Myoblast determination protein 1 (MyoD) is a master transcription factor that triggers myogenesis and drives muscle growth.

The aim was to assess acute exercise-induced MyoD mRNA expression in skeletal muscle for young and older (age > 50) adults.

A meta-analysis and systematic review was conducted.

A literature search was conducted for studies reporting MyoD mRNA changes in biopsied human muscle taken within 48 h after exercise. Fifty eligible studies with 822 participants (young 20-35 years; older 53-85 years) were included for meta-analysis.

Significant increases in MyoD mRNA expression in human skeletal muscle were observed 3-12 h post-exercise (standardized mean difference [SMD] = 1.39, p < 0.001), subsiding within 24-48 h (SMD = 0.47, p < 0.001). Older individuals showed a similar time pattern in MyoD mRNA expression post-exercise, but the response is weaker than in younger individuals. Intriguingly, resting levels of MyoD mRNA were higher in older individuals compared to younger individuals in most age-paired studies (SMD = 0.56, p < 0.01). Considering the decline in anabolic hormones during later life, this systematic review highlights age- and sex-related impacts on exercise-induced MyoD mRNA expression in human skeletal muscle, emphasizing the roles of sex hormones and insulin.

Pooled results from the eligible studies suggest a blunted exercise-induced increase in MyoD mRNA in skeletal muscle after age 50, likely due to elevated basal MyoD expression as a compensatory mechanism against persistent catabolic conditions in aging muscle.

Registration number: CRD42023471840 (PROSPERO).

Immunotherapy has transformed the landscape of cancer treatment, with T cell-based strategies at the forefront of this revolution. However, the durability of these responses is frequently undermined by two intertwined phenomena: T cell exhaustion and senescence. While exhaustion is driven by chronic antigen exposure in the immunosuppressive tumor microenvironment, leading to a reversible state of diminished functionality, senescence reflects a more permanent, age- or stress-induced arrest in cellular proliferation and effector capacity. Together, these processes represent formidable barriers to sustained anti-tumor immunity. In this review, we dissect the molecular underpinnings of T cell exhaustion and senescence, revealing how these dysfunctions synergistically contribute to immune evasion and resistance across a range of solid tumors. We explore cutting-edge therapeutic approaches aimed at rewiring the exhausted and senescent T cell phenotypes. These include advances in immune checkpoint blockade, the engineering of "armored" CAR-T cells, senolytic therapies that selectively eliminate senescent cells, and novel interventions that reinvigorate the immune system's capacity for tumor eradication. By spotlighting emerging strategies that target both exhaustion and senescence, we provide a forward-looking perspective on the potential to harness immune rejuvenation. This comprehensive review outlines the next frontier in cancer immunotherapy: unlocking durable responses by overcoming the immune system's intrinsic aging and exhaustion, ultimately paving the way for transformative therapeutic breakthroughs.

Senescent cells are characterized by a persistent cessation of their cell cycle, rendering them valuable targets for anti-tumor strategies in cancer treatment. Numerous studies have explored induced senescence as a promising approach in tumor therapy. Nevertheless, these treatments often come with drawbacks, including adverse side effects and weaker senescence-inducing effects. To address these challenges, we synthesized 223Ra/Ba single-atom nanozyme (SAzyme), wherein Ba SAzyme acts concurrently as a carrier for 223RaCl2, facilitating targeted delivery and minimizing side effects. The 223Ra/Ba SAzyme complex enhances various enzyme-mimicking functions, including catalase (CAT) and peroxidase (POD) activities. Importantly, 223Ra/Ba SAzyme induces cellular senescence and boost anti-tumor immunity. The persistent presence of a senescence-associated secretory phenotype (SASP) in the tumor microenvironment presents risks of immune suppression and tumor recurrence, which can be effectively mitigated by senolytics. As a result, 223Ra/Ba SAzyme were combined with anti-PD-L1 checkpoint blockade to achieve a one-two punch therapy, wherein 223Ra/Ba SAzyme exploits senescence followed by anti-PD-L1 therapy to eradicate senescent cells. This one-two punch strategy approach presents a straightforward and potent intervention for both primary tumors and distant tumor.

Cellular senescence is a stable state of cell cycle arrest caused by telomere shortening or various stresses. After senescence, cells cease dividing and exhibit many age-related characteristics. Unlike the halted proliferation of senescence cells, cancer cells are considered to have unlimited growth potential. When cells display senescence-related features, such as telomere loss or stem cell failure, they can inhibit tumor development. Therefore, inducing cells to enter a senescence state can serve as a barrier to tumor cell development. However, many recent studies have found that sustained senescence of tumor cells or normal cells under certain circumstances can exert environment-dependent effects of tumor promotion and inhibition by producing various cytokines. In this review, we first introduce the causes and characteristics of induced cellular senescence, analyze the senescence process of immune cells and cancer cells, and then discuss the dual regulatory role of cell senescence on tumor growth and senescence-induced therapies targeting cancer cells. Finally, we discuss the role of senescence in tumor progression and treatment opportunities, and propose further studies on cellular senescence and cancer therapy.

