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At least 19 recordsLinked to original sources
PubMed2025

The impacts of chronic infections on shaping cellular senescence.

Cellular senescence is a fundamental biological process characterized by stable cell cycle arrest, genomic instability, and the acquisition of a proinflammatory secretory phenotype. While senescence is traditionally associated with aging, growing evidence reveals that chronic infections such as viral, bacterial, and protozoan parasites can serve as powerful inducers of senescence, contributing to premature aging and long-term tissue damage. This review explores the diverse mechanisms by which persistent pathogens trigger or sustain senescence in host cells. We highlight how these chronic infections manipulate host DNA repair, mitochondrial dynamics, telomere maintenance, oxidative stress, and immune function to promote senescence and immunosenescence. Emerging findings also reveal how pathogens hijack the host cellular machinery to induce senescence across various tissue types. In many cases, senescence not only enables pathogen persistence but also drives pathological outcomes such as fibrosis, neurodegeneration, cardiomyopathy, and immune exhaustion. Collectively, this emerging evidence highlights a unifying strategy among diverse pathogens: the exploitation of cellular senescence to support chronic infection and promote disease. Understanding how infectious agents drive senescence offers new insights into age-related pathologies and highlights potential therapeutic targets, such as senolytic and senomorphic agents, to mitigate the long-term impacts of chronic infections.

Bacterial infection↗
PubMed1992

Cellular senescence.

The ageing of cells, cellular senescence, is an event that is encountered in all normal cells. Cells grown in vitro have a limited life span and do not grow well after a certain number of divisions. They cease to divide and eventually die. In accordance with this, the life expectancy of an established cell culture depends on the age of the donor. Cells that have undergone immortalization via a crisis period of transformation by chemicals or viruses, as well as malignant cell lines in general, have an ability to divide indefinitely. A distinct form of cell death, apoptosis or programmed cell death, is encountered in many physiological situations like in keratinocyte differentiation.

Animals↗
PubMed2026

Luteolin is associated with alleviation of cigarette smoke-induced cellular senescence and inflammation in mice involving the CREB/c-Fos/NQO1 pathway.

Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD) and is closely associated with cellular senescence. Previous studies have demonstrated the efficacy of luteolin in treating aging-related symptoms. This study aims to elucidate the therapeutic potential of luteolin against CS-induced cellular senescence. Using a CS-exposed mouse model and cigarette smoke extract (CSE) treated mouse lung epithelial cells (TC-1), we demonstrate that luteolin significantly attenuates CS-induced histopathological alterations and inflammatory cytokine release while alleviating cellular senescence. Transcriptome sequencing suggests that NQO1 and Fos may serve as a common molecular target for both CS-induced pathology and luteolin treatment. Subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) enrichment analysis and pathway validation experiments revealed that the cAMP agonist Forskolin inhibits senescence marker expression by activating the CREB pathway, exhibiting a mechanism similar to that of luteolin. Notably, luteolin activation of this pathway may not depend on PKA activation. Ultimately, the study found that luteolin mitigates inflammatory responses and prevents lung epithelial cell senescence via the CREB/c-Fos/NQO1 pathway. These findings not only suggest the pivotal role of NQO1 in regulating CS-induced cellular senescence but also underscore the potential of luteolin as a therapeutic drug.

Animals↗
PubMed2025

Pharmacologic activation of Δ133p53α reduces cellular senescence in progeria patients-derived cells.

BACKGROUND: Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of Δ133p53α, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate Δ133p53α protein levels. METHODS: To investigate whether celastrol and ADZ1981 upregulate endogenous Δ133p53α in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays (Δ133p53α, progerin, and p21WAF1, which mediates p53-induced senescence and is inhibited by Δ133p53α), senescence-associated β-galactosidase (SA-β-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21WAF1 and IL-6). RESULTS: Treatment with celastrol (0.1 μM for 24 h) or AZD1981 (10 μM for 24 h) reproducibly increased Δ133p53α expression and decreased p21WAF1 expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-β-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin. CONCLUSION: Celastrol and ADZ1981 upregulate endogenous Δ133p53α and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which Δ133p53α-regulated senescence plays a role.

