC-MSCs) to mitigate D-galactose-induced immune senescence by enhancing the structural and functional integrity of aging immune organs and regulating the gut microbiota. The findings show that UC-MSCs treatment significantly delayed thymus and spleen atrophy and reduced the number of senescence-associated β-galactosidase (SA-β-gal) positive cells. At the molecular level, UC-MSCs treatment downregulated the expression of aging-related genes, including p16, p53, p21, and RB. It also boosted antioxidant enzyme activity, increasing the levels of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), while decreasing serum malondialdehyde (MDA) levels by activating the Nrf2/HO-1 pathway. Additionally, UC-MSCs treatment restored the balance of the gut microbiota. These results demonstrate that UC-MSCs significantly improve the structural and functional integrity of immune organs and enhance the composition of the gut microbiome, offering a potential strategy for delaying immune senescence.

Neutrophils are initial responders in inflammation and contribute to non-alcoholic fatty liver disease (NAFLD) progression to steatohepatitis (NASH). Neutrophil extracellular traps (NETs) are implicated in liver injury, yet their precise mechanisms in NASH progression remains unclear.

This study investigates how NETs drive NASH progression by exacerbating hepatocyte lipotoxicity and explore the regulatory mechanism of NETs formation and its downstream effects on liver pathology.

Clinical samples from NASH patients and diet-induced NASH mice were analyzed for NET levels. NETs were pharmacologically inhibited, and senescent cells were selectively eliminated in mice. Myeloid-specific RBP-J knockout mice were generated to disrupt Notch signaling, with subsequent evaluation of NET formation, senescence markers, steatosis, fibrosis, and inflammation.

NETs were elevated in NASH patients and mice, correlating with hepatocyte senescence and lipotoxicity. Pharmacological NET disruption reduced hepatocyte senescence, accompanied by attenuated steatosis and fibrosis. Senescent cell clearance replicated these improvements, confirming liver senescence emerges is a vital step for NETs to promote the progression of NASH. Myeloid-specific Notch signaling ablation suppressed NET generation, concurrently decreasing lipid deposition and liver inflammation.

Our findings elucidate a novel mechanism by which neutrophil-derived Notch driven NETs exacerbate NASH by promoting cell senescence, thereby contributing to hepatic steatosis and fibrosis. This insight may provide potential intervention strategies and therapeutic targets for NASH treatment.

Senescence is a nonproliferative survival state that cancer cells can enter to escape therapy. In addition to soluble factors, senescence cells secrete extracellular vesicles (EV), which are important mediators of intercellular communication. To explore the role of senescent cell (SC)-derived EVs (senEV) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators. SenEVs were both necessary and sufficient to trigger immune-mediated clearance of SCs, thereby suppressing tumor growth. In the absence of senEVs, the recruitment of MHC-II+ antigen-presenting cells (APC) to the senescence microenvironment was markedly impaired. Blocking senEV release redirected the primary target of SC signaling from APCs to neutrophils. Comprehensive transcriptional and proteomic analyses identified six ligands specific to senEVs, highlighting their role in promoting APC-T cell adhesion and synapse formation. APCs activated CCR2+CD4+ TH17 cells, which seemed to inhibit B-cell activation, and CD4+ T cells were essential for preventing tumor recurrence. These findings suggest that senEVs complement the activity of secreted inflammatory mediators by recruiting and activating distinct immune cell subsets, thereby enhancing the efficient clearance of SCs. These conclusions may have implications not only for tumor recurrence but also for understanding senescence during de novo carcinogenesis. Consequently, this work could inform the development of early detection strategies for cancer based on the biology of cellular senescence. Significance: Chemotherapy-treated senescent tumor cells release extracellular vesicles that trigger an immune response and suppress tumor recurrence. See related commentary by Almeida and Melo, p. 833.

