Chemokines are small molecule secreted proteins that regulate biological processes such as chemotaxis, hematopoiesis, and angiogenesis, typically functioning through binding to G-protein-coupled receptors (GPCRs) on the cell surface. The chemokine family can be classified into four major types based on the differences in their conserved cysteine motifs at the N-terminal: CC, CXC, CX3C, and XC. Among them, the CXC family occupies a central position in the chemokine group. Due to their vital role in biological processes, chemokines have become a key focus of research in various complex diseases. Cell senescence is linked to various factors, including DNA damage and telomere shortening, marked by cell cycle arrest. Senescent cells impact both local and systemic microenvironments via the senescence-associated secretory phenotype (SASP), and CXC chemokines, as critical components of SASP, have been demonstrated to play important roles in various age-related diseases and cancers. However, the role of chemokines, especially CXC chemokines, in cellular senescence and the diseases they mediate has not been fully elucidated. This review summarizes the mechanism of action of CXC chemokines, the latest progress in their role in cellular senescence and related diseases, and discusses the potential of CXC chemokines as biomarkers and therapeutic targets.

Ovarian aging, recognized as one of the initial signs of systemic aging, is marked by a progressive reduction in both the number and quality of oocytes, which has a profound effect on female fertility. In spite of the advancements in assisted reproductive technologies, these methods fail to tackle the fundamental molecular mechanisms that drive ovarian senescence. Recent surveys have underscored the significant role of epitranscriptomic regulation, especially the N6-methyladenosine (m6A) modification, in regulating RNA stability, translation, and cellular functionality. Fat mass and obesity-associated (FTO), a m6A demethylase, has been identified as a crucial regulator of granulosa cell homeostasis, influencing pathways related to oxidative stress, mitochondrial integrity, apoptosis, and cellular senescence. A decrease in FTO expression in aging ovaries is associated with increased m6A levels, destabilization of heterochromatin, dysregulation of transposable elements, and the upregulation of senescence-associated genes such as FOS. Moreover, regulation of genes such as MFN2, MMP2, and P53 by FTO has been shown to sustain mitochondrial function, uphold ERK signaling, and prevent apoptosis in granulosa cells. In summary, these discoveries position FTO as a pivotal element in the molecular framework governing ovarian aging, presenting promising opportunities for therapeutic strategies aimed at preserving female reproductive capacity.

Telomerase and chronic inflammation as central molecular links in aging.

Follistatin‑like protein 1 (FSTL1), a secreted glycoprotein, serves a key role in regulating various biological processes. The present review explores the molecular mechanisms through which FSTL1 influences inflammation, cellular senescence and tumour progression. As a multifunctional protein with both autocrine and paracrine properties, FSTL1 regulates cell survival, proliferation, differentiation and migration, while also modulating immune responses. Evidence indicates that FSTL1 exerts context‑dependent regulatory effects on pathological conditions by modulating signalling pathways, such as TGF‑β, NF‑κB and MAPK. Furthermore, increased FSTL1 expression has been found in the inflammatory synovial tissues of patients with osteoarthritis and it contributes to nucleus pulposus cell inflammation. In conclusion, the distinctive structural features and widespread expression of FSTL1 position it as a key target for understanding the mechanisms underlying inflammation, senescence and tumourigenesis, providing potential options for novel diagnostic and therapeutic strategies for these conditions.