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a multifunctional secreted glycoprotein that regulates p16-dependent cellular senescence and cell differentiation and accelerates brown adipogenesis. We recently demonstrated that the CREG1 levels in serum, liver, and kidney were significantly increased in aged wild-type (WT) mice, where age-related renal impairment was further aggravated by promoting cellular senescence. Based on these findings, we hypothesized that the constitutive regulation of CREG1 expression in vivo may affect lifespan. In this study, we revealed that the average lifespan of adipocyte P2-CREG1 transgenic (Tg) mice was shorter than that of WT mice. Moreover, we determined that this reduced lifespan was associated with an increased incidence of liposarcoma (LPS). Our findings indicated that the development of LPS in Tg mice may be driven by chronic inflammation induced by the p19Arf-mouse double minute 2 pathway in white adipose tissue (WAT). These findings indicate that long-term alterations in CREG1 expression in vivo may affect tumor development in the WAT.

Conventional cancer treatments often induce a sustained DNA damage response (DDR) in tumor cells, leading to therapy-induced senescence (TIS), characterized by permanent cell cycle arrest and resistance to apoptosis. These senescent cells secrete senescence-associated secretory phenotypes (SASP), which can promote tumor progression and create an immunosuppressive microenvironment. This study introduces a novel approach to enhance chemotherapy efficacy by using functionalized curcuma-derived extracellular vesicles (DR5-CNV/DOX) to target and eliminate senescent tumor cells and inhibit their SASP. Curcuma-derived extracellular vesicles (CNV) were loaded with the chemotherapeutic drug doxorubicin (DOX) and surface-modified with an antibody targeting death receptor 5 (DR5), which is overexpressed on senescent tumor cells. In vitro experiments demonstrated that DR5-CNV/DOX effectively targeted senescent tumor cells, promoting apoptosis and suppressing SASP production. In vivo studies confirmed the inhibition of epithelial-mesenchymal transition (EMT) initiation, angiogenesis, and modulation of the tumor immune microenvironment, enhancing chemotherapy efficacy and demonstrating promising biocompatibility. This study highlights the potential of plant-derived extracellular vesicles as a novel drug delivery system to overcome senescent tumor cells and their SASP.

To identify robust markers of lung adenocarcinoma (LUAD) using DNA methylation profiles from blood samples informed by tissue lung adenocarcinoma.

This study analyzed 56 LUAD blood samples from patients attending clinic at Siriraj Hospital, Thailand and 51 samples from healthy participants, using 644 tumor and 59 normal tissue methylome datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases for candidate gene identification. We performed comparative analysis to identify DNA methylation (DNAm) changes present in tumors that are also observable in blood, to be taken forward for validation.

DNAm profiling of lung tumor datasets identified 59,639 differentially methylated positions (DMPs), of which 17,251 exhibited a negative correlation with gene expression. In blood samples, 46,680 DMPs were identified among LUAD patients, which were enriched in pathways associated with the ribosome, spliceosome, cell cycle, ubiquitin mediated proteolysis and nucleocytoplasmic transport. Comparative analysis revealed a two DMP epigenetic signature of matching changes in both tissue and blood. This signature offered high diagnostic performance in distinguishing LUAD from normal lung tissue (AUC: 0.77-0.91) and in blood samples from LUAD patients (AUC:0.92-0.96). Similarly high performance was observed in two independent tissue validation datasets (AUC:0.90-0.92).

Our novel two DMP signatures offer robust performance in both lung tissue and blood for the identification of LUAD.

Specific genetic variants in the ATP-binding cassette transporter A7 locus (ABCA7) are associated with an increased risk of Alzheimer's disease (AD). ABCA7 transports lipids from/across cell membranes, regulates Aβ peptide processing and clearance, and modulates microglial and T-cell functions to maintain immune homeostasis in the brain. During AD pathogenesis, neuroinflammation is one of the key mechanisms involved. Therefore, we wanted to investigate the specific role of ABCA7 in microglial activation via the NLRP3 inflammasome.

We developed the first humanized, Cre-inducible ABCA7flx knock-in mouse model, crossbred it with the APPPS1-21 β-amyloidosis model, and generated constitutive ABCA7ko and microglia Cx3cr1-specific conditional ABCA7ko AD mice. The role of ABCA7 was analyzed using histological, biochemical, molecular and mass spectrometry methods.

Constitutive knockout of the Abca7 gene in APPPS1 mice increased the levels of Aβ42 and the number of IBA1+ (microglia) and GFAP+ (astrocytes) cells. Changes in the levels of astrocytes and microglia are associated with the activation of the NLRP3 inflammasome and increased levels of proinflammatory cytokines, such as IL1β and TNFα. Interestingly, microglia-specific ABCA7ko restored Aβ42 peptide levels and IBA1+ and GFAP+ and NLRP3-related gene expression to the original APPPS1 mouse levels. In primary glial cell cultures of APPPS1-hA7ko microglia and APPPS1 astrocytes from newborn pups, we observed that conditioned media from LPS-stimulated microglia was able to induce NLRP3 inflammasome expression and proinflammatory cytokine release in astrocytes.

Our data suggest that ABCA7 transporters regulate the communication between microglia and astrocytes through the NLRP3 inflammasome and the release of proinflammatory cytokines. This regulation implicates ABCA7 as a key driver ultimately involved in the persistence of the inflammatory response observed in AD.

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.

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.

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.

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.

