Search Results (287)

Paclitaxel (PTX), a taxane-derived chemotherapeutic agent, is frequently used in the treatment of breast cancer (BC). Its anticancer effects are primarily associated with microtubule stabilization, disruption of cell-cycle progression, and triggering of apoptotic cell death. In the present study, we investigated the effects of PTX on the expression of genes involved in cancer-related pathways, energy metabolism, and drug resistance in four molecularly distinct BC cell lines: MCF-7, BT-474, SK-BR-3, and MDA-MB-231. The half-maximal inhibitory concentrations (IC₅₀) of PTX in BC cell lines and the non-tumorigenic hTERT-HME1 breast epithelial cell line were determined by the MTT assay to assess cell cytotoxicity. BC cells were exposed to nine different concentrations of PTX for 24, 48, and 72 h to evaluate concentration- and time-dependent effects. Following treatment, total RNA was isolated and converted into cDNA, and RT-qPCR analysis was performed to investigate PTX-mediated alterations in the expression of genes associated with cancer-related pathways. The impact of PTX on the cell-cycle phase distribution and apoptotic cell death was evaluated by flow cytometry. Treatment with PTX for 48 h at concentrations of 12.60 nM in MCF-7, 5.09 nM in BT-474, 16.09 nM in SK-BR-3, and 36.66 nM in MDA-MB-231 cells reduced cell viability and increased apoptosis. PTX treatment also altered the expression of genes involved in apoptosis, cell-cycle regulation, angiogenesis, epithelial–mesenchymal transition, hypoxia-related signaling, energy metabolism, telomere maintenance, and therapy resistance. Collectively, these findings demonstrate that PTX elicits heterogeneous molecular and cellular responses across molecularly distinct BC cell lines, particularly in cell viability, apoptosis, metabolic regulation, and treatment response. These in vitro findings suggest potential molecular mechanisms that could explain why some cells are more sensitive to PTX than others, but further experimental and clinical validation is needed to confirm this. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition in both adults and children. Dysregulated telomere maintenance has been proposed as a mechanism underlying disease progression, although pediatric evidence remains limited and controversial. This study aimed to investigate the relationship between telomere length (TL) and hepato-metabolic features in children with MASLD. A total of 212 pediatric patients with biopsy-proven MASLD and 40 controls were enrolled. Telomere length in leukocytes (LTL) and liver tissue (HTL) was measured using quantitative polymerase chain reaction, and telomerase reverse transcriptase (TERT) mRNA and protein expression were also evaluated. Associations between TL and clinical, metabolic, and perinatal variables were analyzed. Children with MASLD showed significantly shorter LTL and HTL compared to controls. Shorter LTL was observed in more advanced steatohepatitis (MASH) and was associated with fibrosis severity. TERT expression was reduced in patients. LTL was also associated with perinatal factors, including preterm birth and low birthweight. Multivariable analysis identified MASH, fibrosis, and small-for-gestational-age status as independently associated with shorter LTL. In conclusion, LTL is associated with disease severity in pediatric MASLD, particularly fibrosis. These findings support a potential role of telomere dynamics in disease progression, although causal relationships require confirmation in longitudinal studies. Full article

Primary hepatocytes are limited by poor proliferative capacity and a finite replicative lifespan, restricting their utility in long-term in vitro studies. Here, we report the generation of expandable hepatocyte-like progenitor cells from GGTA1 knockout pigs, a large-animal model with reduced immunogenicity. Porcine fibroblasts were directly reprogrammed using a non-integrative episomal system encoding hepatic transcription factors, enabling stable lineage conversion without genomic integration. A simplified two-vector configuration combined with codon optimization enabled evaluation of vector-dependent effects while maintaining genomic safety without viral integration. The resulting cells exhibited hepatocyte-like morphology and gene expression, and transcriptomic analysis revealed a progressive shift toward liver-associated profiles during extended culture. Chromosomal analysis revealed vector-dependent differences in genomic stability, with codon-optimized cells showing increased aneuploidy, indicating a trade-off between proliferative capacity and genomic integrity. The cells also demonstrated sustained proliferative capacity, supported by maintenance of telomere length, increased expression of TERT and MYC, and reduced CDKN1A levels. Importantly, sustained proliferation was supported by complementary evidence from chromosomal and telomeric analyses. Although chromosomal alterations were observed during long-term culture, their biological significance remains to be fully determined. These cells partially recapitulate hepatocyte functions and provide a renewable in vitro system for studies of hepatic biology, proliferation, drug metabolism, toxicity, and repeated in vitro applications. Full article