Human genetics studies lent firm evidence that microglia are key to Alzheimer's disease (AD) pathogenesis over a decade ago following the identification of AD-associated genes that are expressed in a microglia-specific manner. However, while alterations in microglial morphology and gene expression are observed in human postmortem brain tissue, the mechanisms by which microglia drive and contribute to AD pathology remain ill-defined. Numerous mouse models have been developed to facilitate the disambiguation of the biological mechanisms underlying AD, incorporating amyloidosis, phosphorylated tau, or both. Over time, the use of multiple technologies including bulk tissue and single cell transcriptomics, epigenomics, spatial transcriptomics, proteomics, lipidomics, and metabolomics have shed light on the heterogeneity of microglial phenotypes and molecular patterns altered in AD mouse models. Each of these 'omics technologies provide unique information and biological insight. Here, we review the literature on the approaches and findings of these methods and provide a synthesis of the knowledge generated by applying these technologies to mouse models of AD.

The global aging trend has posed significant challenges, rendering healthcare for older adults a crucial focus in medical research. Among the numerous health concerns related to aging, vascular aging and dysfunction are important risk factors and underlying causes of age-related diseases. Histone methylation and demethylation, which are involved in gene expression and cellular senescence, are closely associated with the occurrence and development of vascular aging. Consequently, this review aimed to identify the role of histone methylation in the pathogenesis of vascular aging and its potential for treating age-related vascular diseases and provided new insights into therapeutic strategies targeting the vascular system.

Cellular senescence is defined as a permanent proliferation arrest caused by various stresses, including DNA damage. We have recently identified the riboflavin transporter SLC52A1, whose expression is increased in response to senescence-inducing stimuli. Interestingly, increased expression of SLC52A1 suppresses cellular senescence through the uptake of riboflavin and an increase in intracellular flavin adenine dinucleotide (FAD), an enzyme cofactor synthesized from riboflavin. However, how FAD suppresses cellular senescence has not been fully elucidated. Therefore, in this study, we focused on lysine-specific demethylase 1 (LSD1), which uses FAD as a cofactor. First, we found that LSD1 inhibition promoted DNA damage-induced cellular senescence, whereas ectopic expression of LSD1 suppressed cellular senescence, suggesting that LSD1 suppresses senescence. In addition, the demethylation activity of LSD1 against histone H3 and p53 was increased by senescence-inducing stress in a riboflavin uptake-dependent manner. Furthermore, it was revealed that the LSD1 demethylation activity was required for suppression of pro-senescence genes Sirtuin-4 and p21 whose expression is modified by methylation status of histone H3 and possibly p53, respectively. Collectively, these results suggest that the FAD increase by senescence-inducing stress leads to LSD1-mediated demethylation of histone H3 and p53, which results in the suppression of pro-senescence genes to inhibit senescence induction.

Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU. Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network.

Thyroid cancer (THCA) is the most common endocrine tumor. Research on Cell Senescence Associated Genes (CSAGs), which impact many cancers, remains limited in the THCA field.

In this study, we downloaded THCA sample data from several public databases and selected a set of CSAGs for subsequent analysis. Differential expression genes (DEGs) obtained through differential analysis were intersected with prognostic genes identified by Cox regression analysis to explore the correlation among these crossed genes. We constructed a prognostic model using the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm and verified its efficacy. Kaplan-Meier survival curves were plotted, and Receiver Operating Characteristic (ROC) curves rigorously confirmed the accuracy of model predictions.

To evaluate the predictive power of prognostic models across different phenotypic traits, we performed survival analysis, Gene Set Enrichment Analysis (GSEA), and immune-related differential analysis. Differences in tumor mutation burden (TMB) and treatment response between high-risk and low-risk patient groups were also analyzed. Finally, the predictive effect of our model on immunotherapy response was validated, showing promising results for THCA patients.

Our study enhances the understanding of THCA cell senescence and provides new therapeutic insights. The proposed model not only accurately predicts patient survival but also reveals factors related to immunotherapy response, offering new perspectives for personalized medicine.

