Search Results (351)

Aging is a complex physiological process that profoundly affects the functionality of the musculoskeletal system, contributing to an increase in the incidence of diseases such as osteoporosis, osteoarthritis, and sarcopenia. Cellular senescence plays a crucial role in these degenerative processes, promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Recently, senotherapeutics have shown promising results in improving musculoskeletal health. Natural compounds such as resveratrol, rapamycin, quercetin, curcumin, vitamin E, genistein, fisetin, and epicatechin act on key signaling pathways, offering protective effects against musculoskeletal decline. On the other hand, molecules such as dasatinib, navitoclax, UBX0101, panobinostat, and metformin have been shown to be effective in eliminating or modulating senescent cells. However, understanding the mechanisms of action, long-term safety, and bioavailability remain areas for further investigation. In this context, physical exercise emerges as an effective non-pharmacological countermeasure, capable of directly modulating cellular senescence and promoting tissue regeneration, representing an integrated strategy to combat age-related diseases. Therefore, we have provided an overview of the main anti-aging compounds and examined the potential of physical exercise as a strategy in the management of age-related musculoskeletal disorders. Further studies should focus on identifying synergistic combinations of pharmacological and non-pharmacological interventions to optimize the effectiveness of anti-aging strategies and promoting healthier musculoskeletal aging. Full article

Cellular senescence is closely connected with cancer progression, recurrence, and metastasis. Senotherapy aims to soothe the harmful effects of senescent cells either by inducing their apoptosis (senolytic) or by suppressing the senescence-associated secretory phenotype (SASP) (senomorphic). Fisetin, a well-studied senotherapeutic drug, was selected for this study to evaluate its efficiency when delivered in a liposomal formulation. The experiment evaluated the impact of liposome-encapsulated fisetin on senescent cells induced by doxorubicin (DOX) from two cell lines: WI-38 (normal lung fibroblasts) and A549 (lung carcinoma). Senescence was characterized by SA-β-galactosidase (SA-β-gal) activity, proliferation, morphology, and secretion of pro-inflammatory interleukin 6 (IL-6) and interleukin 8 (IL-8). Due to fisetin’s hydrophobic nature, it was encapsulated in liposomes to enhance cellular delivery. Cellular uptake studies confirmed that the liposomes were effectively internalized by both senescent cell types. Treatment with fisetin-loaded liposomes revealed a lack of senolytic effects but showed senomorphic activity, as evidenced by a significant reduction in IL-6 and IL-8 secretion in senescent cells. The liposomal formulation enhanced fisetin’s therapeutic efficacy, showing comparable results even at the lowest tested concentration. Full article

Background: Senescence, a state of permanent cell cycle arrest, is a complex cellular phenomenon closely affiliated with age-related diseases and pathological fibrosis. Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-β) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. Methods: We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Results: Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-β and inhibition by Oxy210. Conclusions: These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases. Full article

Replicative or stress-induced senescence disrupts the functioning of multipotent mesenchymal stromal cells (MSCs) required for tissue renewal and regeneration. Aged MSCs demonstrate reduced proliferation, impaired differentiation, and aberrant secretory activity, defined as “senescence-associated secretory phenotype” (SASP). SASP is characterized by elevated secretion of proinflammatory cytokines and specific extracellular vesicles (SASP-EVs), which affect the cellular microenvironment and promote tissue dysfunction. However, molecular mechanisms responsible for senescent phenotype propagation remain largely obscure. Earlier, we demonstrated suppression of adipogenic differentiation and insulin sensitivity of young MSCs by SASP-EVs. In this study, we elucidated potential mechanisms underlying SASP-EVs’ effects on MSCs. Bioinformatic analysis revealed that insulin signaling components are the most probable targets of SASP-EVs microRNA cargo. We demonstrated that SASP-EVs downregulated intracellular AGO1 levels, but surprisingly, PTEN levels were upregulated. Specifically, the increase in PTEN content was provided by its nuclear fraction. We have found that the intracellular PTEN distribution in young MSCs treated by SASP-EVs was similar to senescent MSCs. Furthermore, PTEN upregulation was accompanied by increased PTENP1 expression—a molecular sponge for PTEN-targeting microRNAs. Our findings indicate that nuclear PTEN could be a hallmark of senescent MSCs, and SASP-EVs propagate the senescent phenotype in young MSCs by promoting PTEN nuclear localization. Full article

