Search Results (236)

The accumulation of senescent cells, characterized by a pro-inflammatory secretory phenotype (SASP), metabolic dysfunction, and irreversible cell cycle arrest, is a driving force behind numerous age-related pathologies and directly undermines the therapeutic potential of mesenchymal stem cells (MSCs). In this study, we explore the senotherapeutic potential of urolithin A, a renowned antioxidant compound, in human adipose-derived MSCs (AD-hMSCs). Our findings reveal that urolithin A is non-cytotoxic to senescent AD-hMSCs and significantly suppresses the SASP by reducing the secretion of key pro-inflammatory mediators, including MCP1, PAI2, and IL1B. In addition, it was demonstrated that urolithin A was capable of reversing the decline in H3K9me3 levels induced by Doxorubicin treatment, restoring them to levels observed in untreated cells. The results of this study suggest that urolithin A functions as a senomorphic agent, capable of modulating cellular senescence. Moreover, its combination with senolytic therapies has the potential to yield novel and effective treatment strategies for regenerative medicine. Full article

Chronological age (C-Age), determined by the time elapsed since the birth of an individual, is considered one of the main risk factors for the onset and prognosis of multiple sclerosis (MS). Biological age (B-Age), in contrast, conditioned by genetic, lifestyle, comorbidity, and environmental factors, defines the aging of tissues that contributes to the decline of organ function, the loss of functional reserve, and decrease in the regenerative capacity. In this context immunosenescence is increasingly evidenced as a factor that contributes to the MS progressive course and loss of efficacy of MS drugs. B-Age can be estimated through different measurement strategies such as telomere length, epigenetic clocks and biomarker composites. These biomarkers are gaining attention in MS research since they seem to be associated with disability progression and are modulated by lifestyle interventions. This review summarizes the roles of C-Age and B-Age in MS and highlights implications for prognosis and therapeutic development. Full article

Reactive oxygen species (ROS) and mitochondrial dysfunction play a major role in skin aging. Due to Tropaeolum majus’ suggested protective actions against ROS, a link between T. majus extract and increased cytoglobin (CYGB) expression was evaluated for cultured skin cells. Human dermal fibroblasts and keratinocytes were treated with 0.5% v/v T. majus extract and the effect of this treatment on the expression of CYGB and on a range of cellular markers of aging were evaluated. In fibroblasts, the treatment with the extract was associated with an increase in CYGB levels. It also decreased ROS concentrations, improved the function of mitochondria, and stimulated the synthesis of collagen and elastin. Moreover, it downregulated a set of genes controlling the terminal differentiation of keratinocytes. T. majus extract activates oxygen transport within natural killer cells and thus enhances their activity, suggesting a potential senolytic effect. This extract seemed to exert a protective effect on various aging pathways such as ROS production, mitochondrial dysfunction, and collagen homeostasis, playing a promising role against skin aging. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder involving free radical overload, neuroinflammation, and a deranged cell stress response. In particular, the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system, a key component of the brain stress response, is currently regarded as a promising therapeutic approach for AD. Cellular senescence, defined as a process of cell cycle arrest due to oxidative stress, DNA damage, mitochondrial dysfunction, and oncogene activation, has been identified as a pivotal factor in the development of AD. A mounting body of research has demonstrated that the accumulation of senescent cells in the brain can lead to a variety of neurotoxic effects, including synaptic dysfunction, the destruction of the blood–brain barrier, and impaired remyelination. Finally, the release of proinflammatory molecules by senescent cells further exacerbates neurodegeneration. A considerable number of xenobiotics, with well-documented neuroprotective effects through the activation of the HO/BVR system, have been shown to modulate pathways involved in cellular senescence outside the brain. Unfortunately, a direct link between HO/BVR and cellular senescence in AD is yet to be established. This compelling evidence should motivate basic and clinical researchers to address such a significant gap in knowledge and conduct novel studies in this field. Full article

Cardiovascular aging is a multifactorial and systemic process that contributes significantly to the global burden of cardiovascular disease, particularly in older populations. This review explores the molecular and cellular mechanisms underlying cardiovascular remodeling in age-related conditions such as hypertension, atrial fibrillation, atherosclerosis, and heart failure. Central to this process are chronic low-grade inflammation (inflammaging), oxidative stress, cellular senescence, and maladaptive extracellular matrix remodeling. These hallmarks of aging interact to impair endothelial function, promote fibrosis, and compromise cardiac and vascular integrity. Key molecular pathways—including the renin–angiotensin–aldosterone system, NF-κB, NLRP3 inflammasome, IL-6, and TGF-β signaling—contribute to the transdifferentiation of vascular cells, immune dysregulation, and progressive tissue stiffening. We also highlight the role of the senescence-associated secretory phenotype and mitochondrial dysfunction in perpetuating inflammatory and fibrotic cascades. Emerging molecular therapies offer promising strategies to reverse or halt maladaptive remodeling. These include senescence-targeting agents (senolytics), Nrf2 activators, RNA-based drugs, and ECM-modulating compounds such as MMP inhibitors. Additionally, statins and anti-inflammatory biologics (e.g., IL-1β inhibitors) exhibit pleiotropic effects that extend beyond traditional risk factor control. Understanding the molecular basis of remodeling is essential for guiding future research and improving outcomes in older adults at risk of CVD. Full article