Astragalus membranaceus, a medicinal plant used in traditional Chinese medicine for centuries, has attracted growing scientific attention for its potential anti-aging and anticancer properties, particularly for skin and bone health. Its key bioactive compounds like astragalosides, cycloastragenol, and its commercial derivative TA-65, have been associated with telomerase activation and telomere maintenance, suggesting a possible role in modulating cellular senescence and tissue repair processes. In addition to the claimed telomere maintenance, A. membranaceus exhibits antioxidant, anti-inflammatory, and DNA-protective activities, properties that contribute to its anti-aging effects. Emerging evidence also suggests that telomerase modulation by A. membranaceus influences cancer cell dynamics, either suppressing tumor progression through immune regulation and apoptosis induction or, in some contexts, potentially promoting tumor growth. This duality highlights the importance of dose, formulation, and targeted application. Clinically, TA-65 has been reported to improve vascular health, bone mineral density, and skin elasticity in aging individuals. Preclinical studies further support its protective effects against osteoporotic bone loss and photoaging-induced dermal degeneration. This review summarizes the phytochemical composition of A. membranaceus and critically evaluates the mechanistic and therapeutic evidence underlying its anti-aging and anticancer actions on skin and bone tissues. It also discusses the pharmacokinetic properties of A. membranaceus, including its absorption, bioavailability, and safety profile. The integration of A. membranaceus into evidence-based senile therapeutic strategies holds promise, but further mechanistic and clinical studies are required to optimize its safety and efficacy. Full article

Human ageing and longevity are increasingly understood as biologically integrated and heterogeneous processes shaped by interactions among genetic susceptibility, epigenetic remodelling, and environmental modulation. This narrative review examines these interconnections within a nutrigenomic framework, with particular emphasis on how inherited variation and epigenetic plasticity may influence responses to ageing-related interventions. A structured literature search was conducted in PubMed, Scopus, Web of Science, and Embase, focusing on English-language studies published during the last 10 years. The review was organized into three major domains: (i) genetic determinants of longevity, (ii) epigenetic mechanisms of ageing, and (iii) intervention-responsive pathways relevant to precision geroscience. Current evidence supports a polygenic model of longevity in which loci such as FOXO3 and APOE show the most consistent human associations, while telomere maintenance, insulin/IGF-1 and mTOR signalling, sirtuins, Klotho, inflammatory mediators, and DNA repair remain biologically important but variably supported at the variant level. Epigenetic mechanisms, including DNA methylation drift, epigenetic clocks, histone modifications, chromatin remodelling, heterochromatin loss, and non-coding RNA regulation, provide an environmentally responsive interface linking genetic background to ageing phenotypes. Nutritional, pharmacological, behavioural, and circadian interventions converge on overlapping molecular pathways involving AMPK, mTOR, FOXO, sirtuins, autophagy, mitochondrial maintenance, and inflammatory signalling, although human evidence remains heterogeneous and biomarker modulation should not be equated with clinically meaningful slowing of organismal ageing. Overall, this review highlights the value of integrating genetics, epigenetics, and intervention biology to support a more cautious and translationally relevant model of healthy ageing. It also underscores the need for precision nutrigeroscience approaches that account for tissue context, baseline physiology, and inter-individual molecular variability. Full article

Osteosarcoma is the most common primary bone tumor in children, adolescents, and young adults, and metastasis remains the main determinant for a poor outcome. We conducted an exploratory retrospective cohort study using formalin-fixed, paraffin-embedded tissue from 97 patients with histopathologically confirmed osteosarcoma treated between 2005 and 2019 to evaluate telomere maintenance mechanisms. To assess alternative lengthening of telomeres (ALT), colocalization of telomeric DNA and promyelocytic leukemia protein (TEL–PML) was evaluated as a tissue-based proxy. TEL–PML colocalization was assessed using combined PML immunofluorescence and telomere DNA PNA-FISH. Furthermore, telomerase reverse transcriptase (TERT) expression was evaluated by immunohistochemistry in relation to metastasis and disease progression. Logistic regression models were adjusted for age, sex, and smoking. TEL–PML was evaluable in 45/97 cases, including 10 positive and 35 negative tumors; the remaining samples were non-evaluable because of non-determinable signal or predominant necrosis. TERT immunohistochemistry was scorable in 58/97 cases, of which 33 were positive. TEL–PML evaluability was associated with amputation specimens, whereas TERT positivity was associated with non-osteoblastic histology and was inversely associated with age. Neither TEL–PML nor TERT was significantly associated with metastasis, recurrence, or death. Exploratory time-to-metastasis curves suggested an earlier increase of metastatic events among TEL–PML-positive cases. However, the small number of positive tumors precludes definitive prognostic interpretation. These hypothesis-generating findings indicate that TEL–PML assessment is feasible in osteosarcoma, but it is strongly influenced by tissue adequacy. On the other hand, TERT immunohistochemistry appears to reflect subtype- and age-related heterogeneity rather than providing robust outcome stratification in this cohort. Full article

