Search Results (37)

Chronic kidney disease (CKD) and kidney aging share many pathological and molecular features, with cellular senescence emerging as a potentially important contributor to disease progression. Senescent cells accumulate in the kidneys due to persistent stressors, contributing to chronic inflammation and fibrosis via the senescence-associated secretory phenotype (SASP). This review explores the intersection between CKD and renal aging, focusing on the mechanisms driving senescence, its impact on kidney function, and potential therapeutic interventions. We explore various senotherapeutic approaches, such as senolytics, senomorphics, and rejuvenating agents, and highlight the increasing role of artificial intelligence (AI) and machine learning (ML) in detecting and monitoring senescent cells, enabling high-throughput and precise assessment across experimental and clinical settings. Understanding these mechanisms offers new avenues for developing targeted treatments to slow CKD progression and improve patient outcomes. Full article

Osteoporosis is a major global health challenge, causing millions of fragility fractures each year and imposing an escalating socioeconomic burden worldwide. Despite advances with antiresorptive and anabolic therapies, substantial residual fracture risk persists, and targeting aging biology may yield disease modifying benefits beyond current standards of care. Senescent cells secrete senescence-associated secretory phenotype (SASP) factors, which impair osteoblast differentiation and contribute to bone loss. We investigated foretinib, a quinoline-based multi-tyrosine kinase inhibitor, as a potential anti-aging agent in osteoblast lineage cells. Foretinib inhibited doxorubicin-induced senescence in osteoblast progenitors via the p53/p21 and p16 pathways and reduced the expression of osteogenesis-inhibiting SASP factors, including CCL2, interleukin (IL)-1α, IL-1β, and IL-6. As a result, foretinib restored the impaired osteogenic differentiation of aged osteoblasts to near-normal levels in vitro. In ovariectomized, estrogen-deficient mice, foretinib significantly reduced trabecular and cortical bone loss by enhancing in vivo osteoblast differentiation, as shown by histological analysis and micro-computed tomography of femoral bone. These results suggest that foretinib alleviates osteoblast senescence and enhances osteogenic differentiation, supporting its promise as a therapeutic candidate for postmenopausal osteoporosis. Full article

Background/Objectives: With the rapid aging of the global population, the interest in therapies for age-related diseases has increased substantially. The skin is particularly important, as aging-related changes are visible and negatively impact quality of life. Therefore, the identification of senotherapeutic candidates that are effective against skin aging is of considerable importance. Given the cost and reproducibility limitations of existing senescence models, this study established three dermal fibroblast senescence models induced by etoposide, hydrogen peroxide, and ultraviolet A, representing intrinsic and extrinsic aging. Furthermore, considering the adverse effects of current photoaging treatments, such as tretinoin and methoxsalen, we investigated the senotherapeutic potential of araliadiol, a plant-derived compound, in these models. Methods: Senescence induction and validation were assessed using trypan blue-based cell counting, senescence-associated β-galactosidase (SA-β-gal) staining, and adenosine triphosphate content assays. The senotherapeutic potential of araliadiol was further evaluated using quantitative reverse transcriptase–polymerase chain reaction, Western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay. Results: Compared with non-senescent fibroblasts, senescent cells exhibited increased SA-β-gal positivity, elevated intracellular reactive oxygen species levels, and upregulated p16 and p21 expression. The senolytic agent ABT-737 selectively induced apoptosis in senescent fibroblasts but not in non-senescent fibroblasts, validating the models. Araliadiol showed no senolytic activity but demonstrated potential senomorphic effects, including reduced expression of senescence-associated secretory phenotype (SASP) genes (IL1β, IL6, IL8, CCL2, and CXCL1) and NF-κB p65 phosphorylation, suppression of MMP-1 (up to 2.35-fold reduction) and MMP-3 (up to 30.53-fold reduction) expression and AP-1 activation, and increased extracellular procollagen type I content (up to 18.35% increase). Conclusions: Araliadiol exerted senomorphic—but not senolytic—effects across three validated dermal fibroblast senescence models, supporting its potential as a natural topical therapeutic agent for mitigating skin aging. Full article