Cellular senescence is characterized by a stable cell cycle arrest and a hypersecretory, proinflammatory phenotype in response to various stress stimuli. Traditionally, this state has been viewed as a tumor-suppressing mechanism that prevents the proliferation of damaged cells while activating the immune response for their clearance. However, senescence is increasingly recognized as a contributing factor to tumor progression. This dual role necessitates a careful evaluation of the beneficial and detrimental aspects of senescence within the tumor microenvironment (TME). Specifically, senescent cells display a unique senescence-associated secretory phenotype that releases a diverse array of soluble factors affecting the TME. Furthermore, the impact of senescence on tumor-immune interaction is complex and often underappreciated. Senescent immune cells create an immunosuppressive TME favoring tumor progression. In contrast, senescent tumor cells could promote a transition from immune evasion to clearance. Given these intricate dynamics, therapies targeting senescence hold promise for advancing antitumor strategies. This review aims to summarize the dual effects of senescence on tumor progression, explore its influence on tumor-immune interactions, and discuss potential therapeutic strategies, alongside challenges and future directions. Understanding how senescence regulates antitumor immunity, along with new therapeutic interventions, is essential for managing tumor cell senescence and remodeling the immune microenvironment.

Expression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD.

CDKN1A expression levels were evaluated in different patient cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a -/- and Cdkn1a +/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH (ethanol) binges, or a DuAL diet (metabolic dysfunction-associated fatty liver disease and alcohol-related liver). Primary hepatocytes were isolated and functional assays performed.

A significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAFLD Activity Score and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a +/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53) contributing to steatosis and inflammation. In contrast, Cdkn1a -/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in fatty acid oxidation and reduction in free fatty acid uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a-deleted animals.

Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAFLD Activity Score and fibrosis in patients with SLD. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in patients with SLD, with and without alcohol consumption.

Expression of p21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD), but the molecular mechanisms remain elusive. Interestingly, in this study we found that Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis, via the AMPK-SIRT3 axis. Translationally, Cdkn1a expression was found to be directly correlated with increased severity of NAFLD Activity Score (NAS) and fibrosis in SLD patients, and therefore, CDKN1A might be used potential theragnostic target for the treatment of metabolically induced SLD, with and without alcohol consumption.

Extensive immune adaptations occur during pregnancy to ensure successful delivery. However, these changes can increase the risk of disease in the mother. Here, we conducted single-cell RNA sequencing on peripheral blood mononuclear cells from pregnant women at different stages of pregnancy to elucidate the dynamic transcriptional changes in the maternal immune system. Gradual reduced cytotoxicity phenotype in highly variable cytotoxic T and natural killer cell types were observed during pregnancy. Reduced T- and B-cell response-related MHC-II and CD40 signaling as well as enhanced protolerance inducible costimulator and activin signaling may underlie the pregnancy-related weakening of adaptive immunity. Conversely, pro-inflammatory genes and pathways were upregulated in monocytes, possibly to compensate for the reduced T-cell response. Moreover, the transition from adaptive immune reduction to activation in late pregnancy in dendritic cells and CD4+ T cells was also detected. Notably, we proposed a novel view of the pro-aging effect of pregnancy from the perspective of immunity, and this effect may be restored postpartum. This work expands our knowledge of pregnancy immunity and may provide insights into the altered disease risks during pregnancy.

Senescence, caused by cell-cycle arrest, is a hallmark of aging. Senescence has also been described in embryogenesis, wound healing, and acute injuries. Sepsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and mortality. Most of the pathophysiology of human sepsis is recapitulated in the mouse model of polymicrobial sepsis, developed by cecal ligation and puncture (CLP). In this report, we demonstrate a rapid onset of cellular senescence in the liver of mice subjected to CLP-induced sepsis, characterized by the upregulation of p21, p53, and other senescence markers, including SA-βgal. Using RNAscope, confocal microscopy, and flow cytometry, we further confirm the emergence of p21-expressing senescence phenotype in the liver 24 h after sepsis induction. Senescence was observed in several cell types in the liver, including hepatocytes, endothelial cells, and macrophages. We determined the landscape of senescence phenotype in murine sepsis by single-cell sequencing, which further ascertained that this cell fate is not confined to any particular cell type but displays a heterogeneous distribution. Furthermore, we observed a significant reduction in mortality following sepsis when mice were treated with senolytics, a combination of dasatinib and quercetin, before the CLP surgery. Our experiments unequivocally demonstrated a rapid development of cellular senescence with sepsis and, for the first time, described the senescence landscape in the sepsis liver and the possible role of senescent cells in the worsening outcome following sepsis.

Tendinopathy is a chronic tendon disease. Mesenchymal stem cells (MSCs), known for their anti-inflammatory properties, may lose effectiveness with extensive culturing. Previous research introduced "small umbilical cord-derived fast proliferating cells" (smumf cells), isolated using a novel minimal cube explant method. These cells maintained their MSC characteristics through long-term culture. Thus, the purpose of the present study was to assess the anti-inflammatory effects of late-passage smumf cells at P10 on tenocytes derived from degenerative rotator cuff tears in a tendinopathic environment.