Hutchinson-Gilford progeria syndrome↗
PubMedDate not supplied

Molecular genetic studies of cellular senescence.

The limited doubling potential of normal cells in culture was first proposed as a model for cellular aging by Hayflick in 1961. This phenomenon of in vitro cellular senescence is now well documented for a number of different normal human cell types. In an attempt to determine whether random events or programmed genetic processes were responsible for cellular aging, we performed a series of cell fusion studies. We determined that hybrids from fusion of normal with immortal human cells had limited proliferative potential, indicating that senescence is a dominant phenotype. We exploited the fact that immortality was recessive to assign a large number of different immortal human cell lines to four complementation groups for indefinite division. More recently, we have determined that the introduction of a single normal human chromosome 4 into HeLa (cervical carcinoma) cells by microcell fusion induced senescence in this immortal line. The results of these whole cell and microcell fusion studies support the hypotheses that propose senescence results from active, genetic mechanisms.

Cell Division↗
PubMed1979

Cellular senescence and the analysis of generation time distributions.

Generation time analysis by time lapse cinematography is an important method for investigating cellular senescence in culture, but its interpretation is complicated by several types of bias and artifact, including small sample size, cut-off bias, changes in global growth rate, and phase of the population growth cycle. When these factors are considered, interpretation of the data base used by previous investigators changes considerably, and does not reveal any differences in growth behavior between middle and late passage WI-38 cells. Nor does it support the transition probability theory either of cell cycle transit or of culture senescence.

Cell Cycle↗
PubMed2026

Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.

Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated manner, characterized by widespread protein depletion on chromatin. Moreover, components of the cytoplasmic translation machinery are depleted, while mitochondrial proteins display increased insolubility. Autophagic and proteasome activity is compromised in senescent cells along with remodeling of ubiquitin linkages and depletion of ubiquitin E3 ligases. Comparison of the senescent proteome with different pathophysiological cellular states reveals a distinctive senescent signature shaped by changes in the proteostasis network. Collectively, we provide a resource for the exploration of temporally resolved changes in the senescent proteome.

Cellular Senescence↗
PubMed1975

Contributions of cytoplasmic factors to in vitro cellular senescence.

Mass populations of normal human lung fibroblasts were enucleated by centrifugation at greater than or equal to 25,000 g in 4 mug/ml cytochalasin B. The 1 per cent of cells that did not enucleate where rendered nonviable by treatment with mitomycin C. Whole cells were poisoned with a 99 per cent lethal dose of the sulfhydryl reagent iodoacetate. The washed cells were then mixed with the anucleate cytoplasms, fused with inactivated Sendai virus, and planted in rotenone for 20 hours. Whereas normal cells are able to survive this rotenone treatment, the 1 per cent surviving iodoacetate-treated cells cannot withstand this additional stress. However, iodoacetate treated cells that fuse to untreated cytoplasms receive sufficient amounts of active enzymes to allow them to survive. Since this selective system does not rely on using enzymatic mutants, it should permit the selection of hybrids between anucleate cytoplasms and any type of whole cell. Cytoplasmic hybrids were cultured in order to determine their proliferative capacity. The life-spans of cytoplasmic hybrids between young and old cells were compared to those of young/young and old/old controls. Cytoplasmic factors do not appear to control in vitro cellular senescence.

Cell Division↗
PubMed1992

Mitochondrial production of pro-oxidants and cellular senescence.

Mitochondria are the major intracellular producers of O2- and H2O2. The level of oxidative stress in cells, as indicated by the in vivo exhalation of alkanes and the concentration of molecular products of oxy-radical reactions, increases during aging in mammals as well as insects. In this paper, we discuss the relationship between mitochondrial generation of O2- and H2O2, and the aging process. The rate of mitochondrial O2- and H2O2 generation increases with age in houseflies and the brain, heart and liver of rat. This rate has been found to correspond to the life expectancy of flies and to the maximum life span potential (MLSP) of six different mammalian species, namely, mouse, rat, guinea pig, rabbit, pig and cow. In contrast, the level of antioxidant defenses provided by activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione concentration neither uniformly declines with age nor corresponds to variations in MLSP of different mammalian species. It is argued that the rate of mitochondrial O2- and H2O2 generation rather than the antioxidant level may act as a longevity determinant.