Senescent cells secrete pro-inflammatory cytokines, collectively referred to as the senescence-associated secretory phenotype (SASP). Certain pro-inflammatory SASP factors are known to inhibit the differentiation of bone-forming osteoblast while promoting the differentiation of bone-resorbing osteoclasts, thereby causing osteoporosis. In this study, we screened cabozantinib, a tyrosine kinase inhibitor used to treat medullary thyroid cancer, for its ability to reduce doxorubicin-induced cellular senescence in both osteoblast and osteoclast progenitors. This non-cytotoxic agent suppressed the secretion of SASP factors (e.g., TNFα, IL1α, IL1β, IL6, and CCL2) from senescent osteoblast and osteoclast progenitors, resulting in enhanced osteoblast differentiation and reduced osteoclast differentiation. Furthermore, intraperitoneal administration of cabozantinib to age-related estrogen-deficient mice subjected to ovariectomy prevented bone loss without apparent side effects, increasing osteoblast numbers and reducing osteoclast numbers along the surface of the trabecular bone. In summary, our findings suggest that anti-aging cabozantinib has potential as a preventive anti-osteoporotic agent by promoting osteogenesis and inhibiting osteoclastogenesis through the repression of SASP. Full article

DNA is inherently unstable and is susceptible to damage from both endogenous sources (such as reactive oxygen species) and exogenous factors (including UV, ionizing radiation, and chemicals). The accumulation of DNA damage manifests as genetic mutations, chromosomal instability, and the stalling of DNA replication and transcription processes. Accumulated DNA damage influences apoptosis and cell cycle checkpoints, serving as one of the key triggers for the manifestation of the senescent phenotype. Both aging and cancer are associated with the accumulation of mutations in somatic cells. Disruption of cell cycle control and uncontrolled proliferation are fundamental characteristics of any cancer cell, with the majority of anticancer drugs acting as inhibitors of cyclin-dependent kinases, thereby inducing a transition of cells into a senescent state. Consequently, disturbances in the dynamics and regulation of inflammatory responses, oxidative stress, cell proliferation, DNA damage repair, and epigenetic anomalies, along with the influence of retroviruses and transposons, lead to the accumulation of senescent cells within the human body, characterized by blocked replication and cell cycle, as well as a distinct secretory phenotype. The age-related or disease-associated accumulation of these senescent cells significantly alters the physiology of tissues and the organism as a whole. Many secondary metabolites of higher plants exhibit senolytic and senomorphic activities, although most of them are not fully characterized. In this review, we will explore the principal signaling pathways in mammalian cells that govern the cell cycle and cellular senescence, with a particular emphasis on how their dynamics, expression, and regulation have been modified through the application of senotherapeutic compounds. The second section of the review will identify key target genes for the metabolic engineering, primarily aimed at enhancing the accumulation of plant secondary metabolites with potential therapeutic benefits. Lastly, we will discuss the rationale for utilizing liver cells as a model system to investigate the effects of senolytic compounds on human physiology and health, as well as how senotherapeutic substances can be leveraged to improve gene therapy approaches based on CRISPR/Cas9 and prime-editing technologies. Full article