C. asiatica (L.) Urban is a medicinal plant widely used in traditional Asian medicine with potential geroprotective properties. Its major bioactive compounds—including asiaticoside, madecassoside, asiatic acid, and madecassic acid—exhibit antioxidant, anti-inflammatory, regenerative, neuroprotective, and cytoprotective activities. Experimental studies demonstrate modulation of signaling pathways involved in oxidative stress, inflammation, apoptosis, extracellular matrix remodeling, and cellular survival, including NF-κB, PI3K/Akt/mTOR, MAPK, Nrf2/HO-1, and TGF-β/Smad pathways. Preclinical evidence further indicates attenuation of cellular senescence, improvement of mitochondrial function, enhanced collagen synthesis, and regulation of cytokine production. In experimental models, C. asiatica has shown beneficial effects on wound healing, skin aging, neuroinflammation, β-amyloid aggregation, neuroplasticity, metabolic dysfunction, and vascular protection. Preliminary preclinical findings also suggest possible effects on telomerase activity and telomere maintenance. However, clinical translation remains limited due to insufficient randomized controlled trials, low oral bioavailability of triterpenoids, variability in extract standardization, and limited pharmacokinetic and long-term safety data. This narrative review summarizes the phytochemistry, molecular mechanisms, pharmacological activities, and potential geroprotective applications of c. asiatica, highlighting its translational relevance in healthy aging and age-related disorders while emphasizing the need for standardized clinical studies. Full article

Background: Migraine is a complex neurovascular disorder with a substantial genetic component, yet many contributing loci remain poorly characterised. Methods: This study investigated the association between 21 biologically prioritised single nucleotide variants (SNVs) and migraine susceptibility in a case-control cohort of 548 individuals of European ancestry, of whom 304 (164 cases, 140 controls) remained after quality control and principal component analysis (PCA). Genotyping was performed using a targeted Sequenom MassARRAY platform, and substantial missingness (mean 30.3% per SNV) was addressed using multiple imputation by chained equations (MICE). Association testing was conducted using three complementary logistic regression frameworks: unadjusted single-variant analysis, covariate-adjusted marginal models, and a multivariable joint model incorporating all SNVs with L2 regularisation. Results: Across analyses, two variants in ASTN2 (rs1052053 and rs6478241) showed the most robust associations with migraine, surviving Bonferroni correction in the joint model (p = 0.001 and p = 0.002, respectively) and false discovery rate (FDR) correction in marginal models (q = 0.003 for both). A third variant, rs7304841 (12p12), demonstrated a risk-increasing effect that reached FDR significance in marginal analysis (q = 0.035) and remained nominally significant in the joint model. In contrast, rs62624978 in CTC1 showed a strong signal in unadjusted analysis (OR = 0.217, p = 0.0014) and remained nominally significant after adjustment (p = 0.011), although it did not survive multiple-testing correction in imputed models. The joint model demonstrated good discriminatory performance (AUC = 0.822), though this is not intended as a predictive tool. Biologically, implicated loci suggest contributions from both neuronal circuit organisation (ASTN2) and telomere and vascular maintenance pathways (CTC1), supporting a broader neurovascular model of migraine susceptibility. Conclusions: These findings are consistent with shared genetic architecture between migraine and microvascular dysfunction, potentially involving endothelial integrity, neurovascular coupling, and cortical excitability mechanisms. Full article