Aging↗
PubMed2026

Senotypes define the diverse landscape of senescent cells.

Cellular senescence was initially defined in vitro as a stable cell-cycle arrest that occurs after repeated replication, but it is now recognized as a heterogeneous state shaped by cell type, species, senescence-inducing stress, tissue microenvironment and time. To organize this complexity, we propose the term 'senotype' to classify senescent cells by their inputs, molecular features and functional effects. We outline a practical framework incorporating: (1) cell identity and context; (2) inducing mechanism; (3) temporal stage; (4) multimodal molecular and structural features; and (5) physiological or pathological functions. Experimentally defined senotypes can serve as references for interpreting tissue-derived senotypes, where parameters may be incomplete. Senotypes should be anchored in combinations of core hallmarks (that is, durable cell-cycle arrest, altered secretory profiles, macromolecular or organelle damage, disrupted homeostasis) rather than single markers. Advances in single-cell, spatial, proteomic and computational methods enable rigorous senotype characterization, improving consistency and accelerating development of targeted senotherapeutics.

Cellular Senescence↗
PubMed2026

DNA methylation as a driver of lung fibroblast senescence in COPD.

Cellular senescence is increasingly recognized as a hallmark of chronic obstructive pulmonary disease (COPD), with higher levels in lung fibroblasts from COPD patients. Upon senescence, both hypomethylation and hypermethylation have been described but not in COPD-derived fibroblasts yet. This study investigated whether altered DNA methylation can be a driver of fibroblast senescence in COPD. Genome-wide gene expression and DNA methylation data were generated from primary lung fibroblasts of 11 COPD stage IV patients and 10 matched controls. Gene expression of six well-known senescence genes was compared between COPD and control. COPD-associated senescence genes were correlated with their related CpG sites in an expression quantitative trait methylation (eQTM) analysis. Methylation levels of significant eQTMs were compared between COPD and control fibroblasts. A causal relationship between altered DNA methylation and senescence was validated in 5-Aza-2'-deoxycytidine (5-Aza-2'-dC)-treated primary lung fibroblasts. Gene expression of CDKN1A, CDKN2A, and CDKN2B was higher, while LMNB1 expression was lower in COPD-derived fibroblasts compared to controls. A total of 19 eQTMs were found for the COPD-associated senescence genes CDKN1A (9), CDKN2A (1), and LMNB1 (9). Among these, seven CpG sites (4 for CDKN1A and 3 for LMNB1) exhibited differential methylation between COPD and control. Treatment with 5-Aza-2'-dC led to global demethylation and increased senescence and, importantly, confirmed the association between senescence and hypomethylation of the COPD-associated CpG site cg04924375. Altered DNA methylation is linked to fibroblast senescence in COPD, and seven CpG sites are identified as potential epigenetic regulators of the senescence genes CDKN1A and LMNB1.NEW & NOTEWORTHY This study identifies DNA methylation as a mechanistic contributor to lung fibroblast senescence in chronic obstructive pulmonary disease (COPD). By integrating DNA methylation data with the transcriptomic data of senescence-related genes, we uncovered seven COPD-associated CpG sites linked to the senescence regulators CDKN1A and LMNB1. Pharmacological demethylation induces fibroblast senescence and is consistent with a functional role for hypomethylation at cg04924375, providing new insight into epigenetic regulation of cellular senescence in COPD lung fibroblasts.

Humans↗
PubMed1992

Common senescent cell-specific antibody epitopes on fibronectin in species and cells of varied origin.