With the intensification of global aging, the incidence of age-related diseases (including cardiovascular, neurodegenerative, and musculoskeletal disorders) has been on the rise, and cellular senescence is identified as the core driving mechanism. Cellular senescence is characterized by irreversible cell cycle arrest, which is caused by telomere shortening, imbalance in DNA damage repair, and mitochondrial dysfunction, accompanied by the activation of the senescence-associated secretory phenotype (SASP). In this situation, proinflammatory factors and matrix-degrading enzymes can be released, thereby disrupting tissue homeostasis. This disruption of tissue homeostasis induced by cellular senescence manifests as characteristic pathogenic mechanisms in distinct disease contexts. In cardiovascular diseases, senescence of cardiomyocytes and endothelial cells can exacerbate cardiac remodeling. In neurodegenerative diseases, senescence of glial cells can lead to neuroinflammation, while in musculoskeletal diseases, it can result in the degradation of cartilage matrix and imbalance of bone homeostasis. This senescence-mediated dysregulation across diverse organ systems has spurred the development of intervention strategies. Interventional strategies include regular exercise, caloric restriction, senolytic drugs (such as the combination of dasatinib and quercetin), and senomorph therapies. However, the tissue-specific regulatory mechanisms of cellular senescence, in vivo monitoring, and safety-related clinical translational research still require in-depth investigation. This review summarizes the progress in pathological mechanisms and interventions, providing theoretical support for precision medicine targeting senescence, which is of great significance for addressing health challenges associated with aging. Full article

Taken together, cardiovascular diseases (CVDs) have become one of the prime causes of the global disease burden. Aging is closely related to CVDs and is considered to be one of the crucial factors in the incidence of CVDs. In the process of aging, cellular senescence is an important cause of CVDs such as atherosclerosis and atrial fibrillation. The treatment for CVDs by targeting senescent cells has been carried out in cellular models, animal experiments, and anti-aging clinical trials. Chemical approaches to regulate the fate of senescent cells by senolytics and senomorphics, which could selectively eliminate senescent cells or inhibit their senescence-associated secretory phenotype (SASP) secretion, have been increasingly explored. Importantly, many natural products with promising biological activity extracted from food or medicine–food homology have the above-mentioned effects. Furthermore, the identification of the target cells or target proteins of these natural products is of great significance for the indication of their mechanism of action, and it also lays a scientific foundation for the realization of precision nutrition intervention in the future. This review details how senescent cells affect CVDs, how natural products target senescent cells through nutritional intervention, and research methods for natural products in cardiovascular aging. Full article

Reproductive efficiency in cattle remains sub-optimal, with pregnancy rates often below 50%, despite fertilization rates approaching 100%, indicating that implantation failure and/or early embryonic loss are major limiting factors. This disparity highlights the need to understand the biological and physiological mechanisms underlying implantation failure. This review elucidates the cellular and molecular mechanisms underlying reduced pregnancy rates, with a particular focus on biological aging and fibrosis in the reproductive organs as emerging contributors to uterine dysfunction. Accumulated evidence suggests that metabolic demands associated with intensive breeding strategies aimed at maximizing meat and milk productivity may induce multiple forms of stress, including oxidative stress, metabolic stress, and inflammation, which accelerate biological aging and fibrosis in the female reproductive tract. However, the direct molecular mechanisms remain poorly characterized. We hypothesize that biological aging and fibrosis are interconnected mechanisms contributing to impaired uterine function, resulting in reduced implantation rates. By summarizing recent findings and adopting a comparative perspective, this review explores the extent to which insights from human and mouse models can be applied to cattle, considering species-specific reproductive physiology and metabolic adaptations. It explores their relevance to reproductive inefficiencies and discusses potential strategies to enhance fertility and extend bovine reproductive longevity. Full article

Cellular senescence is a complex process that significantly contributes to the pathogenesis of various diseases, including cancer and neurodegenerative disorders. It is characterized by permanent cell cycle arrest and morphological changes, such as cell enlargement and a decrease in lamin B levels. As organisms age, a secretory phenotype known as the senescence-associated secretory phenotype (SASP) develops, which produces pro-inflammatory factors that can impact surrounding tissues and promote disease. This article discusses the molecular mechanisms regulating senescence, notably the p53/p21 and p16INK4a/pRb pathways, which are crucial for inducing cell cycle arrest. While increased activity of cyclin inhibitors like p16 and p21 serves as a protective mechanism against cancer, their prolonged activation can lead to pathological effects. Additionally, the article examines therapies involving senolytics and senomorphics, which aim to eliminate senescent cells. Current research suggests that targeting senescence may represent a promising strategy for treating various diseases, improving health outcomes, and enhancing the overall quality of life as we age. Full article