The Retinoblastoma (RB) protein is crucial for regulating gene transcription and chromatin remodeling, impacting cell cycle progression, cellular senescence, and tumorigenesis. Cellular senescence, characterized by irreversible growth arrest and phenotypic alterations, serves as a vital barrier against tumor progression and age-related diseases. RB is crucial in mediating senescence and tumor suppression by modulating the RB-E2F pathway and cross talking with other key senescence effectors such as p53 and p16INK4a. The interplay between RB-mediated cell cycle arrest and cellular senescence offers critical insights into tumorigenesis and potential therapeutic strategies. Leveraging RB-mediated senescence presents promising opportunities for cancer therapy, including novel approaches in tumor immunotherapy designed to enhance treatment efficacy. This review highlights recent advancements in the RB signaling pathway, focusing on its roles in cellular senescence and tumor suppression, and discusses its potential to improve tumor management and clinical outcomes.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease typically characterized by chronic airway inflammation, with emerging evidence highlighting the driving role of cellular senescence-related lung aging. Accelerated lung aging and inflammation mutually reinforce each other, creating a detrimental cycle that contributes to disease progression. Growth arrest and DNA damage-inducible (GADD45) family has been reported to involve in multiple biological processes, including inflammation and senescence. However, the role of GADD45 family in COPD remains elusive.

To investigate the role and mechanism of GADD45 family in COPD pathogenesis.

Expressions of GADD45 family were evaluated by bioinformatic analysis combined with detections in clinical specimens. The effects of GADD45B on inflammation and senescence were investigated via constructing cell model with siRNA transfection or overexpression lentivirus infection and animal model with Gadd45b knockout. Targeted bisulfite sequencing was performed to probe the influence of DNA methylation in GADD45B expression in COPD.

GADD45B expression was significantly increased in COPD patients and strongly associated with lung function, whereas other family members presented no changes. GADD45B upregulation was confirmed in mice exposed by cigarette smoke (CS) and HBE cells treated by CS extract as well. Moreover, experiments involving bidirectional modulation of GADD45B expression in HBE cells further substantiated its positive regulatory role in inflammatory response and cellular senescence. Mechanically, GADD45B-facilitated inflammation was directly mediated by p38 phosphorylation, while GADD45B interacted with FOS to promote cellular senescence in a p38 phosphorylation-independent manner. Furthermore, Gadd45b deficiency remarkably alleviated inflammation and senescence of lungs in CS-exposed mice, as well as improved emphysema and lung function. Eventually, in vivo and vitro experiments demonstrated that GADD45B overexpression was partially mediated by CS-induced DNA hypomethylation.

Our findings have shed light on the impact of GADD45B in the pathogenesis of COPD, thereby offering a promising target for intervention in clinical settings.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide, necessitating new treatment approaches with minimal side effects. In the present study, the potential of Bergapten (5-methoxypsoralen), a natural furanocoumarin compound, as a therapeutic agent against NSCLC was investigated by using network pharmacology, molecular docking and in vitro validation. Bergapten targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and SwissTarget databases, whilst lung cancer-related targets were sourced from GeneCards and DisGeNET. Protein-protein interaction analysis and molecular docking were performed to identify key targets. The inhibitory effects of Bergapten on lung cancer cells were assessed using Cell Counting Kit-8 assays, wound healing assays, cell migration experiments, flow cytometry and western blotting. SC79 was used to verify the regulation of Bergapten on the PI3K/AKT pathway. Network pharmacology identified 51 targets, one signaling pathway and four Gene Ontology projects associated with the action of Bergapten against NSCLC. Key targets identified included glycogen synthase kinase-3β, Janus kinase 2, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α and protein tyrosine kinase 2. In vitro experiments demonstrated that Bergapten significantly inhibited cell viability, promoted apoptosis, induced cellular senescence and inhibited the PI3K/AKT signaling pathway in NSCLC cells. In conclusion, Bergapten exerts its anti-NSCLC effects through the PI3K/AKT pathway, promoting cell senescence and inhibiting inflammation. These findings suggest that Bergapten has potential as a therapeutic agent for NSCLC.

Epimedium Tourn. ex L. is a traditional Chinese medicine used for thousands of years in China to treat forgetfulness. Icariin is a principal component of the genus Epimedium.

The metabolic mechanism of icariin treating forgetfulness is explored.