Background: Cutaneous aging is a multifactorial process, increasingly understood through the lens of cellular senescence, a state of stable cell cycle arrest accompanied by a pro-inflammatory secretory phenotype that disrupts tissue homeostasis. Recent research has highlighted the accumulation of senescent dermal fibroblasts as a key contributor to age-related skin changes, including loss of elasticity, collagen degradation, and impaired regeneration. Objective: This review explores the emerging hypothesis that energy-based devices (EBDs), particularly lasers, may act as senotherapeutic tools by targeting cellular senescence pathways in aging skin. We examine the molecular and histological effects of laser therapy in relation to known biomarkers of senescence and evaluate their potential role in regenerative dermatology. Methods: We conducted a review of published studies on fractional lasers, red-light therapies, and other EBDs, focusing on their impact on fibroblast activity, extracellular matrix remodeling, and senescence-associated markers such as p16^INK4a, p21^Cip1, telomerase, and SASP-related cytokines. Comparative analysis with pharmacologic senotherapeutics was also performed. Results: Preclinical and clinical data suggest that specific EBDs can modulate dermal aging at the molecular level by enhancing mitochondrial activity, increasing type III collagen synthesis, reducing senescence-related gene expression, and promoting fibroblast turnover. In contrast to systemic senolytics, lasers provide localized and titratable interventions with a favorable safety profile. Conclusions: Energy-based devices, particularly fractional lasers and red-light systems, hold promise as non-invasive senotherapeutic interventions in dermatology. By modulating senescence-associated pathways, EBDs may offer not only cosmetic improvement but also biological rejuvenation. Further mechanistic studies and biomarker-based trials are warranted to validate this paradigm and refine treatment protocols for longevity-oriented skin therapies. Full article

Alzheimer’s disease, a neurodegenerative brain disorder leading to the progressive decline in cognitive functions, is the most common type of dementia. The main risk factor for its development is aging. Recent studies indicate that cellular senescence mechanisms are among the major factors in a heterogeneous aging process. Cellular senescence is characterized by a permanent proliferative arrest. Many factors might initiate senescence, for example, damage of DNA, shortening of telomeres, dysfunction of mitochondria, and oncogene activation. These processes lead to alterations in the morphology and function of senescent cells. Research is still ongoing to identify one universal marker that could detect senescent cells and distinguish them from other non-proliferating cells. Those cells are involved in age-related pathologies through many heterogeneous processes, including secretion of pro-inflammatory senescence-associated secretory phenotype factors, which affect the brain differently. Alzheimer’s disease is an example of a neurodegenerative condition connected to cellular senescence. Senescent cells have been demonstrated to accumulate near Aβ plaques and neurofibrillary tangles. In this review, the multifactorial connection between Alzheimer’s disease and cellular senescence is discussed, including topics such as senescence of astrocytes, defective mitochondria, dysregulation of cellular autophagy, and the role of senescent microglia. Full article

Cellular senescence, a state of permanent cell cycle arrest, represents a double-edged sword in biology—providing tumor-suppressive functions while contributing to tissue degeneration, chronic inflammation, and age-related diseases when senescent cells persist. A key driver of senescence is oxidative stress, primarily mediated by excessive reactive oxygen species that damage mitochondrial DNA, modulate redox-sensitive signaling pathways, and trigger the senescence-associated secretory phenotype. Emerging evidence highlights the pathogenic role of SASP in promoting local inflammation, immune evasion, and senescence propagation. This review explores the intricate interplay between redox imbalance and cellular senescence, emphasizing mitochondrial dysfunction, SASP dynamics, and their implications in aging and cancer. We discuss current senotherapeutic strategies—including senolytics, senomorphics, antioxidants, gene therapy, and immunotherapy—that aim to eliminate or modulate senescent cells to restore tissue homeostasis. Understanding the heterogeneity and context-specific behavior of senescent cells remains crucial for optimizing these therapies. Future research should focus on addressing key knowledge gaps, including the standardization of senescence biomarkers such as circulating miRNAs, refinement of predictive preclinical models, and development of composite clinical endpoints. These efforts are essential to translate mechanistic insights into effective senotherapeutic interventions and enable the safe integration of senescence-targeting strategies into routine clinical practice. 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