Objectives: Mesothelin (MSLN) is overexpressed in pancreatic ductal adenocarcinoma (PDAC), promoting cell proliferation, migration, and inhibiting apoptosis. While its oncogenic properties have been documented, the role of MSLN in regulating cellular senescence—a tumor-suppressive mechanism—has remained unexplored. This study is the first to identify and characterize a novel mesothelin-associated anti-senescence (MAAS) effect in PDAC. Methods: A proteogenomic analysis of PDAC tissue samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was performed to evaluate MSLN-associated senescence pathways using WebGestalt. Human and murine PDAC cell lines with modified MSLN expression were analyzed for senescence phenotypes via SA-β-gal staining, Western blotting of key regulators (P53, P21^waf1, and P16^ink4a), γH2AX immunoblotting, and IL-8 quantification using ELISA. Results: The CPTAC analysis revealed an inverse correlation between MSLN expression and DNA damage/repair pathways. MSLN-deficient cells exhibited classic senescence features—growth arrest, an enlarged morphology, and elevated SA-β-gal activity. The expression of P53, P21^waf1, and P16^ink4a was upregulated, alongside increased γH2AX levels, indicating the activation of the DNA damage response. IL-8 secretion was significantly higher in the MSLN knockdown cells and reduced in the MSLN-overexpressing cells, consistent with the modulation of the SASP. Notably, MSLN deficiency impaired cell viability without inducing overt cytotoxicity, supporting a shift toward senescence. Conclusions: Our findings uncover a previously unrecognized mechanism through which MSLN promotes tumor progression by suppressing senescence via P53-associated pathways. Targeting the MAAS pathway may offer a novel therapeutic strategy to restore tumor-suppressive senescence and enhance treatment efficacy in PDAC. Full article

Cellular senescence leads to stable cell cycle arrest and an inflammatory senescence-associated secretory phenotype that varies with stressor and cell type. To mitigate these effects and improve health, senotherapeutics (e.g., senolytics and senomorphics) have been developed. Senescent-like endometrial stromal cells (eSCs) lining the uterus of patients with endometriosis and infertility are proposed to impair decidualization, a differentiation process required for uterine receptivity in humans. Quercetin, a natural flavonoid senolytic, dramatically improves decidualization and reduces endometriosis in rodent models. However, little is known about the comparative effects of various senotherapeutics on eSCs. Using menstrual effluent-derived eSCs, we evaluated the effects of flavonoid and non-flavonoid compounds on eSC functions associated with endometriosis, aiming to identify optimal senotherapeutics for future clinical trials. Among flavonoids tested, all senolytics (quercetin, fisetin, and luteolin) and kaempferol, a senomorphic, significantly improved decidualization without cytotoxicity. Although non-flavonoids exhibited notable cytotoxicity, dasatinib, but neither ABT-737 nor navitoclax, enhanced decidualization. Flavonoid senotherapeutics and dasatinib significantly inhibited eSC migration. Mechanistic studies revealed that all flavonoids and dasatinib suppressed AKT phosphorylation and upregulated p53 expression. Notably, only quercetin and fisetin reduced ERK1/2 phosphorylation. Furthermore, flavonoid-senolytics and dasatinib consistently eliminated senescent eSCs. These findings support future studies to assess the therapeutic potential of in vivo supplementation with flavonoid senolytics on eSC function using menstrual effluent. Full article