Intervertebral disc degeneration is a leading contributor to chronic back pain and disability worldwide. This review comprehensively explores the complex interplay of cellular, molecular, and biomechanical alterations within the disc microenvironment that underlie intervertebral disc degeneration pathophysiology. Emphasis is placed on extracellular matrix degradation, cellular senescence, inflammation, oxidative stress, angiogenesis, and multiple forms of programmed cell death including apoptosis, pyroptosis, and ferroptosis. An in-depth analysis of key signaling pathways and regulatory molecules illustrates how these processes disrupt homeostasis and drive disease progression. Additionally, the review highlights emerging therapeutic approaches aimed at modifying the disc microenvironment, including mesenchymal and notochordal cell-based therapies, senolytics, ferroptosis inhibitors, gene therapy, and biomaterial innovations such as hydrogels, scaffolds, and nanocarriers. These strategies target degenerative cascades at the molecular level and represent a shift toward regenerative and disease-modifying interventions. While several approaches show promise in preclinical and early clinical studies, challenges related to safety, delivery, and long-term efficacy remain. This review underscores the importance of integrating molecular insights with translational innovations to develop targeted therapies for intervertebral disc degeneration and guide future research efforts. Full article

Stem cell (SC)-based therapy exploits the ability of cells to migrate to damaged tissues and repair them. In this context, there is a strong interest in the use of mesenchymal stem cells (MSCs), multipotent SCs that are easy to obtain and are able to differentiate into various cell lineages. However, MSCs undergo cellular senescence during in vitro expansion, and may also become senescent in vivo, influenced by multiple molecular, cellular, and environmental interactions. Therefore, the development of in vitro cell models is crucial to study the mechanisms underlying senescence in MSCs. This study aimed to investigate the effects of tert-butyl hydroperoxide (t-BHP) as a senescence inducer in human dermal MSCs (hDMSCs), a promising tool for tissue repair. t-BHP induced a pro-senescent effect on hDMSCs greater than hydrogen peroxide (H₂O₂), as evidenced by ROS production, DNA damage, cell cycle arrest, inhibition of cell proliferation, changes in cellular and nuclear morphology, and cytoskeletal reorganization, as well as the increase in other senescence markers, including senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and senescence-associated secretory phenotype (SASP). These results indicate that t-BHP could be a promising compound for inducing stress-induced premature senescence (SIPS) in hDMSCs, providing a valuable tool to investigate this process and evaluate the efficacy of senolytic compounds. Full article

Cellular senescence is a heterogeneous and dynamic state characterised by stable proliferation arrest, macromolecular damage and metabolic remodelling. Although markers such as SA-β-galactosidase staining, yH2AX foci and p53 activation are widely used as de facto standards, they are imperfect and differ in terms of sensitivity, specificity and dependence on context. We present a multifactorial imaging platform integrating scanning electron, flow cytometry and high-resolution confocal microscopy. This allows us to identify senescence phenotypes in three in vitro models: replicative ageing via serial passaging; dose-graded genotoxic stress under serum deprivation; and primary fibroblasts from young and elderly donors. We present a multimodal imaging framework to characterise senescence-associated phenotypes by integrating LysoTracker and MitoTracker microscopy and SA-β-gal/FACS, p16INK4a immunostaining provides independent confirmation of proliferative arrest. Combined nutrient deprivation and genotoxic challenge elicited the most pronounced and concordant organelle alterations relative to single stressors, aligning with age-donor differences. Our approach integrates structural and functional readouts across modalities, reducing the impact of phenotypic heterogeneity and providing reproducible multiparametric endpoints. Although the framework focuses on a robustly validated panel of phenotypes, it is extensible by nature and sensitive to distributional shifts. This allows both drug-specific redistribution of established markers and the emergence of atypical or transient phenotypes to be detected. This flexibility renders the platform suitable for comparative studies and the screening of senolytics and geroprotectors, as well as for refining the evolving landscape of senescence-associated states. Full article

Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the rapidly evolving field of senotyping based on cellular heterogeneity in lung development and aging in health and disease. It also delves into the molecular mechanisms driving senescence and SASP production, highlighting pathways such as p53/p21, p16^INK4a/RB, mTOR, and p38 MAPK as therapeutic targets. The involvement of various novel SASP proteins, such as GDP15, cytokines/chemokines, growth factors, and DNA damage response proteins. We further highlight the effectiveness of senotherapeutics in mitigating the detrimental effects of senescent cell (SnC) accumulation within the lungs. It also outlines two main therapeutic approaches: senolytics, which selectively trigger apoptosis in SnCs, and senomorphics (also known as senostatics), which mitigate the detrimental effects of the SASP without necessarily removing the senescent cells. Various classes of senolytic and senomorphic drugs are currently in clinical trials including natural products (e.g., quercetin, fisetin, resveratrol) and repurposed drugs (e.g., dasatinib, navitoclax, metformin, rapamycin) that has demonstrated therapeutic promise in improving tissue function, alleviating LARDs, and extending health span. We discuss the future of these strategies in lung research and further elaborate upon the usability of novel approaches including HSP90 inhibitors, senolytic CAR-T cells, Antibody drug conjugate and galactose-modified prodrugs in influencing the field of personalized medicine in future. Overall, this comprehensive review highlights the progress made so far and the challenges faced in the field of cellular senescence including SnC heterogeneity, states of senescence, senotyping, immunosenescence, drug delivery, target specificity, long-term safety, and the need for robust cell-based biomarkers. Future perspectives, such as advanced delivery systems, and combination therapies, are considered critical for translating the potential of senotherapeutics into effective clinical applications for age-related pulmonary diseases/conditions. Full article

Cellular senescence is a state of irreversible growth arrest characterized by a pro-inflammatory phenotype, playing dual roles in development. In the fetal intestine, the regulation of senescent cells is critical for maintaining tissue homeostasis. Human breast milk (HBM), known for its rich composition of bioactive molecules, may play a role in modulating senescence, although its effects on senescent intestinal cells remain unexplored. This study investigated whether HBM selectively eliminates senescent cells in the FHs74Int fetal intestinal epithelial cell line. Senescence was assessed via β-galactosidase activity and expression of p16 and p21. The model cell line was treated with HBM, infant formula, and milk fractions, and outcomes included cell recovery, senescence markers, apoptosis, and mitochondrial potential. Total free fatty acids (FFA) were quantified and correlated with senolytic activity. HBM reduced senescent cell recovery without affecting non-senescent cells, correlating with decreased β-galactosidase activity, reduced phospho-p38 and γH2AX expression, mitochondrial depolarization, and caspase activation. Only the lipid fraction retained senolytic activity, which was associated with elevated FFA levels. Incubation of HBM at 37 °C increased FFA content and conferred senolytic activity. These findings are consistent with the idea that HBM exerts selective senolytic effects via FFA, revealing a novel mechanism by which breast milk could contribute to intestinal homeostasis. Full article

Aging is a complex, multifactorial process characterized by progressive physiological decline and increased vulnerability to chronic diseases and syndromes. Recent studies have highlighted nine interrelated hallmarks of aging, emerging primarily from an understanding of cellular homeostasis, health, and senescence, such as genomic instability, telomere attrition, and cellular senescence. These hallmarks provide a conceptual framework for advancing pharmacotherapeutic interventions. In this review, we present an overview of old and new pharmacotherapeutic interventions that are being developed using these hallmarks of aging to enhance healthspan delay and ameliorate age-related pathologies. We classify these strategies into five broad categories, including senolytics, senomorphics, NAD⁺ precursors, mTOR inhibitors, and metabolic modifiers, such as metformin, and review the mechanisms by which they act, preclinical evidence for efficacy, and their translational potential to a clinical context. In addition, we consider the clinical landscape and report the important trials that are currently underway and some of the main obstacles, including key challenges such as biomarker identification, safety issues, and regulatory challenges. Overall, we discuss ahead-of-time gerotherapeutics and the important role of a collective, mechanism-focused basis for therapeutically targeting aging biology. Full article

Vascular dementia (VaD) represents the second-most common dementia type after Alzheimer’s disease since it results from complications of cerebrovascular disease. Mixed pathologies combining vascular and neurodegenerative processes are the rule rather than exception in elderly dementia patients. The condition known as VaD includes various types of vascular damage that affect both large and small blood vessels in the brain which results in cerebral hypoperfusion, blood–brain barrier disruption, glymphatic dysfunction, and molecular cascades causing neuronal damage. The mechanisms of VaD include endothelial dysfunction, oxidative stress, chronic neuroinflammation, impaired glymphatic clearance, white matter demyelination, and synaptic failure. The disease susceptibility of individuals depends on genetic factors which include NOTCH3 mutations and vascular risk polymorphisms. The diagnostic field uses neuroimaging tools and fluid biomarkers such as neurofilament light chain, inflammatory markers, and Aβ/tau ratios for mixed pathology. The current practice of vascular risk management combines with new therapeutic approaches that use phosphodiesterase inhibitors for cerebral perfusion and NLRP3 inflammasome inhibitors for neuroinflammation, senolytics for cellular senescence, and remyelination agents for white matter repair. However, the majority of new treatment methods remain investigational with limited Phase III data. Future medical treatment development will depend on precision medicine approaches which use biomarker-guided treatment selection and combination strategies targeting multiple pathological mechanisms. Full article