Introduction: Established differences between young versus adult dermal fibroblasts characteristics and functions have been previously reported, which are due to various changes in skin cells with aging such as cellular senescence, etc. However, a comparison of human neonatal versus adult dermal fibroblasts has not been investigated in the production of collagen type I along with testing estrogenic stimulatory compounds like phytoestrogens (equol and its isomers) or the primary natural steroid hormone, 17β-estradiol in short-term cultures. Methods: Experiment 1 tested neonatal human dermal fibroblasts exposed to R-equol, racemic equol, S-equol or 17β-estradiol at 10 nM for 48 hours. Experiment 2 tested adult skin cells in tri-culture (epidermal keratinocytes; dermal fibroblasts and epidermal melanocytes in a 1:1:1 ratio) exposed to R-equol, racemic equol, S-equol or 17β-estradiol at 10 nM or 50 nM for 48 hours. Results: Collagen type I levels in neonatal fibroblasts (in controls and under estrogenic stimulation) displayed a significantly greater robust response compared to the adult tri-cultured cells with the same estrogenic treatments. In general, the neonatal cells compared to adult cells showed more than a seven-fold increase in controls levels and more than an eight-fold increase in the various treatments, however, there were no significant differences among the treatments. Conclusion: The findings of this study should encourage investigators to clearly state the age of human fibroblasts that are utilized in experimental reports, since evidently the results are dependent upon the age of the donor tissue/cells or age range of the derived human dermal cells.

Imidacloprid Exposure at Population-Relevant Doses Induces Hepatic Lipid Dysregulation: Exploring the Role of cGAS-STING Pathway-Mediated Hepatocyte Senescence.

Cellular senescence is a stress-induced cell-cycle arrest that constrains expansion of ultraviolet-damaged keratinocytes yet can remodel the microenvironment. This systematic review evaluated histological and genetic or epigenetic senescence markers in actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). PubMed, Scopus, and Web of Science were searched (January 2005–May 2025); 34 human studies were included. AK showed an early senescent signature with frequent cyclin-dependent kinase inhibitor p21 (p21CIP1) expression (82.1%) and DNA damage signaling, including phosphorylated histone H2AX (gamma-H2AX) positivity (77%). In invasive cSCC, p21CIP1 fell to 43.9% and tumor suppressor p53 immunoreactivity often declined, whereas cyclin-dependent kinase inhibitor p16 (p16INK4a) commonly accumulated without arrest, including cytoplasmic staining at invasion fronts. Reported escape pathways involved c-Jun N-terminal kinase 2 activity and long noncoding RNA PVT1–dependent repression of p21. Telomerase reverse transcriptase (TERT) promoter mutations were prevalent in cSCC (about 50%) and BCC (up to 78%) but uncommon in AK, consistent with late telomerase activation. Study heterogeneity, variable antibody scoring, and limited assessment of senescence-associated beta-galactosidase and secretory mediators restricted cross-study comparability. Standardized, spatially resolved profiling may refine risk stratification and support senescence-targeted prevention and therapy in keratinocyte cancers.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, attention deficit/hyperactivity disorder, intellectual disability, and Down syndrome, are increasingly examined through the lens of aging. Emerging evidence indicates that individuals with NDDs may exhibit accelerated or atypical brain aging, characterized by cognitive decline and increased vulnerability to neurodegenerative conditions such as Alzheimer's and Parkinson's disease. This narrative review synthesizes current findings on biological mechanisms implicated in altered aging trajectories, with emphasis on oxidative stress, chronic neuroinflammation, mitochondrial dysfunction, and cellular senescence. These processes, detectable from early development, mirror pathways involved in neurodegeneration, suggesting shared molecular cascades that increase susceptibility to early aging. Biomarker studies report telomere shortening, elevated plasma glial fibrillary acidic protein and neurofilament light chain levels, and deviations in neuroimaging-derived brain age, supporting the hypothesis of altered biological aging in NDDs. However, the limited number of longitudinal lifespan studies, along with marked heterogeneity in etiology, clinical profiles, and comorbidities, constrains causal inference. Psychosocial and environmental factors, including chronic stress, social exclusion, medical comorbidities, and lifestyle influences, further shape aging outcomes. Integrating biological, behavioral, and environmental markers is essential to advance monitoring and inform early interventions aimed at promoting healthier cognitive and functional aging in neurodivergent populations.