Background/Objectives: Uric acid can act as a prooxidant or an antioxidant; therefore, its effects on human umbilical vein endothelial cells (HUVECs) were investigated to better understand its role in promoting cellular senescence and vascular dysfunction. Methods: HUVECs were exposed to different concentrations of exogenous uric acid levels typically found in patients with cardiovascular conditions (5 mg/dL, 7.5 mg/dL, and 10 mg/dL) to assess cell viability, proliferation, and senescence markers including SA-β-Gal activity, γ-H2A.X and 53BP1 expression, as well as mitochondrial dysfunction parameters such as reactive oxygen species (ROS) production, mitochondrial mass, and mitochondrial membrane potential (ΔΨm). Additionally, the secretion of factors related to the senescence-associated secretory phenotype (SASP) was quantified. Results: Uric acid concentrations of 7.5 mg/dL and above significantly reduced HUVEC viability, enhanced proliferation, and increased markers of cellular senescence, including SA-β-Gal activity and γ-H2A.X/53BP1 expression. Higher uric acid levels also led to increased ROS production, increased mitochondrial mass, and reduced membrane potential. Uric acid also dose-dependently increased IL-6, IL-8, HGF, GRO-1, and TGF-β1 levels. Conclusions: High uric acid concentrations (≥7.5 mg/dL) promote HUVEC senescence, possibly due to ROS-induced DNA damage. In addition, uric acid triggers the production of pro-inflammatory cytokines and growth factors. Full article

Aerobic exercise mitigates age-related intestinal senescence through gut microbiota modulation, but the underlying mechanism has remained unclear. In this study, we performed 16S rRNA sequencing of gut contents from young, old, and old exercise C57BL/6J mice to assess exercise-induced alterations in microbiota community structure. Differential taxa analyses were applied to reveal age-associated bacterial signatures, gut barrier integrity, and systemic inflammation. Additionally, untargeted metabolomic profiling was employed to characterize gut metabolic profiles and reveal the key pathways through differential metabolite enrichment analyses. Aging significantly exacerbated the senescence-associated secretory phenotypes and the overgrowth of pathogenic bacteria in mice. However, aerobic exercise ameliorated these age-related deteriorations, restored gut microbial homeostasis, and reduced intestinal permeability. Notably, exercise intervention led to a significant increase in Akkermansia abundance in feces, establishing this mucin-degrading bacterium as a prominent exercise-responsive microbe. Metabolomic profiling identified eicosanoid metabolism as the most significantly perturbed pathway, and chronic exercise was found to regulate 14,15-Dhet levels. Our multi-omics integration confirmed that exercise is a potent modulator of the gut–microbiota–metabolite axis during aging. Elucidating the “Akkermansia–eicosanoid signaling” axis provided mechanistic insights into how exercise promotes healthy aging, identifying novel targets for anti-aging strategies via microbiota. Full article

Cellular senescence is a fundamental mechanism in aging, marked by irreversible growth arrest and diverse functional changes, including, but not limited to, the development of a senescence-associated secretory phenotype (SASP). While transient senescence contributes to beneficial processes such as tissue repair and tumor suppression, the persistent accumulation of senescent cells is implicated in tissue dysfunction, chronic inflammation, and age-related diseases. Notably, the SASP can exert both pro-inflammatory and immunosuppressive effects, depending on cell type, tissue context, and temporal dynamics, particularly in early stages where it may be profibrotic and immunomodulatory. Recent advances in senotherapeutics have led to two principal strategies for targeting senescent cells: senolytics, which selectively induce their apoptosis, and senomorphics, which modulate deleterious aspects of the senescence phenotype, including the SASP, without removing the cells. This review critically examines the molecular mechanisms, therapeutic agents, and clinical potential of both approaches in the context of anti-aging interventions. We discuss major classes of senolytics, such as tyrosine kinase inhibitors, BCL-2 family inhibitors, and natural polyphenols, alongside senomorphics including mTOR and JAK inhibitors, rapalogs, and epigenetic modulators. Additionally, we explore the biological heterogeneity of senescent cells, challenges in developing specific biomarkers, and the dualistic role of senescence in physiological versus pathological states. The review also highlights emerging tools, such as targeted delivery systems, multi-omics integration, and AI-assisted drug discovery, which are advancing precision geroscience and shaping future anti-aging strategies. Full article