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

Parkinson’s disease (PD) is an aging-related neurodegenerative disease characterized by a progressive loss of dopamine (DA)-secreting neurons in the substantia nigra. Most of the currently available treatments attempt to alleviate the disease symptoms by increasing DA transmission in the brain and are associated with unpleasant side effects. Since there are no treatments that modify the course of PD or regenerate DA neurons, identifying therapeutic strategies that slow, stop, or reverse cell death in PD is of critical importance. Here, factors that confer vulnerability of substantia nigra DA neurons to cell death and the primary mechanisms of PD pathogenesis, including cellular senescence, a cellular stress response that elicits a stable cell cycle arrest in mitotic cells and profound phenotypic changes including the implementation of a pro-inflammatory secretome, are reviewed. Additionally, a discussion of the characteristics, mechanisms, and markers of cellular senescence and the development of approaches to target senescent cells, referred to as senotherapeutics, is included. Although the senotherapeutics curcumin, fisetin, GSK-650394, and astragaloside IV had disease-modifying effects in in vitro and in vivo models of PD, the potential long-term side effects of these compounds remain unclear. It remains to be elucidated whether their beneficial effects will translate to non-human primate models and/or human PD patients. The enhanced selectivity, safety, and/or efficacy of next generation senotherapeutic strategies including senolytic peptides, senoreverters, proteolysis-targeting chimeras, pro-drugs, immunotherapy, and nanoparticles will also be reviewed. Although these next generation senotherapeutics may have advantages, none have been tried in models of PD. Full article

Aging is a general biological process inherent in all living organisms. It is characterized by progressive cellular dysfunction. For many years, aging has been widely recognized as a highly effective mechanism for suppressing the progression of malignant neoplasms. However, in recent years, increasing evidence suggests a “double-edged” role of aging in cancer development. According to these data, aging is not only a tumor suppressor that leads to cell cycle arrest in neoplastic cells, but also a cancer promoter that ensures a chronic proinflammatory and immunosuppressive microenvironment. In this regard, in our review, we discuss recent data on the destructive role of senescent cells in the pathogenesis of cancer. We also identify for the first time correlations between the modulation of the senescence-associated secretory phenotype and the antitumor effects of naturally occurring molecules. Full article

To identify the differences between aged and young human hematopoiesis, we performed a direct comparison of aged and young human hematopoietic stem and progenitor cells (HSPCs). Alterations in transcriptome profiles upon aging between humans and mice were then compared. Human specimens consist of CD34+ cells from bone marrow, and mouse specimens of hematopoietic stem cells (HSCs; Lin− Kit+ Sca1+ CD150+). Single-cell transcriptomic studies, functional clustering, and developmental trajectory analyses were performed. A significant increase in multipotent progenitor 2A (MPP2A) cluster is found in the early HSC trajectory in old human subjects. This cluster is enriched in senescence signatures (increased telomere attrition, DNA damage, activation of P53 pathway). In mouse models, the accumulation of an analogous subset was confirmed in the aged LT-HSC population. Elimination of this subset has been shown to rejuvenate hematopoiesis in mice. A significant activation of the P53–P21WAF1/CIP1 pathway was found in the MPP2A population in humans. In contrast, the senescent HSCs in mice are characterized by activation of the p16Ink4a pathway. Aging in the human HSC compartment is mainly caused by the clonal evolution and accumulation of a senescent cell cluster. A population with a similar senescence signature in the aged LT-HSCs was confirmed in the murine aging model. Clearance of this senescent population with senotherapy in humans is feasible and potentially beneficial. Full article