Background: Early-onset Alzheimer’s disease (EOAD) caused by autosomal dominant mutations provides a deterministic framework for investigating genetic modifiers of neurodegeneration. Telomere biology has emerged as a central regulator of genomic stability, cellular ageing, and stress response integration, yet its role in EOAD, particularly in under-represented populations, remains poorly defined. Methods: We conducted a cross-sectional case–control study to evaluate the genetic distribution, disease association, and predicted regulatory consequences of common variants in the telomere maintenance genes TERT and TERC in individuals from Western Mexico. The EOAD group comprised genetically confirmed carriers of the PSEN1 p.Ala431Glu (A431E) founder mutation with clinical EOAD (n = 69), and controls were unrelated individuals without dementia (n = 179). Five common variants were analyzed: rs2242652, rs2853677, rs2736100, and rs10069690 (TERT), and rs12696304 (TERC). Results: Genotype distributions in controls conformed to the Hardy–Weinberg equilibrium. Single-variant analyses showed no significant allele-level associations. Most TERT variants did not show significant allele-level associations with EOAD. However, a preliminary genotype-level enrichment for the GC allele at rs12696304 (TERC) was observed among EOAD cases compared with controls; allele-level associations were not significant. Linkage disequilibrium analysis revealed low r² values (<0.20), supporting variant independence. Population-level allele frequency comparisons revealed ancestry-dependent divergence across loci; in silico functional annotation localised all variants to non-coding regulatory regions. GTEx-based analyses indicated that rs12696304 acts as an eQTL for ACTRT3 in whole blood and pituitary, as well as for LRRC34 in the cerebellar hemisphere, suggesting a potential regulatory network within the TERC locus (3q26.2). Conclusions: Overall, common regulatory variants in TERT did not show strong independent effects on EOAD susceptibility in PSEN1 A431E carriers. However, the convergence of association patterns, functional annotation, and regulatory evidence provides hypothesis-generating support for the TERC locus (3q26.2), particularly rs12696304, as a candidate region for further investigation. Additional studies integrating telomere dynamics, functional validation, and multi-omics analyses are needed to clarify the role of telomere biology in the pathogenesis of autosomal dominant EOAD. Full article

Leaf senescence in perennial species constitutes a highly orchestrated developmental phase that differs fundamentally from the obligate monocarpic senescence of annual plants. While individual organs undergo programmed senescence, prerennial organisms maintain longevity across multiple growing seasons through a sophisticated interplay between endogenous programs and exogenous cues. This review provides a systematic synthesis of the regulatory mechanisms governing leaf senescence in herbaceous perennials (Lolium perenne and Festuca arundinacea) and woody perennials (Populus, Pinus, and Agave). We highlight a multi-layered regulatory landscape, encompassing divergent and conserved pathways in transcriptional orchestration, hormonal crosstalk, metabolic reprogramming, and telomere maintenance. Specific emphasis is placed on how these mechanisms allow for tissue-specific and seasonal adaptation, such as the integration of dormancy signals in woody taxa versus stress-plasticity in perennial grasses. By elucidating these complex frameworks, this review not only advances our fundamental understanding of plant life-span regulation but also provides a theoretical foundation for the molecular breeding of delayed senescence germplasm, offering transformative potential for enhancing agricultural productivity and ecological resilience. Full article

Telomerase reverse transcriptase subunit (TERT) is a key factor involved in telomere maintenance and genome stability, and the decline in its expression is closely related to cellular senescence. In this study, we established TERT monoallelic knockout (TERT+/−) and TERT overexpression (TERT-Over) cell lines in porcine iliac artery endothelial cells (PIEC) using CRISPR/Cas9 and PiggyBac systems to compare the effects of TERT monoallelic knockout versus overexpression on cellular biology. TERT expression and telomere length were assessed via qPCR and Western blot analysis. Cellular proliferation and senescence were evaluated using CCK-8 assays, cell cycle analysis, and SA-β-gal staining. Furthermore, the expression of key genes involved in cell proliferation, metabolism, and related signaling pathways was quantified using q-PCR. The results showed that the TERT mRNA level and telomere length decreased in TERT+/− cells. Meanwhile, we also observed that TERT+/− cells exhibited G1 phase arrest in the cell cycle, with suppressed proliferation and increased SA-β-gal-positive cells. This was accompanied by downregulation of cell cycle and proliferation-related genes, including c-Myc, the E2F family, and Ki-67, as well as downregulation of cell metabolism-related genes, including HIF1α, HK2, GLUT1, the SMAD family, FOXO1, and ATF4. In addition, cytochrome C was downregulated, suggesting activation of mitochondrial apoptotic signaling. Together, these findings indicate impaired proliferative and metabolic activity and are consistent with cellular senescence associated with telomere shortening. In TERT-overexpressing cells, the TERT gene expression and telomere length increase, cell proliferation accelerates, and the survival rate significantly increases under H₂O₂ treatment. This indicated that the overexpression of TERT can enhance resistance to oxidative stress, thus showing a kind of anti-aging phenotype. In conclusion, TERT monoallelic knockout induces cellular senescence-associated phenotypes in porcine endothelial cells, whereas TERT overexpression enhances proliferation and resistance to oxidative stress under the experimental conditions used in this study. The two porcine cell models established here may provide useful experimental materials for studying aging-related mechanisms and evaluating anti-aging interventions in large animals. Further studies are needed to directly determine their effects on cellular replicative lifespan. Full article