The periodontium is a uniquely dynamic tissue system requiring precise signaling for lifelong adaptation. The canonical Wnt/β-catenin pathway is a master regulator of bone homeostasis; however, its role in the specialized environment of the alveolar bone-marked by rapid turnover, complex mechanical forces, and exposure to the oral microbiome-remains incompletely understood, particularly in the context of aging. This review critically synthesizes evidence on Wnt signaling in alveolar bone remodeling, with a focus on age-related dysregulation, contrasting established paradigms from long bone biology with emerging oral-tissue-specific data. Wnt/β-catenin signaling is essential for periodontal homeostasis, orchestrating osteoblastogenesis and mechanotransduction. Its activity is compartment-specific within the periodontium and is potently suppressed in pathology. Key mechanisms of age-related decline include the upregulation of Wnt antagonists (e.g., sclerostin, DKK1), cellular senescence, altered FoxO-Wnt crosstalk under oxidative stress, and impaired mechanosensing. These changes converge to disrupt regenerative capacity, tipping the balance toward net alveolar bone loss. Therapeutically, sclerostin inhibition demonstrates robust preclinical efficacy in rescuing bone loss in models of periodontitis and estrogen deficiency. However, the potential cardiovascular risks of systemic Wnt activation suggest that redirecting efforts toward localized delivery strategies could be a promising alternative. Aging induces a multifaceted suppression of regenerative Wnt signaling in the periodontium. Modulating the Wnt pathway shows great potential for oral bone regeneration. However, significant challenges exist, especially in designing local delivery systems that are both safe and effective. Overcoming these hurdles is crucial for successful clinical applications. Future research must bridge the gap between skeletal biology and direct oral-specific investigations to enable targeted therapies that preserve periodontal health in an aging population.

Osteoarthritis (OA), a leading cause of disability worldwide, impacts over 300 million people through progressive joint degeneration marked by chronic pain and functional impairment. A key driver of osteoarthritis progression is synovitis, characterized by inflamed synovial tissue harboring senescent fibroblasts and pro-inflammatory macrophages. These senescent cells secrete senescence-associated secretory phenotype (SASP) components, includining cytokines and proteases, which drive macrophage polarization toward a pro-inflammatory M1 state. Simultaneously, M1 macrophages release reactive oxygen species (ROS) and inflammatory mediators, amplifying cellular senescence and establishing a pathological feedback loop. Unfortunately, conventional single-target therapies, such as senolytics or macrophage modulators, fail to address this interdependence vicious cycle. Herein, guided by bioinformatics analysis integrated with clinical and murine specimen data, we developed an easy-to-produce combinatorial nanomedicine platform comprising: (i) synovium-targeting liposomes delivering senolytics to clear senescent fibroblasts and suppress SASP, and (ii) M2 macrophage-derived exosomes to convert M1 macrophages into regenerative M2 phenotypes. In rat OA models, this dual approach combined disrupted the senescence-inflammation cascade, achieving 73.53% synovitis index reduction and 75.00% OARSI score reduction. In summary, by concurrently clearing SASP-producing senescent cells and pro-inflammatory M1 macrophages, our strategy restores joint homeostasis and presents a translatable framework for treating age-related inflammatory disorders.

To investigate dysregulated ion channels and epithelial-to-mesenchymal transition (EMT) genes in Fuchs endothelial corneal dystrophy (FECD) and to identify potential drugs interacting with dysregulated ion channels. Five RNA-sequencing datasets from patients with FECD were analyzed with DESeq2 to identify differentially expressed genes. Dysregulated ion channels and EMT-related genes underwent enrichment analysis and EMT scoring via the KS method. Coexpression patterns were identified using weighted gene coexpression network analysis. A pathway map highlighted altered cellular processes in FECD, and potential drugs were identified using the Drug-Gene Interaction Database. Molecular docking assessed binding of drugs with TRPV4 and TRPM8. Selected gene expression changes were validated by quantitative real-time polymerase chain reaction. Analysis identified 12,550 differentially expressed genes, including 229 ion channels (157 up-regulated, 72 down-regulated) and 502 EMT-related genes (304 up-regulated, 198 down-regulated). Functional enrichment revealed disrupted biological processes including interleukin-1 production and extracellular matrix organization organization. Coexpression analysis uncovered 2 modules linked to apoptosis and senescence. Up-regulated transient receptor potential cation (TRP) cation channels correlated with elevated senescence; altered NFKBIA, NFKB1, and TNFSF10 expression with endothelial apoptosis. We identified 1052 drugs targeting 133 dysregulated ion channels and performed docking analysis for TRP channels. Experimental validation confirmed altered expression of TRPV1, CDKN2A, and KRT7. Dysregulated TRP cation channels contribute to cellular senescence and peripheral sensitization in FECD, whereas altered apoptotic regulators drive corneal endothelial cell death. Most likely, these pathways represent potential targets for treatment of patients with FECD.

Immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have been targeted in cancer therapy, however, the efficacy of these interventions remains limited. Beyond its immune function on T cell surfaces, CTLA-4 is also expressed in various intrinsic cancer cells, where it influences cell proliferation, metastasis, and apoptosis. The present study aimed to investigate the function of CTLA-4 in cancer cells by investigating the consequences of CTLA-4 depletion in melanoma cells. We found that targeting CTLA-4 in melanoma cells inhibited proliferation via the induction of senescence, which was attributed to genomic instability resulting from a decrease in Aurora B expression, leading to the activation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-stimulator of interferon genes (STING) pathway. Notably, DNA-PKcs coordinates CTLA-4 depletion-induced senescence by regulating the STING pathway. Mouse study showed that the tumor suppressive effect of CTLA-4 depletion in allograft cancer models via senescence induction. Furthermore, public data analysis showed a negative correlation between CTLA-4 and DNA-PKcs expressions in patients. Conclusively, CTLA-4-depletion induces senescence via genome instability, which activates DNA-PKcs and ultimately leads to cancer growth regression. These findings suggest that intracellular CTLA-4 targeting can confer to cancer therapy.CTLA-4 depletion-induced senescence in cancer. CTLA-4 depletion-induced senescence in cancer. CTLA-4 deficiency induces senescence via the DNA PKcs-STING-AKT pathway in cancer cells. When CTLA-4 is depleted in cancer cells, the genome becomes unstable due to the reduction of Aurora B expression, then consequently DNA damage occurs accompanied by micronuclei formation in the cytosol. Subsequently, DNA-PKcs is activated and sequentially promotes the STING-AKT-p21 signaling pathway, which mediates cellular senescence and eventually prevents tumor growth.

Inhibiting Endoplasmic Reticulum/Plasma Membrane Contact Ameliorates Endometrial Fibrosis by Preventing Senescence in Endometrial Epithelial Cells.

Failures of the lysosome-autophagy system are a hallmark of ageing and many disease states. As a consequence, interventions that enhance lysosome function are of keen interest in the context of drug development. Throughout the biomedical literature, evolutionary biologists have found cases in which challenges faced by humans in clinical settings have been resolved by non-model organisms adapting to wild environments. Here, we used a primary cell culture approach to survey lysosomal characteristics in species of the genus Mus. We found that fibroblasts from M. spretus, a wild Mediterranean mouse, exhibited elevated lysosomal mass and enzyme activity along with reduced activity of β-galactosidase, a classical marker of cellular senescence, compared with those from M. musculus, a related species adapted to human-associated environments. We propose that classic laboratory models of lysosome function and senescence may reflect characters that diverge from the phenotypes of wild mice. The M. spretus phenotype may ultimately serve as a blueprint for interventions that ameliorate lysosomal dysfunction under conditions of stress and disease.

Psychological stress (or simply "stress") is a major contributor to chronic disease worldwide, affecting 35% of the global population, including younger generations. Furthermore, it plays a significant role in human premature aging; hence, its detrimental effects on people's health compel us to comprehend and control the ways in which psychological stress impacts our bodies, including our skin. For example, flavonoids, a class of polyphenolic phytochemicals, are an important group of plant secondary metabolites and appear as a promising solution. These compounds exhibit a number of general biological activities, such as anti-inflammatory and antioxidant properties, as well as certain skin-specific ones, like wound healing, photoprotection, and the treatment of inflammatory and cancerous disorders associated with the skin. For this reason alone, flavonoids could be regarded as a promising solution. Further, these substances have demonstrated beneficial effects on the different hallmarks of aging, demonstrating their potential as anti-aging agents. They also have the ability to influence hormones linked to stress, which, considering their effects on skin health and aging mechanisms, seems to suggest that flavonoids may be effective ways to mitigate the negative effects of stress on premature skin aging. Therefore, this review seeks to demonstrate the potential of flavonoids as potential anti-aging agents for the skin, either by improving the so-called hallmarks of aging or by directly protecting the skin from external aggressors like UV radiation while reducing the negative effects of psychological stress and its known mediators.