Telomeres, the protective chromosomal ends, progressively shorten and potentially are implicated in the pathogenesis of age-related diseases. In type 2 diabetes (T2DM), telomere shortening may play an important role, but the whole ‘picture’ remains limited. From a therapeutic perspective, the phytonutrient quercetin appears to be clinically effective and safe for patients with T2DM. Considering the above, we aimed to examine whether quercetin could interfere with telomere length (TL) dynamics. One hundred patients with T2DM on non-insulin medications registered within a primary healthcare facility were stratified by age and sex and randomly assigned to either standard care or standard care plus quercetin (500 mg/day) for 12 weeks, succeeded by an 8-week washout period and another 12 weeks of supplementation. Of the 88 patients completing the trial, 82 consented to blood sampling for TL measurements. Health assessments and whole blood absolute TL measurements using quantitative polymerase chain reaction (qPCR) were conducted at baseline and study end, and the findings of this subcohort are presented. Quercetin supplementation was associated with a significant increase in mean TL (odds ratio ≥ 2.44; p < 0.05) with a strengthened association after full adjustment for potential confounders through multiple logistic regression analysis (odds ratio = 3.48; p = 0.026), suggesting it as a potentially promising supplementation option. Further studies are needed to confirm this finding, elucidating the underlying molecular mechanisms of quercetin. Full article

The skin is the layer of tissue that covers the largest part of the body in vertebrates, and its main function is to act as a protective barrier against external environmental factors, such as microorganisms, ultraviolet light and mechanical damage. Due to its important function, investigating the factors that lead to skin aging and age-related diseases, as well as understanding the biology of this process, is of high importance. Indeed, it has been reported that several external and internal stressors contribute to skin aging, similar to the aging of other tissues. Moreover, during aging, senescent cells accumulate in the skin and express senescence-associated factors, which act in a paracrine manner on neighboring healthy cells and tissues. In this review, we will present the factors that lead to skin aging and cellular senescence, as well as ways to study senescence in vitro and in vivo. We will further discuss the adverse effects of the accumulation of chronic senescent cells and therapeutic agents and tools to selectively target and eliminate them. Full article

Therapy-induced senescence (TIS) represents a major cellular response to anticancer treatments. Both malignant and non-malignant cells in the tumor microenvironment undergo TIS and may be harmful for cancer patients since TIS cells develop a senescence-associated secretory phenotype (SASP) that can sustain tumor growth. The SASP also modulates anti-tumor immunity, although the immune populations involved and the final results appear to be context-dependent. In addition, senescent cancer cells are able to evade senescence growth arrest and to resume proliferation, likely contributing to relapse. So, research data suggest that TIS induction negatively affects therapy outcomes in cancer patients. In line with this, new interventions aimed at the removal of senescent cells or the reprogramming of their SASP, called senotherapy, have become attractive therapeutic options. To date, the lack of reliable, cost-effective, and easy-to-use TIS biomarkers hinders the application of recent anti-senescence therapeutic approaches in the clinic. Hence, the identification of biomarkers for the detection of TIS tumor cells and TIS non-neoplastic cells is a high priority in cancer research. In this review article, we describe the current knowledge about TIS, outline critical gaps in our knowledge, and address recent advances and novel approaches for the discovery of TIS biomarkers. Full article

Senescence is a physiological and pathological cellular program triggered by various types of cellular stress. Senescent cells exhibit multiple characteristic changes. Among them, the characteristic flattened and enlarged morphology exhibited in senescent cells is observed regardless of the stimuli causing the senescence. Several studies have provided important insights into pro-adhesive properties of cellular senescence, suggesting that cell adhesion to the extracellular matrix (ECM), which is involved in characteristic morphological changes, may play pivotal roles in cellular senescence. Matricellular proteins, a group of structurally unrelated ECM molecules that are secreted into the extracellular environment, have the unique ability to control cell adhesion to the ECM by binding to cell adhesion receptors, including integrins. Recent reports have certified that matricellular proteins are closely involved in cellular senescence. Through this biological function, matricellular proteins are thought to play important roles in the pathogenesis of age-related diseases, including fibrosis, osteoarthritis, intervertebral disc degeneration, atherosclerosis, and cancer. This review outlines recent studies on the role of matricellular proteins in inducing cellular senescence. We highlight the role of integrin-mediated signaling in inducing cellular senescence and provide new therapeutic options for age-related diseases targeting matricellular proteins and integrins. Full article