G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in gene regulation and genome stability. Among them, the telomeric repeat-containing RNA (TERRA) forms biologically relevant RNA G4s (rG4s) that participate in telomere maintenance and genome stability. Although many ligands targeting DNA G4s have been reported, the recognition and modulation of RNA G4 topologies remain less explored. In this work, we investigated the interaction between TERRA and the spermine-functionalized Zn(II) porphyrin, ZnTCPPSpm4, using UV–vis absorption, fluorescence, resonance light scattering (RLS), and circular dichroism (CD) spectroscopy. In K⁺, where TERRA adopts a parallel G4 conformation, ZnTCPPSpm4 binds through a stepwise mechanism involving external end-stacking, forming discrete supramolecular complexes without altering the native topology. In contrast, under Na⁺ conditions, ZnTCPPSpm4 induces a gradual conformational rearrangement of TERRA from the antiparallel to a parallel-like G4 topology. A CD melting study showed that ZnTCPPSpm4 stabilizes the parallel RNA G4, while slightly destabilizing the antiparallel topology. Overall, our results demonstrate that ZnTCPPSpm4 is not a simple G4 binder, but a topology-selective ligand capable of remodeling TERRA G4 structures, highlighting the potential of metalloporphyrins as RNA G4-targeting scaffolds. Full article

Establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) is an acetyltransferase involved in sister chromatid cohesion. Here we demonstrated that ESCO2 has a new role in telomere maintenance through its binding with telomeric repeat-binding factor TRF1 and TRF2. Loss of ESCO2 induces aberrant DNA damage at telomeres and leads to dramatic telomere shortening. ESCO2 associates with several proteins involved in DNA replication and repair, including BLM, WRN, TopBP1, BRIP1, BRCA1, and MUS81. Moreover, we show that ESCO2 acts in epistasis with BLM in promoting telomere stability. Taken together, our data suggest that ESCO2 is required for the maintenance of telomere stability, presumably by coordinating multiple replication and repair factors to facilitate telomere replication and protection. Full article

Death domain-associated protein 6 (DAXX) was originally identified as a key regulator of Fas receptor-mediated apoptosis. Recent studies have found that it plays a central role in many biological processes, such as cell metabolism, aging and immunity. DAXX, through its nuclear localization and epigenetic regulatory capabilities, participates in the maintenance of metabolic homeostasis, DNA damage repair, and telomere stability, and modulates immune responses by regulating the transcriptional programs of immune-related genes. This review systematically summarizes recent studies that reveal in various biological processes, including cell metabolism, aging, and immunity, and explores its potential as a therapeutic target, providing a theoretical basis for the study of related diseases and clinical interventions. Full article

Tankyrases (TNKS1 and TNKS2) are multifunctional enzymes of the poly(ADP-ribose) polymerase (PARP) family that regulate cellular homeostasis by catalyzing poly(ADP-ribosyl)ation and stabilizing protein–protein interactions through their ankyrin repeat clusters. By engaging with diverse sets of proteins, TNKSs act as central hubs that coordinate signaling and metabolic pathways. In this review, we discuss how TNKS –protein interactions underpin their roles across multiple biological pathways, including Wnt/β-catenin, YAP and SRC signaling, mTORC1 signaling, DNA damage repair (via PARP crosstalk and recruitment of repair factors), telomere maintenance, cell-cycle regulation, glucose metabolism, cytoskeleton rearrangement, autophagy, proteasomal degradation, and apoptosis. We highlight the structural basis of these interactions, emphasizing ankyrin repeat domain recognition motifs and the consequences of TNKS-mediated PARylation on protein stability and localization. By integrating findings from oncology, virology, and metabolism, we illustrate how TNKS functions as a nodal regulator linking genome stability, signaling fidelity, and metabolic control. The interplay between TNKS and these varied pathways is essential for the well-being of the organism, with its dysregulation having severe biological and clinical consequences, which are discussed here. Finally, we consider therapeutic implications of disrupting TNKS–protein interactions, with particular attention paid to selective small-molecule inhibitors and their translational potential in cancer, viral infections, and degenerative diseases. Full article