Chemotherapy-induced senescence (CIS) contributes to tumor persistence and relapse. In this study, we investigated the senolytic activity of piceatannol (PCT) in 5-fluorouracil (5FU)-induced senescent colorectal cancer (CRC) cells. Senescence was established in P53-proficient HCT116 cells and normal colon fibroblasts (CCD18Co) following prolonged 5FU exposure, as shown by increased SA-β-gal activity, upregulation of P16, P21, and P53, mitochondrial depolarization, and enhanced oxidative stress. Subsequent PCT treatment selectively induced apoptosis in senescent populations, while non-senescent or p53-mutant, senescence-resistant HT29 cells were minimally affected. This effect was prevented by N-acetylcysteine, indicating a redox-sensitive mechanism. Mechanistically, PCT triggered mitochondrial depolarization and AIF-associated, caspase-independent apoptosis without increasing ROS. Morphological analysis with MitoTracker and quantitative morphometry using Fiji confirmed a fragmented mitochondrial network, characterized by reduced form factor, length, and number per cell. Western blotting revealed downregulation of fusion proteins (MFN1, MFN2), decreased FIS1, stable DRP1, and marked upregulation of the DRP1 adaptor MFF, consistent with suppressed fusion and enhanced fission competence. Together, these findings demonstrate that PCT selectively targets chemotherapy-induced senescent CRC cells through mitochondrial fragmentation and AIF-dependent apoptosis, highlighting its potential as an adjuvant strategy to limit the long-term burden of therapy-induced senescence. Full article

Background/Objectives: Osteoarthritis (OA) is a complex joint disease involving chronic inflammation, aging, and obesity, affecting nearly 6 million people worldwide. Senescent cells in OA are linked to increased inflammation, oxidative stress, and DNA damage, making them potential therapeutic targets. APPA, a combination of apocynin (AP) and paeonol (PA), has shown anti-inflammatory and antioxidant properties. This study evaluated the effects of APPA on cellular senescence in human articular chondrocytes. Methods: Using a chondrocyte cell line (T/C-28a2) and primary human chondrocytes, senescence was induced with etoposide and Oncostatin M (Eto + OSM), followed by treatment with APPA, AP, or PA. Senescence markers (SA-β-gal, P21_CDKN1A_), apoptosis, proliferation (Ki67), and rps6 protein levels were analyzed. Results: APPA significantly reduced SA-β-gal activity and p21 expression in cell model—effects not replicated by AP or PA alone. APPA increased early apoptosis and dual-labeled senescent-apoptotic cells, along with total cell numbers and rps6 levels. It also altered Ki67 expression in different cell subpopulations, suggesting effects on proliferation. Conclusions: This study suggests that APPA exerts senotherapeutic effects on human senescent chondrocytes. A reduction in SA-β-gal together with an increase in cell numbers and the proliferation marker Ki67 suggests possible senomorphic effects, whereas a reduction in SA-β-Gal accompanied by an increase in apoptosis indicates senolytic activity. These findings support recent evidence that the distinction between senolytic and senomorphic agents is ‘fuzzy’. Full article

Senolytics, a category of drugs targeting aging processes, have garnered significant attention since their emergence in 2015. Unlike traditional drug development approaches that rely on randomized screening, research on aging-related pharmaceuticals has employed mechanism-based strategies, resulting in the discovery of the pioneering combination therapy of dasatinib (D) and quercetin (Q). Although preliminary studies with senolytic drug combinations have shown promising outcomes, the predictive capabilities of the research in this field remain limited by the extensive experimental data requirements. In this study, we employed differential gene expression analysis and machine learning techniques to investigate the combinatorial effects of senolytic drugs. We identified 1624 core aging-related genes and used this dataset to retrain a multimodal attention mechanism model, creating a specialized framework, SenolyticSynergy, for predicting effective senolytic drug combinations. We then utilized 63 established senolytic compounds as starting points for combination testing, developing a comprehensive dataset of 1953 potential drug combinations for aging interventions. Following rigorous filtration, we identified 190 high-confidence drug combinations and predicted their synergistic scores. Among these combinations, ten demonstrated exceptionally high synergistic scores, exceeding 8. The combination of temsirolimus and nitazoxanide ranked first and may be the most promising candidate. The analysis of the literature data and computational studies of molecular structures using 3D modeling validated the accuracy of these predictions. This framework paves the way for large-scale research into anti-aging drug combinations, advancing research capabilities in this field. Full article