Advances in antiretroviral therapy (ART) have normalized the life expectancy of people living with HIV (PLWH) but have been linked to a premature presentation of age-related comorbidities, including cancer. Telomere length (TL) is a marker of cellular aging and was investigated in blood leukocytes from 78 PLWH on ART, compared with 163 HIV-uninfected controls. The PLWH group was stratified into three subgroups: HIV-only (<em>n</em> = 57), HIV with AIDS-defining cancer (ADC, <em>n</em> = 9), and HIV with NADC (<em>n</em> = 12). Quantitative polymerase chain reaction (qPCR) was used to measure the Relative Telomere Length (RTL), expressed as a T/S ratio. The mean RTL was significantly longer in PLWH (<em>p</em> = 0.0002) and in the HIV/Cancer group (<em>p</em> = 0.0125) than in the control group (<em>n</em> = 163). In addition, the mean RTL was significantly longer in the PLWH group with non-AIDS-defining cancers (NADCs) compared to the control group (<em>p</em> = 0.03). However, no statistical difference between the HIV-only versus the HIV/cancer groups concerning RTL was observed. PLWH with a longer time since diagnosis of HIV infection (>13 years) had a trend towards longer RTL, showing a borderline statistical significance (<em>p</em> = 0.06). Analysis by cancer type showed ADCs were mainly Kaposi’s sarcoma (44.5%) and cervical cancer (33.3%), while NADCs were most commonly anal cancer (25%) and breast cancer (16.7%). These findings support the thesis that long-term ART may be associated with telomere elongation in PLWH, challenging the general perception of telomere shortening in this population. The significantly longer RTL in the NADC group suggests that telomere elongation confers greater cellular replicative potential, which might contribute to the elevated cancer risk in PLWH.

Platinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) and high-grade serous ovarian cancer (HGSOC) treatments, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumor-promoting activities, but both are largely unexplored in these cancers. In this study, using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescence strongly promotes malignant phenotypes and tumor progression, which is stimulated by aging. Mechanistically, we found that a transforming growth factor-beta (TGFβ)-enriched SASP drives pro-proliferative effects through TGFBR1 and AKT/mTOR. TGFBR1 inhibition with galunisertib or senolytic treatment reduces tumor progression driven by cisplatin-induced senescence, and concomitant use of TGFBR1 inhibitors with platinum-based chemotherapy reduces tumor burden and improves survival. Finally, we validate the translational relevance of tumor-promoting TGFβ-enriched SASP using clinical NSCLC and HGSOC samples from patients who received neoadjuvant platinum-based chemotherapy. Together, our findings identify a potential cancer therapy resistance mechanism and provide preclinical proof of concept for future trials.