The phenomenon of in vitro cellular senescence has been demonstrated in cultured cells derived from humans and various other species. We have previously shown that monoclonal antibodies SEN-1, SEN-2, and SEN-3 react to epitopes on fibronectin that are exposed when human diploid fibroblasts become senescent. We here present results demonstrating that exposure of these epitopes is specific to senescence for a variety of human cells: epidermal keratinocytes, mammary epithelial cells, as well as fibroblasts. Fibronectin from 11 additional species was also analyzed by Western immunoblot for ability to bind the SEN antibodies. SEN-1 bound only human and gorilla fibronectin, whereas SEN-2 and SEN-3 bound fibronectin from those two species as well as the horse, cow, sheep, goat, dog, and chick. None of the antibodies reacted with fibronectin from the rabbit, rat, or mouse. These data indicated a correlation between the ability of the SEN antibodies to bind fibronectin from a particular species and the ability of cells from that species to exhibit a stable senescent phenotype in vitro. Therefore, exposure of this region of fibronectin may be important in the establishment and maintenance of cellular senescence. In addition, the ability of the SEN antibodies to react with fibronectin from a variety of senescent cells emphasizes their usefulness as markers for cellular senescence.

Animals↗
PubMed2026

p21-senescent cells drive pancreatic islet dysfunction through targetable paracrine signaling in type 2 diabetes.

Cellular senescence is an irreversible stress response, which leads to loss of cellular function and remodeling of the cellular secretory profile. In humans, pancreatic β cells undergo cellular senescence during the progression to type 2 diabetes (T2D). However, the mechanism linking β cell senescence to islet dysfunction remains unknown, and thus the therapeutic potential of targeting senescent cells in T2D is not established. Herein, we identified a subpopulation of senescent β cells expressing p21, which emerged early in the progression of T2D in humans and mice. Spatial transcriptomics and proteomics analyses confirmed senescence and loss of cellular identity in this subpopulation in humans. Functional analysis revealed lack of glucose responsiveness, high basal insulin secretion, and transcription of senescence-associated secretory phenotype (SASP) factors. SASP factors from p21+ β cells induced secondary senescence in neighboring cells, characterized by dysfunction and loss of identity. JAK inhibitors counteracted the induction of secondary senescence and restored β cell function in islets from humans with T2D and in mice fed a high-fat diet. These findings reveal the critical role of p21+ β cells in T2D pathogenesis and the therapeutic potential of targeting this pathophysiological process.

Animals↗
PubMed2026

Direct targeting of ORAI1 by ginsenoside Rg3 modulates calcium signaling and senescence-associated AMPK-NRF2 activation.

BACKGROUND: 20(S)-ginsenoside Rg3 (Rg3(S)), a major saponin derived from red ginseng, exhibits diverse biological activities, including antioxidant and anti-senescence effects. However, the direct molecular targets through which Rg3(S) regulates calcium signaling and its role at membrane contact sites during cellular senescence remain largely unknown. METHODS: Plasma membrane (PM)-endoplasmic reticulum (ER) contacts and related protein interactions were analyzed using proximity ligation assays and co-immunoprecipitation. Direct binding of Rg3(S) to ORAI1 was validated using cellular thermal shift assays and microscale thermophoresis. Molecular docking simulations followed by site-directed mutagenesis were used to define critical binding residues. Cytosolic calcium levels and cellular senescence were assessed using calcium imaging and senescence-associated β-galactosidase staining. RESULTS: Rg3(S) increased cytosolic calcium levels independently of ER calcium depletion and was accompanied by a reduction in PM-ER contacts. Rg3(S) directly bound to ORAI1 in a dose-dependent manner, identifying ORAI1 as a previously unrecognized molecular target of ginsenoside Rg3. Molecular docking revealed LYS204 and ILE229 within the extracellular loop of ORAI1 as key residues maintaining this interaction. Mutation of these residues abolished Rg3(S)-induced calcium influx, leading to impaired activation of the AMPK-NRF2 pathway and attenuation of the anti-senescence effect of Rg3(S). CONCLUSION: These findings identify ORAI1 as a key molecular mediator of ginsenoside Rg3(S)-induced calcium signaling linked to cellular senescence. By modulating PM-ER contact sites and cytosolic calcium dynamics, Rg3(S) attenuates senescence, providing new mechanistic insight into the anti-aging potential of ginseng-derived compounds beyond autophagy-centered pathways.

Calcium signaling↗