The mRNA expression with respect to aging of MSCs and secretion of growth factors (GFs) by smumf cells at P10 were measured. mRNA and protein synthesis in tenocytes with respect to the tenocyte phenotype, inflammatory cytokines, and matrix- degradation enzymes were measured. The inflammatory signal pathways involving nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) in tenocytes were also investigated. The proliferative response of degenerative tenocytes to co-culture with smumf cells over 7 days in varying IL-1β induced tendinopathic environments was investigated.

smumf cells at P10 showed no signs of aging compared to those at P3. smumf cells at P10, secreting 2,043 pg/ml of hepatocyte growth factor (HGF), showed a 1.88-fold (p = .002) increase in HGF secretion in a tendinopathic environment. Degenerative tenocytes co-cultured with smumf cells showed significantly increased protein expression levels of collagen type I (Col I) and the Col I/III ratio by 1.46-fold (p < .001) and 1.66-fold (p < .001), respectively. The smumf cells at P10 reduced both mRNA and protein expression levels of matrix metalloproteinases-1, -2, -3, -8, -9, and -13 in tenocytes and attenuated NF-κB (phosphorylated IκBα/IκBα and phosphorylated p65/p65) and MAPK (phosphorylated p38/p38 and phosphorylated JNK/JNK) pathways activated by IL-1β. Removal of IL-1β from the co-culture accelerated the growth of tenocytes by 1.42-fold (p < .001). Removal of IL-1β accelerated tenocyte growth in co-cultures.

Late-passage smumf cells exert anti-inflammatory effects on tenocytes derived from degenerative rotator cuff tears under a tendinopathic environment, primarily through the secretion of growth factors (GFs).

Bone regeneration following a fracture is dependent on multiple factors including skeletal stem cells (SSCs). Recruitment, proliferation, and differentiation of the SSCs is guided by the proteins and metabolites found within the fracture microenvironment. Understanding how intrinsic factors affect the fracture microenvironment has been a topic of ongoing investigation. This study sought to determine whether the levels of select proteins and metabolites within the fracture hematoma would be differentially expressed depending on the age of the patient. We hypothesized that a distinct set of proteins and metabolites found within the fracture hematoma microenvironment would be present at varying levels depending on patient age.

The research study was reviewed and approved by an Institutional Review Board. Hematomas were collected from subjects aged 18 years old or older undergoing surgical intervention for a fracture. Hematoma samples were selected from the biorepository and assigned to one of two fracture groups including young ankle/hindfoot and aged ankle/hindfoot. Protein and metabolite levels within each hematoma were analyzed by liquid chromatography-mass spectrometry.

A total of seven hematomas were included in each the young ankle/hindfoot and aged ankle/hindfoot groups. From the global metabolomic analysis, creatine, 2-methylindoline, and acetyl-L-carnitine were identified as being differentially expressed between both groups. An untargeted metabolomic analysis of the two groups identified significant differences in the levels of an additional 66 metabolites. Proteomic analysis identified 34 proteins that were expressed at significantly different levels.

The level of metabolites and proteins found within the local fracture environment vary by patient age. Future investigations will focus on identifying a role for these proteins and metabolites in bone homeostasis and fracture healing.

N/A, basic science investigation.

The online version contains supplementary material available at 10.1007/s43465-024-01284-3.

Many popular spatial transcriptomics techniques lack single-cell resolution. Instead, these methods measure the collective gene expression for each location from a mixture of cells, potentially containing multiple cell types. Here, we developed scResolve, a method for recovering single-cell expression profiles from spatial transcriptomics measurements at multi-cellular resolution. scResolve accurately restores expression profiles of individual cells at their locations, which is unattainable with cell type deconvolution. Applications of scResolve on human breast cancer data and human lung disease data demonstrate that scResolve enables cell-type-specific differential gene expression analysis between different tissue contexts and accurate identification of rare cell populations. The spatially resolved cellular-level expression profiles obtained through scResolve facilitate more flexible and precise spatial analysis that complements raw multi-cellular level analysis.

Microglia-mediated neuroinflammation has been linked to neurodegenerative disorders. Inflammation and aging contribute to microglial senescence. Microglial senescence promotes the development of neurodegenerative disorders, including Alzheimer's disease (AD). In this study, we investigated the anti-neuroinflammatory and anti-senescence activity of Honokiol (HNK), a polyphenolic neolignane from Magnolia officinalis Rehder & E.H Wilson, in comparison with its synthetic analogue Honokiol Hexafluoro (CH). HNK reduced the pro-inflammatory cell morphology of LPS-stimulated BV2 microglia cells and increased the expression of the anti-inflammatory cytokine IL-10 with an efficacy comparable to CH. HNK and CH were also able to attenuate the alterations in cell morphology associated with cellular senescence in BV2 cells intermittently stimulated with LPS and significantly reduce the activity and expression of the senescence marker ß-galactosidase and the expression of p21 and pERK1/2. The treatments reduced the expression of senescence-associated secretory phenotype (SASP) factors IL-1ß and NF-kB, decreased ROS production, and abolished H2AX over phosphorylation (γ-H2AX) and acetylated H3 overexpression. Senescent microglia cells showed an increased expression of the Notch ligand Jagged1 that was reduced by HNK and CH with a comparable efficacy to the Notch inhibitor DAPT. Overall, our data illustrate a protective activity of HNK and CH on neuroinflammation and cellular senescence in microglia cells involving a Notch-signaling-mediated mechanism and suggesting a potential therapeutic contribution in aging-related neurodegenerative diseases.