MASH is a progressive liver disease closely associated with cellular senescence, which is present in more than 80% of hepatocytes in patients who develop hepatocellular carcinoma (HCC). Although MASH affects both sexes, the incidence of MASH-related HCC is two to four times higher in males. Our group has previously described two apoptotic switches during MASH progression and HCC development, implicating the ATP1A1 signalosome in the late switch. Here, we investigated the role of ATP1A1 and sex-specific differences in the early apoptotic switch during preclinical MASH progression. Male and female C57BL/6J mice (7 weeks old) were fed normal mouse chow (NMC) or a high-fat diet (HFD) for 12, 24, or 48 weeks (n = 5/sex/group). Total body weight (TBW) and body composition were assessed by serial measurement and echo-MRI. Plasma was analyzed by non-targeted metabolomics and glutathione profiling using LC-MS/MS. NAFLD activity scores (NAS), hepatic senescence, and apoptosis were quantified in liver tissue. Statistical analyses were performed using GraphPad Prism and R. Males gained greater TBW and lean and fat mass than females (p < 0.05). At 24 W, males demonstrated higher GSH:GSSG ratios and lower ophthalmate levels than females (p < 0.05), consistent with altered redox balance. HFD-fed females showed increased succinic and deoxycholic acid levels, whereas males exhibited higher butyric acid levels across all time points (p < 0.05). Males had a higher mTOR 1 expression at 24 W and P53 at 12 W compared to females on HFD, but a lower Grb2 expression at 24 W (p < 0.05). By 24 W, males had lower fibrosis scores and reduced apoptotic activity compared with females (p < 0.05), despite similar levels of cellular senescence. The expression of ATP1A1, survivin, and SMAC did not differ by sex or diet, although an upregulation trend in both ATP1A1 and survivin was noted in the male-HFD group. There is sexual dimorphism in the response to HFD during the transition from senescence to the apoptosis-first apoptotic switch in MASH progression.

A fundamental question in biology is whether all cells age. Embryonic stem cells (ESCs) defy the norm as rare normal cells capable of indefinite in vitro passage. However, the mechanisms underlying ESC lineage immortality remain unresolved. Using long-term live-cell imaging to follow the fates of single ESCs, we show that ESC lineage renewal is achieved through sporadic entry into a state characterized by the expression of two-cell embryo-specific markers. During this state, cells undergo asymmetric fate divisions, enriching accumulated DNA damage into one daughter lineage that is destined for elimination, while producing a second lineage that reverts to the pluripotent state. Importantly, the latter lineage exhibits signs of rejuvenation, including reduced DNA damage and enhanced chimeric efficiency. These findings underscore the crucial role of asymmetric cell division in maintaining the long-term health of the ESC lineage against mounting damage within individual cells and provide a potential model for studying cellular aging and rejuvenation in mammalian cells.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer and remains a leading cause of cancer-related mortality worldwide. Although, immunotherapy has become a cornerstone of first-line treatment, only 20-30% of patients achieve a durable clinical benefit, largely because of the complexity and heterogeneity of the tumour immune microenvironment. Emerging evidence indicates that cellular senescence, particularly within immune cells, contributes to tumour progression by impairing antitumour immunity; however, its mechanistic role in LUAD remains incompletely understood. We performed an integrative multiomics analysis incorporating genome-wide association studies (GWASs), bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics to characterize immune heterogeneity in LUAD. Cellular senescence was validated by performing staining for senescence-associated β-galactosidase and the canonical markers p16 and p21. SHAP analysis was applied to evaluate the contribution of CXCL16+ macrophages. Functional roles were assessed using coculture assays, in vitro and in vivo tumour models, orthotopic tumour implantation, and multiplex immunofluorescence staining of clinical specimens. A summary data-based on Mendelian randomization analysis integrating GWAS and TCGA data identified CXCL16 as a senescence-associated gene that is causally linked to the LUAD risk. Single-cell RNA sequencing revealed that CXCL16 is predominantly expressed in macrophages, and the pseudotime analysis together with β-galactosidase staining confirmed its association with macrophage senescence. Spatial transcriptomics and immunofluorescence staining showed the marked enrichment of CXCL16+ macrophages in LUAD tissues. The cell-cell communication analysis further revealed a strong association between the number of CXCL16+ macrophages and the activation of the TGF-β signalling pathway within the tumour microenvironment. Functionally, CXCL16+ macrophages promoted LUAD progression via TGF-β signalling, as validated in vitro and in subcutaneous and orthotopic tumour models. Molecular dynamics simulations additionally suggested that LUAD patients with high levels of CXCL16+ macrophage infiltration may exhibit increased sensitivity to bosutinib. CXCL16 promotes macrophage senescence, and senescent CXCL16+ macrophages drive LUAD progression through TGF-β signalling. These findings identify CXCL16+ macrophages as a biologically and therapeutically relevant immune cell population, highlighting a potential target for precision intervention in LUAD.