A D-galactose-induced senescent mouse model was employed. The cognitive performance of mice was assessed in the fear conditioning test. Hippocampal pathology was assessed in the immunohistochemistry assay. Plasma metabolome was analyzed using GC-MS method, and the differential metabolites were further identified by UPLC-MS/MS or GC-MS method. The liver function, including ALT and AST, was assessed by enzyme reaction. Icariin was administered intraperitoneally at 50 and 100 mg/kg. Mice were administered five consecutive days per week for 8 weeks.

Icariin treatment improved hippocampus-related fear memory but not amygdala-related memory, whereas Pexidartinib (PLX3397), a microglial scavenger, did not. Icariin treatment maintained the TMEM119-positive microglial population and decreased the accumulation of the senescent biomarker p16 in the dorsal hippocampus in senescent mouse brains, whereas PLX3397 did not. Notably, p16 in the CA2 subregion significantly decreased in icariin-treated mice than the other hippocampal subregions. The senescent mice exhibited the circulating metabolic characteristics of mild ketoacidosis, active tricarboxylic acid (TCA) cycle, lactic acidosis, hyperglycemia, active detoxification, active cis-oleic acid metabolism, and inhibitory GABA shut. R-3-Hydroxybutyric acid primarily produced in the liver was selectively and robustly decreased by icariin treatment, which was not observed with PLX3397 treatment. The TCA cycle was rescued in senescent mice by icariin treatment. Icariin also protected liver function (plasma ALT) in D-gal-induced senescent mice.

Icariin may protect mouse hippocampal cognition from D-gal-induced senescence by protecting microglial homeostasis, and facilitating the utilization of R-3-hydroxybutyric acid is one of the underpins.

Cellular senescence, a state of permanent cell cycle arrest, recapitulates the aging process at the cellular level. It can be triggered by intrinsic or extrinsic factors including telomere shortening (replicative senescence) and in response to various types of stresses such as oncogenic stress (oncogene-induced senescence, OIS). Senescence has been detected in vitro and in premalignant lesions in mice and humans expressing mutant oncogenes. MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression at the posttranscriptional level, and have been involved in both replicative senescence and OIS. Several methods have been used to identify miRNAs and compare their expression in normal versus oncogene-induced senescent cells, as well as to analyze their role and their targets in senescence. Here, we describe several methods that can be employed to identify miRNAs in cells undergoing OIS, including miRNA-sequencing, RT-qPCR-based detection and quantification of miRNAs and Nanostring miRNA analysis (nCounter miRNA Expression Assay). Moreover, we perform a meta-analysis of studies employing the above methodologies, pinpoint miRNAs with consistent expression changes across senescence models, and predict their target genes and the pathways in which they partake.

With the increasing demand for beauty and a healthy lifespan, studies regarding anti-skin aging have drawn much more attention than ever before. Skin cellular senescence, the primary cause of skin aging, is characterized by a cell cycle arrest in proliferating cells along with a senescence-associated secretory phenotype (SASP), which can be triggered by various internal or external stimuli.

Recent studies have made significant progress in the fields of anti-senescence and anti-aging. However, little is known about the roles and functions of natural compounds, particularly flavonoids, in skin cellular senescence studies.

In this study, using strategies including ionizing radiation (IR), senescence-associated β galactosidase assay (SA-β-Gal), immunofluorescence (IF), flow cytometry, PCR array, as well as in vivo experiments, we investigated the effects and roles of troxerutin (Trx), a natural flavonoid, in skin keratinocyte senescence.

We found that Trx delays skin keratinocyte senescence induced by IR. Mechanistically, Trx protects the skin keratinocyte cells from senescence by alleviating reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and DNA damage caused by IR. In addition, Trx was also proved to relieve skin senescence and SASP secretion in vivo induced by IR stimulation.

Altogether, our findings pointed to a new function of Trx in delaying stress-induced skin keratinocyte senescence, and should thus provide theoretical foundations for exploring novel strategies against skin aging.