Inflammation and stem cell mobilization or homing play pivotal roles in tissue repair and regeneration. This review explores their intricate interplay, elucidating their collaborative role in maintaining tissue homeostasis and responding to injury or disease. While examining the fundamentals of stem cells, we detail the mechanisms underlying inflammation, including immune cell recruitment and inflammatory mediator release, highlighting their self-renewal and differentiation capabilities. Central to our exploration is the modulation of hematopoietic stem cell behavior by inflammatory cues, driving their mobilization from the bone marrow niche into circulation. Key cytokines, chemokines, growth factors, and autophagy, an intracellular catabolic mechanism involved in this process, are discussed alongside their clinical relevance. Furthermore, mesenchymal stem cell homing in response to inflammation contributes to tissue repair processes. In addition, we discuss stem cell resilience in the face of inflammatory challenges. Moreover, we examine the reciprocal influence of stem cells on the inflammatory milieu, shaping immune responses and tissue repair. We underscore the potential of targeting inflammation-induced stem cell mobilization for regenerative therapies through extensive literature analysis and clinical insights. By unraveling the complex interplay between inflammation and stem cells, this review advances our understanding of tissue repair mechanisms and offers promising avenues for clinical translation in regenerative medicine.

Senescent cells accumulate with age and contribute to age-related diseases and organ dysfunctions. Early evidence suggests that removal of senescent cells using senolytic drugs improves the aging phenotype in mice and may improve the health of individuals with chronic diseases. Signs of skin aging, including wrinkles, and sagging, occur largely due to the accumulation of senescent fibroblasts within the dermis; However, there is currently no skin treatment that eliminates senescent cells. In this study, human fibroblasts subjected to replicative aging and ionizing radiation exposure are used to screen plant extracts for potential senescent cell-destructive and/or senescent cell-forming activities. Angelica acutiloba-a traditional Chinese herbal medicine-selectively kills senescent cells without affecting the proliferating cells. Among the major components of this herb, ligustilide shows promising senescent cell-destructive properties, and selectively eliminates senescent cells by inducing an apoptosis. Moreover, ligustilide markedly inhibits senescence-associated secretory phenotypes. Administration of ligustilide to mouse skin eliminates senescent cells and increases dermal collagen density and subcutaneous adipose tissue content; it selectively promotes death of senescent cells without affecting non-senescent cells. These results provide evidence that a natural compound-ligustilide-may exhibit therapeutic effects on the skin aging phenotype by specifically inducing apoptosis in senescent cells.

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.

Our skin provides a physical and immunological barrier against dehydration and environmental insults ranging from microbial attacks, toxins and UV irradiation to wounding. Proper functioning of the skin barrier largely depends on the interplay between keratinocytes- the epithelial cells of the skin- and immune cells. Two spatially distinct populations of keratinocyte stem cells (SCs) maintain the epidermal barrier function and the hair follicle. These SCs are inherently long-lived, but cell death can occur within their niches and impacts their functionality. The default cell death programme in skin is apoptosis, an orderly and non-inflammatory suicide programme. However, recent findings are shedding light on the significance of various modes of regulated necrotic cell death, which are lytic and can provoke inflammation within the local skin environment. While the presence of dying cells was generally regarded as a mere consequence of inflammation, findings in various human dermatological conditions and experimental mouse models of aberrant cell death control demonstrated that cell death programmes in keratinocytes (KCs) can drive skin inflammation and even tumour initiation. When cells die, they need to be removed by phagocytosis and KCs can function as non-professional phagocytes of apoptotic cells with important implications for their SC capacities. It is becoming apparent that in conditions of heightened SC activity, distinct cell death modalities differentially impact the different skin SC populations in their local niches. Here, we describe how regulated cell death modalities functionally affect epidermal SC niches along with their relevance to injury repair, inflammatory skin disorders and cancer.

Cellular senescence is essential to TME development, progression, and remodeling. Few studies have examined cellular senescence in HCC after TACE. Investigating the relationship between cellular senescence, post-TACE prognosis, the TME, and immune treatment responses is crucial.

We analyzed the GSE104580 dataset to identify DEGs. A cellular senescence-related signature was developed using LASSO Cox regression in the GSE14520 dataset and validated in the ICGC dataset. High- and low-risk subgroups were compared using GSVA and GSEA. Correlation studies were conducted to explore the relationship between the prognostic model, immune infiltration, immunotherapy response, and drug sensitivity.

A cellular senescence-related signature comprising FOXM1, CDK1, CHEK1, and SERPINE1 was created and validated. High-risk patients showed significantly lower OS than low-risk patients. High-risk patients had carcinogenetic pathways activated, immunosuppressive cells infiltrated, and immunomodulatory genes overexpressed. They also showed higher sensitivity to EPZ004777_1237 and MK-2206_1053 and potential benefits from GSK-3 inhibitor IX, nortriptyline, lestaurtinib, and JNK-9L.

This study constructed a cellular senescence-related signature that could be used to predict HCC patients' responses to and prognosis after TACE treatment, aiding in the development of personalized treatment plans.

As the most common cause of dementia, Alzheimer's disease (AD) is characterized by neurodegeneration and synaptic loss with an increasing prevalence in the elderly. Increased inflammatory responses triggers brain cells to produce pro-inflammatory cytokines and accelerates the Aβ accumulation, tau protein hyper-phosphorylation leading to neurodegeneration. Therefore, in this paper, we discuss the current understanding of how inflammation affects brain activity to induce AD pathology, the inflammatory biomarkers and possible therapies that combat inflammation for AD.

Helicobacter pylori ( H. pylori ), a spiral-shaped bacterium, is closely associated with chronic, progressive gastric mucosal damage, gastric atrophy, and even gastric cancer (GC). An increasing number of studies have addressed the correlation between long noncoding RNAs (lncRNAs) and H. pylori pathogenicity in GC.

In this study, we found that the expression level of LINC00659 gradually increased in the progression from atrophic gastritis, intestinal metaplasia, and dysplasia to GC in H. pylori -infected patients. Thus, we aimed to further explore the function of LINC00659 in the progression of gastritis to cancer under H. pylori infection.

StarBase predictions, ribonucleic acid (RNA)-binding protein immunoprecipitation assays, and gene ontology functional annotation (GO)/Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed to identify the RNA-binding proteins of LINC00659; moreover, qRT‒PCR, western blotting, RNA interference, and immunofluorescence assays were used to investigate the function of LINC00659.

LINC00659 bound directly to the RNA-binding protein polypyrimidine tract-binding protein (PTBP1). Importantly, qRT‒PCR and western blot assays demonstrated that PTBP1 expression increased in the progression from inflammation to cancer in the stomach of H. pylori -infected patients and H. pylori -infected GES-1 cells. However, LINC00659 knockdown downregulated PTBP1 expression and inhibited PTBP1 binding under H. pylori infection. Finally, LINC00659 knockdown significantly reduced H. pylori -induced human gastric epithelial cell senescence and suppressed interleukin (IL)-6 and IL-8 secretion by reducing the phosphorylation level of NF-κB p65.

This study indicated that LINC00659 may have the potential to be a novel promising prognostic and therapeutic marker for H. pylori -associated gastric diseases.

Gastric cancer (GC) and type 2 diabetes (T2D) contribute to each other, but the interaction mechanisms remain undiscovered. The goal of this research was to explore shared genes as well as crosstalk mechanisms between GC and T2D.

The Gene Expression Omnibus (GEO) database served as the source of the GC and T2D datasets. The differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) were utilized to identify representative genes. In addition, overlapping genes between the representative genes of the two diseases were used for functional enrichment analysis and protein-protein interaction (PPI) network. Next, hub genes were filtered through two machine learning algorithms. Finally, external validation was undertaken with data from the Cancer Genome Atlas (TCGA) database.

A total of 292 and 541 DEGs were obtained from the GC (GSE29272) and T2D (GSE164416) datasets, respectively. In addition, 2,704 and 336 module genes were identified in GC and T2D. Following their intersection, 104 crosstalk genes were identified. Enrichment analysis indicated that "ECM-receptor interaction," "AGE-RAGE signaling pathway in diabetic complications," "aging," and "cellular response to copper ion" were mutual pathways. Through the PPI network, 10 genes were identified as candidate hub genes. Machine learning further selected BGN, VCAN, FN1, FBLN1, COL4A5, COL1A1, and COL6A3 as hub genes.

"ECM-receptor interaction," "AGE-RAGE signaling pathway in diabetic complications," "aging," and "cellular response to copper ion" were revealed as possible crosstalk mechanisms. BGN, VCAN, FN1, FBLN1, COL4A5, COL1A1, and COL6A3 were identified as shared genes and potential therapeutic targets for people suffering from GC and T2D.

Senescent cell accumulation in the pulmonary niche is associated with heightened susceptibility to age-related disease, tissue alterations, and ultimately a decline in lung function. Our current knowledge of senescent cell-extracellular matrix (ECM) dynamics is limited, and our understanding of how senescent cells influence spatial ECM architecture changes over time is incomplete. Herein is the design of an in vitro model of senescence-associated extracellular matrix (SA-ECM) remodeling using a senescent lung fibroblast-derived matrix that captures the spatiotemporal dynamics of an evolving senescent ECM architecture. Multiphoton second-harmonic generation microscopy was utilized to examine the spatial and temporal dynamics of fibroblast SA-ECM remodeling, which revealed a biphasic process that established a disordered and heterogeneous architecture. Additionally, we observed that inhibition of transforming growth factor-β signaling during SA-ECM remodeling led to improved local collagen fiber organization. Finally, we examined patient samples diagnosed with pulmonary fibrosis to further tie our results of the in vitro model to clinical outcomes. Moreover, we observed that the senescence marker p16 is correlated with local collagen fiber disorder. By elucidating the temporal dynamics of SA-ECM remodeling, we provide further insight on the role of senescent cells and their contributions to pathological ECM remodeling.

Cellular senescence and chronic inflammation in response to aging are considered to be indicators of brain aging; they have a great impact on the aging process and are the main risk factors for neurodegeneration. Reviewing the microglial response to aging and neuroinflammation in neurodegenerative diseases will help understand the importance of microglia in neurodegenerative diseases. This review describes the origin and function of microglia and focuses on the role of different states of the microglial response to aging and chronic inflammation on the occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Huntington's chorea, and Parkinson's disease. This review also describes the potential benefits of treating neurodegenerative diseases by modulating changes in microglial states. Therefore, inducing a shift from the neurotoxic to neuroprotective microglial state in neurodegenerative diseases induced by aging and chronic inflammation holds promise for the treatment of neurodegenerative diseases in the future.