Chronic kidney diseases (CKD) are a group of multi-factorial disorders that markedly impair kidney functions with progressive renal deterioration. Aging contributes to age-specific phenotypes in kidneys, which undergo several structural and functional alterations, such as a decline in regenerative capacity and increased fibrosis, inflammation, and tubular atrophy, all predisposing them to disease and increasing their susceptibility to injury while impeding their recovery. A central feature of these age-related processes is the activation of the p53/p21 pathway signaling. The pathway is a key player in cellular senescence, apoptosis, and cell cycle regulation, which are all key to maintaining the health of the kidney. P53 is a transcription factor and a tumor suppressor protein that responds to cell stress and damage. Persistent activation of cell p53 can lead to the expression of p21, an inhibitor of the cell cycle known as a cyclin-dependent kinase. This causes cells to cease dividing and leads to senescence, where cells can no longer increase. The accumulation of senescent cells in the aging kidney impairs kidney function by altering the microenvironment. As the number of senescent cells increases, the capacity of the kidney to recover from injury decreases, accelerating the progression of end-stage renal disease. This article review extensively explores the relationship between the p53/p21 pathway and cellular senescence within an aging kidney and the emerging therapeutic strategies that target it to overcome the impacts of cellular senescence on CKD.

Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation. We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.

To achieve a more beautiful and younger appearance, reducing wrinkles is a key concern. The process of wrinkle formation is complex and the development of truly effective cosmetic ingredients to reduce wrinkles remains a challenge. Recent studies have revealed a close relationship between wrinkles and skin thinning, suggesting that preventing skin thinning could also prevent wrinkle formation. In this study, we examined the role of extracellular adenosine triphosphate (eATP) in the progression of thinning, as eATP reportedly increases skin ageing factors, such as senescence-associated secreted phenotype (SASP) factors in epidermal cells. We determined the effects of Mentha piperita leaf extract on suppressing eATP to reduce thinning and wrinkles.

Adenosine triphosphate (ATP) levels were measured in normal human epidermal keratinocytes (NHEK) in the presence of M. piperita leaf extract. Dryness, high pH, and UVB radiation were used as extrinsic ageing factors. Intrinsic skin ageing was evaluated by comparing cells from adults (AD-NHEK) and newborns (NB-NHEK). A placebo-controlled in vivo study was carried out with a formulation containing 1% M. piperita leaf extract.

The eATP levels were significantly higher in AD-NHEK compared with that in NB-NHEK cells. M. piperita leaf extract significantly decreased eATP levels in adult cells. Extrinsic ageing factors increased eATP levels in NHEK, whereas M. piperita leaf extract significantly suppressed eATP under all conditions. The active components of M. piperita leaf extract, luteolin glucuronide and rosmarinic acid, also decreased eATP. Moreover, compared with placebo lotion, M. piperita leaf extract-formulated lotion markedly increased dermal thickness and reduced wrinkles associated with crow's feet and the neck area.

We demonstrated for the first time that M. piperita leaf extract containing rosmarinic acid and luteolin-7-O-glucuronide has the potential to reduce eATP release from epidermal keratinocytes. An increase in eATP was observed not only during inflammation but also during natural ageing. Furthermore, the in vivo experiment revealing that 1% M. piperita leaf extract-containing lotion improved dermal thinning and wrinkles across multiple areas is attributed to the amelioration of dermal thinning. Thus, our data suggest the possibility of a novel cosmetic approach for reducing skin ageing by reducing eATP-mediated dermal thinning.

DNA damage can lead to mutations that can alter the function of oncogenes or tumor suppressor genes, thus promoting the development of cancer. p53 plays a multifaceted and complex role in the DNA damage response and cancer progression and is known as the 'guardian of the gene'. When DNA damage occurs, p53 is activated through a series of post-translational modifications, which stabilize the protein and enhance its function as a transcription factor. It regulates processes including cell cycle checkpoints, DNA repair and apoptosis, thereby preventing the spread of damaged DNA and maintaining genome integrity. On the one hand, p53 can initiate cell cycle arrest and induce cells to enter the G1/S and G2/M checkpoints, preventing cells with damaged DNA from continuing to proliferate and gaining time for DNA repair. At the same time, p53 can promote the activation of DNA repair pathways, including base excision repair, nucleotide excision repair and other repair pathways, to ensure the integrity of genetic material. If the damage is too severe to repair, p53 will trigger the apoptosis process to eliminate potential cancer risks in time. p53 also plays a pivotal role in cancer progression. Mutations in the p53 gene are frequently found in many cancers, and the mutated p53 not only loses its normal tumor suppressor function but may even acquire pro-cancer activity. Therefore, we also discuss therapeutic strategies targeting the p53 pathway, such as the use of small-molecule drugs to restore the function of wild-type p53, the inhibition of negative regulatory factors and synthetic lethality approaches for p53-deficient tumors. This review therefore highlights the important role of p53 in maintaining genomic stability and its potential in therapeutic strategies for cancer.