Higher intensity exercise, despite causing more tissue damage, improved aging conditions. We previously observed decreased p16INK4a mRNA in human skeletal muscle after high-intensity interval exercise (HIIE), with no change following equivalent work in moderate-intensity continuous exercise. This raises the question of whether the observed senolytic effect of exercise is mediated by inflammation, an immune response induced by muscle damage. In this study, inflammation was blocked using a multiple dose of ibuprofen (total dose: 1200 mg), a commonly consumed nonsteroidal anti-inflammatory drug (NSAID), in a placebo-controlled, counterbalanced crossover trial. Twelve men aged 20-26 consumed ibuprofen or placebo before and after HIIE at 120% maximum aerobic power. Multiple muscle biopsies were taken for tissue analysis before and after HIIE. p16INK4a+ cells were located surrounding myofibers in muscle tissues. The maximum decrease in p16INK4a mRNA levels within muscle tissues occurred at 3 h post-exercise (-82%, p < 0.01), gradually recovering over the next 3-24 h. A concurrent reduction pattern in CD11b mRNA (-87%, p < 0.01) was also found within the same time frame. Ibuprofen treatment attenuated the post-exercise reduction in both p16INK4a mRNA and CD11b mRNA. The strong correlation (r = 0.88, p < 0.01) between p16INK4a mRNA and CD11b mRNA in muscle tissues suggests a connection between the markers of tissue aging and pro-inflammatory myeloid differentiation. In conclusion, our results suggest that the senolytic effect of high-intensity exercise on human skeletal muscle is mediated by acute inflammation.

The myostatin (MSTN) gene also regulates the developmental balance of skeletal muscle after birth, and has long been linked to age-related muscle wasting. Many rodent studies have shown a correlation between MSTN and age-related diseases. It is unclear how MSTN and age-associated muscle loss in other animals are related. In this study, we utilized MSTN gene-edited bovine skeletal muscle cells to investigate the mechanisms relating to MSTN and muscle cell senescence. The expression of MSTN was higher in older individuals than in younger individuals. We obtained consecutively passaged senescent cells and performed senescence index assays and transcriptome sequencing. We found that senescence hallmarks and the senescence-associated secretory phenotype (SASP) were decreased in long-term-cultured myostatin inactivated (MT-KO) bovine skeletal muscle cells (bSMCs). Using cell signaling profiling, MSTN was shown to regulate the SASP, predominantly through the cycle GMP-AMP synthase-stimulator of antiviral genes (cGAS-STING) pathway. An in-depth investigation by chromatin immunoprecipitation (ChIP) analysis revealed that MSTN influenced three prime repair exonuclease 1 (TREX1) expression through the SMAD2/3 complex. The downregulation of MSTN contributed to the activation of the MSTN-SMAD2/3-TREX1 signaling axis, influencing the secretion of SASP, and consequently delaying the senescence of bSMCs. This study provided valuable new insight into the role of MSTN in cell senescence in large animals.

Immunosenescence increases the risk and severity of diseases in elderly individuals and leads to impaired vaccine-induced immunity. With aging of the global population and the emerging risk of epidemics, developing adjuvants and vaccines for elderly individuals to improve their immune protection is pivotal for healthy aging worldwide. Deepening our understanding of the role of immunosenescence in vaccine efficacy could accelerate research focused on optimizing vaccine delivery for elderly individuals. In this review, we analyzed the characteristics of immunosenescence at the cellular and molecular levels. Strategies to improve vaccination potency in elderly individuals are summarized, including increasing the antigen dose, preparing multivalent antigen vaccines, adding appropriate adjuvants, inhibiting chronic inflammation, and inhibiting immunosenescence. We hope that this review can provide a review of new findings with regards to the impacts of immunosenescence on vaccine-mediated protection and inspire the development of individualized vaccines for elderly individuals.

Extracellular vesicles (EVs) are small lipid bilayers released from cells that contain cellular components such as proteins, nucleic acids, lipids, and metabolites. Biological information is transmitted between cells via the EV content. Cancer and senescent cells secrete more EVs than normal cells, delivering more information to the surrounding recipient cells. Cellular senescence is a state of irreversible cell cycle arrest caused by the accumulation of DNA damage. Senescent cells secrete various inflammatory proteins known as the senescence-associated secretory phenotype (SASP). Inflammatory SASP factors, including small EVs, induce chronic inflammation and lead to various age-related pathologies. Recently, senolytic drugs that selectively induce cell death in senescent cells have been developed to suppress the pathogenesis of age-related diseases. This review describes the characteristics of senescent cells, the functions of EVs released from senescent cells, and the therapeutic effects of EVs on age-related diseases. Understanding the biology of EVs secreted from senescent cells will provide valuable insights for achieving healthy longevity in an aging society.