Accumulation of senescent cells in tissues and their downstream effect programs have emerged as key drivers of aging and age-associated pathologies. Recent progresses in senotherapeutics indicated that either selectively killing senescent cells with senolytics or suppressing the senescence-associated secretory phenotype (SASP) secretion using senomorphics contributes to extending of the healthy lifespan and alleviating numerous age-related disorders in mice.

However, the potential side-effects and long-term cytotoxicity of the above novel compounds have not yet been determined. Therefore, it seems to be more efficient to explore new senotherapeutical functions from approved drugs.

The effects of valproic acid (VPA), a derivative of valine, in cellular senescence were evaluated by senescence-associated β galactosidase (SA-β-Gal) staining, flow cytometry and western blot (WB). The cell viability was tested using CCK-8 kits. Cell apoptosis was detected by Annexin V-EGFP/PI apoptosis detection kit. Cell autophagy was checked using GFP-RFP-LC3 ratiometric plasmid. The roles of VPA in lung aging were investigated by in vivo experiments using H&E and Masson staining, WB, as well as electronic microscope strategies.

Here we identified VPA was able to induce an over-accumulation of reactive oxygen species (ROS) (>1.5 times increasing) and apoptosis (>2 times increasing) of senescent cells. Mechanistically, VPA activated the phospholipid modifying enzyme membrane-bound O-acyltransferase domain-containing protein 1 (MBOAT1), which was repressed during senescence, then promoted mitochondrial autophagy and apoptosis. In addition, VPA was also found to alleviate therapy induced abnormal mitochondria and lung aging phenotype (>1.5 times decreasing of lung fibrosis markers and >2.5 times increasing of naïve/memory CD4+ or CD8+ T cells) in vivo.

Taken together, our study demonstrated that VPA was able to selectively kill senescent cells both in vitro and in vivo, and thus shedding light on new functions and novel potential application of VPA in anti-aging and anti-age-associated diseases.

As an important component of the glomerular filtration membrane, the state of the podocytes is closely related to kidney function, they are also key cells involved in aging and play a central role in the damage caused by renal aging. Therefore, understanding the aging process of podocytes will allow us to understand their susceptibility to injury and identify targeted protective mechanisms. In fact, the process of physiological aging itself can induce podocyte senescence. Pathological stresses, such as oxidative stress, mitochondrial damage, secretion of senescence-associated secretory phenotype, reduced autophagy, oncogene activation, altered transcription factors, DNA damage response, and other factors, play a crucial role in inducing premature senescence and accelerating aging. Senescence-associated-β-galactosidase (SA-β-gal) is a marker of aging, and β-hydroxybutyric acid treatment can reduce SA-β-gal activity to alleviate cellular senescence and damage. In addition, CCAAT/enhancer-binding protein-α, transforming growth factor-β signaling, glycogen synthase kinase-3β, cycle-dependent kinase, programmed cell death protein 1, and plasminogen activator inhibitor-1 are closely related to aging. The absence or elevation of these factors can affect aging through different mechanisms. Podocyte injury is not an independent process, and injured podocytes interact with the surrounding epithelial cells or other kidney cells to mediate the injury or loss of podocytes. In this review, we discuss the manifestations, molecular mechanisms, biomarkers, and therapeutic drugs for podocyte senescence. We included elamipretide, lithium, calorie restriction, rapamycin; and emerging treatment strategies, such as gene and immune therapies. More importantly, we summarize how podocyte interact with other kidney cells.

Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.

Cell culture is a fundamental experimental tool for understanding cell physiology. However, translating these findings to in vivo settings has proven challenging. Replicating donor tissue conditions, including oxygen levels, is crucial for achieving meaningful results. Nevertheless, oxygen culture conditions are often overlooked, particularly in the context of chemotherapy-induced neurotoxicity.

In this study, we investigated the role of oxygen levels in primary neuronal cultures by comparing neuronal performance under cisplatin exposure (1 μg/mL) in supraphysiological normoxia (representing atmospheric conditions in a standard incubator; 18.5% O2) and physioxia (representing physiologic oxygen conditions in nervous tissue; 5% O2). Experiments were also conducted to assess survival, neurite development, senescence marker expression, and proinflammatory cytokine secretion.

Under control conditions, both oxygen concentration conditions exhibited similar behaviors. However, after cisplatin administration, sensory neurons cultured under supraphysiological normoxic conditions show higher mortality, exhibit an evolutionarily proinflammatory cytokine profile over time, and activate apoptotic-regulated neuron death markers. In contrast, under physiological conditions, neurons treated with cisplatin exhibited senescence marker expression and an attenuated inflammatory secretome.

These results underscore the critical role of oxygen in neuronal culture, particularly in studying compounds where neuronal damage is mechanistically linked to oxidative stress. Even at identical doses of evaluated neurotoxic drugs, distinct cellular phenotypic fates can emerge, impacting translatability to the in vivo setting.

Alzheimer's disease (AD), commonly known as senile dementia, is a neurodegenerative disease with insidious onset and gradually worsening course. The brain is particularly sensitive to senescence, and neuronal senescence is an important risk factor for the occurrence of AD. However, the exact pathogenesis between neuronal senescence and AD has not been fully elucidated so far. Neuronal senescence is characterized by the permanent stagnation of the cell cycle, and the changes in its structure, function, and microenvironment are closely related to the pathogenesis and progression of AD. In recent years, studies such as the Aβ cascade hypothesis and Tau protein phosphorylation have provided new strategies for the therapy of AD, but due to the complexity of the etiology of AD, there are still no effective treatment measures. This article aims to deeply analyze the pathogenesis between AD and neuronal senescence, and sort out various existing therapeutic methods, to provide new ideas and references for the clinical treatment of AD.

TP53-induced glycolysis and apoptosis regulator (TIGAR) regulates redox homeostasis and provides the intermediates necessary for cell growth by reducing the glycolytic rate. During cellular senescence, cells undergo metabolic rewiring towards the glycolytic pathway, along with the development of the senescence-associated secretory phenotype (SASP), also known as the secretome. We observed that TIGAR expression increased during replicative senescence following the in vitro expansion of human mesenchymal stromal cells (MSCs) and that TIGAR knockout (KO) decreased SASP factors and triggered premature senescence with decelerated progression. Additionally, TIGAR KO impaired flexible lysosomal movement to the perinuclear region and decreased the autophagic flux of MSCs. Research on the mechanism of lysosomal movement revealed that, while native senescent MSCs presented low levels of Ac-α-tubulin (lysine 40) and increased sirtuin 2 (SIRT2) activity compared with those in growing cells, TIGAR KO-MSCs maintained Ac-α-tubulin levels and exhibited decreased SIRT2 activity despite being in a senescent state. The overexpression of SIRT2 reduced Ac-α-tubulin as a protein target of SIRT2 and induced the positioning of lysosomes at the perinuclear region, restoring the cytokine secretion of TIGAR KO-MSCs. Furthermore, TIGAR expression was positively correlated with SIRT2 activity, indicating that TIGAR affects SIRT2 activity partly by modulating the NAD+ level. Thus, our study demonstrated that TIGAR provides a foundation that translates the regulation of energy metabolism into lysosome positioning, affecting the secretome for senescence development. Considering the functional value of the cell-secretome in aging-related diseases, these findings suggest the feasibility of TIGAR for the regulation of secretory phenotypes.