We have previously shown that PM10 exposure causes oxidative stress and reduces Nrf2 protein levels, and SKQ1 pre-treatment protects against this damage in human corneal epithelial cells (HCE-2). The current study focuses on uncovering the mechanisms underlying acute PM10 toxicity and SKQ1-mediated protection. HCE-2 were pre-treated with SKQ1 and then exposed to 100 μg/mL PM10. Cell viability, oxidative stress markers, programmed cell death, DNA damage, senescence markers, and pro-inflammatory cytokines were analyzed. Nrf2 cellular location and its transcriptional activity were determined. Effects of the Nrf2 inhibitor ML385 were similarly evaluated. Data showed that PM10 decreased cell viability, Nrf2 transcriptional activity, and mRNA levels of antioxidant enzymes, but increased p-PI3K, p-NFκB, COX-2, and iNOS proteins levels. Additionally, PM10 exposure significantly increased DNA damage, phosphor-p53, p16 and p21 protein levels, and β-galactosidase (β-gal) staining, which confirmed the senescence. SKQ1 pre-treatment reversed these effects. ML385 lowered the Nrf2 protein levels and mRNA levels of its downstream targets. ML385 also abrogated the protective effects of SKQ1 against PM10 toxicity by preventing the restoration of cell viability and reduced oxidative stress. In conclusion, PM10 induces inflammation, reduces Nrf2 transcriptional activity, and causes DNA damage, leading to a senescence-like phenotype, which is prevented by SKQ1.

Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium to maintain organismal homeostasis. Aging, however, significantly reduces intestinal regenerative capacity. While cellular senescence is a key feature of the aging process, little is known about the in vivo effects of senescent cells on intestinal fitness. Here, we identify the accumulation of senescent cells in the aging gut and, by harnessing senolytic CAR T cells to eliminate them, we uncover their detrimental impact on epithelial integrity and overall intestinal homeostasis in natural aging, injury and colitis. Ablation of intestinal senescent cells with senolytic CAR T cells in vivo or in vitro is sufficient to promote the regenerative potential of aged ISCs. This intervention improves epithelial integrity and mucosal immune function. Overall, these results highlight the ability of senolytic CAR T cells to rejuvenate the intestinal niche and demonstrate the potential of targeted cell therapies to promote tissue regeneration in aging organisms.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high heterogeneity, poor prognosis, and a low 10-year survival rate of less than 50%. Although cellular senescence displays extensive effects on cancer, the comprehensions of cellular senescence-related characteristics in TNBC patients remains obscure.

Single-cell RNA sequencing (scRNA-seq) data were analyzed by Seurat package. Scores for cellular senescence-related pathways were computed by single-sample gene set enrichment analysis (ssGSEA). Subsequently, unsupervised consensus clustering was performed for molecular cluster identification. Immune scores of patients in The Cancer Genome Atlas (TCGA) dataset and associated immune cell scores were calculated using Estimation of STromal and Immune cells in MAlignantTumours using Expression data (ESTIMATE) and Microenvironment Cell Populations-counter (MCP-counter), Tumor Immune Estimation Resource (TIMER) and Estimating the Proportion of Immune and Cancer cells (EPIC) methods, respectively. Immunotherapy scores were assessed using TIDE. Furthermore, feature genes were identified by univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses; these were used to construct a risk model. Additionally, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and transwell assay were conducted for in vitro validation of hub genes.

TNBC was classified into three subtypes based on cellular senescence-related pathways as clusters 1, 2, and 3. Specifically, cluster 1 showed the best prognosis, followed by cluster 2 and cluster 3. The levels of gene expression in cluster 2 were the lowest, whereas these were the highest in cluster 3. Moreover, clusters 1 and 3 showed a high degree of immune infiltration. TIDE scores were higher for cluster 3, suggesting that immune escape was more likely in patients with the cluster 3 subtype who were less likely to benefit from immunotherapy. Next, the TNBC risk model was constructed and validated. RT-qPCR revealed that prognostic risk genes (MMP28, ACP5 and KRT6A) were up-regulated while protective genes (CT83) were down-regulated in TNBC cell lines, validating the results of the bioinformatics analysis. Meanwhile, cellular experiments revealed that ACP5 could promote the migration and invasion abilities in two TNBC cell lines. Finally, we evaluated the validity of prognostic models for assessing TME characteristics and TNBC chemotherapy response.

In conclusion, these findings help to assess the efficacy of targeted therapies in patients with different molecular subtypes, have practical applications for subtype-specific treatment of TNBC patients, and provide information on prognostic factors, as well as guidance for the revelation of the molecular mechanisms by which senescence-associated genes influence TNBC progression.

Pancreatic cancer is a highly malignant and invasive gastrointestinal tumor that is often diagnosed at an advanced stage with a poor prognosis and high mortality. Currently, carbohydrate antigen199(CA199) is the only biomarker approved by the FDA for the diagnosis of pancreatic cancer, but it has great limitations. Growth differentiation factor-15 (GDF-15) is expected to be a novel biomarker for the diagnosis, efficacy prediction, and prognosis assessment of pancreatic cancer patients. In this paper, we searched the keywords GDF-15, macrophage inhibitory cytokine-1 (MIC-1), CA199, pancreatic cancer, and tumor markers in PubMed and Web of Science, searched related articles, and read and analyzed the retrieved papers. Finally, we systematically described the characteristics, mechanism of action, and clinical value of GDF-15, aiming to provide help for the detection and treatment of pancreatic cancer.