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The biological process of aging is influenced by a complex interplay of genetic, environmental, and epigenetic factors. Recent advancements in the fields of epigenetics and senolytics offer promising avenues for understanding and addressing age-related diseases. Epigenetics refers to heritable changes in gene expression without altering the DNA sequence, with mechanisms like DNA methylation, histone modification, and non-coding RNA regulation playing critical roles in aging. Senolytics, a class of drugs targeting and eliminating senescent cells, address the accumulation of dysfunctional cells that contribute to tissue degradation and chronic inflammation through the senescence-associated secretory phenotype. This scoping review examines the intersection of epigenetic mechanisms and senolytic therapies in aging, focusing on their combined potential for therapeutic interventions. Senescent cells display distinct epigenetic signatures, such as DNA hypermethylation and histone modifications, which can be targeted to enhance senolytic efficacy. Epigenetic reprogramming strategies, such as induced pluripotent stem cells, may further complement senolytics by rejuvenating aged cells. Integrating epigenetic modulation with senolytic therapy offers a dual approach to improving healthspan and mitigating age-related pathologies. This narrative review underscores the need for continued research into the molecular mechanisms underlying these interactions and suggests future directions for therapeutic development, including clinical trials, biomarker discovery, and combination therapies that synergistically target aging processes. [ABSTRACT FROM AUTHOR]

Schematic diagram illustrating the senolytic role of D+Q in lumbar facet joint degeneration [Display omitted] Low back pain (LBP) is a pervasive issue, causing substantial economic burden and physical distress worldwide. Facet joint osteoarthritis (FJ OA) is believed to be a significant contributor to this problem. However, the precise role of chondrocyte senescence in FJ OA remains unclear, as does whether the clearance of chondrocyte senescence can alleviate the progression of FJ OA. The goal of this study was to understand the potential of Dasatinib (D) and Quercetin (Q) as a treatment to clear chondrocyte senescence during the progression of FJ OA. We used a preclinical bipedal standing mice model with the administration of Dasatinib (D) (5 mg/kg) and Quercetin (Q) (50 mg/kg) after 10 weeks of bipedal standing. Human degenerative lumbar facet joint (LFJ) samples were obtained to investigate the relationship between chondrocyte cellular senescence and LFJ osteoarthritis (OA). Subsequently, we established an in vitro model of excessive mechanical stress on chondrocytes and an in vivo bipedal standing mice model to induce LFJ OA. IHC (immunohistochemistry) staining in vivo and SA-β-gal staining, qRT-PCR and Western blot analysis were applied to test the senolytic effect of the combination of Dasatinib (D) and Quercetin (Q). IHC staining and X-ray microscope were also performed to examine the contribution of D+Q to the anabolism in cartilage and subchondral bone recoupling. Immunofluorescence and Western blot analysis in vitro and IHC staining in vivo were conducted to assess the impact of D+Q on the regulation of the NF-κB pathway activation during chondrocyte senescence. We observed that facet joint cartilage degeneration is associated with chondrocyte cellular senescence in both human and mouse degenerative samples. Following treatment with D+Q in vitro, cellular senescence was significantly reduced. Upon oral gavage administration of D+Q in the bipedal standing mice model, decreased cellular senescence and reversed chondrocyte anabolism were observed. Furthermore, administration of D+Q maintained subchondral bone remodeling homeostasis and potentially reversed the activation of the NF-κB pathway in chondrocytes of the lumbar facet joint. In summary, our investigation unveiled a significant correlation between chondrocyte senescence and LFJOA. Treatment with the senolytic combination of D+Q in FJ OA yielded a notable reduction in chondrocyte senescence, along with a decrease in the release of SASP factors. Additionally, it facilitated the promotion of cartilage anabolism, maintenance of subchondral bone coupling, and amelioration of NF-κB pathway activation. Our outcomes revealed that D+Q, the renowned combination used for senolytic treatment, alleviate the progression of LFJ OA. The utilization of D+Q as a senolytic demonstrates a novel and promising alternative for LFJ OA treatment. [ABSTRACT FROM AUTHOR]

Aging is a major risk factor for poor outcomes following respiratory infections. In animal models, the most severe outcomes of respiratory infections in older hosts have been associated with an increased burden of senescent cells that accumulate over time with age and create a hyperinflammatory response. Although studies using coronavirus animal models have demonstrated that removal of senescent cells with senolytics, a class of drugs that selectively kills senescent cells, resulted in reduced lung damage and increased survival, little is known about the role that senescent cells play in the outcome of influenza A viral (IAV) infections in aged mice. Here, we tested if the aged mice survival or weight loss IAV infections could be improved using three different senolytic regimens. We found that neither dasatinib plus quercetin, fisetin, nor ABT‐263 improved outcomes. Furthermore, both dasatanib plus quercetin and fisetin treatments further suppressed immune infiltration than aging alone. Additionally, our data show that the short‐term senolytic agents do not reduce senescent markers in our aged mouse model. These findings suggest that acute senolytic treatments do not universally reverse aging related immune phenotype against all respiratory viral infections. [ABSTRACT FROM AUTHOR]

Cellular senescence is an irreversible cell cycle arrest caused by various stressors that damage cells. Over time, senescent cells accumulate and contribute to the progression of multiple age-related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and antiapoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network-based methods, we identified various genes that could represent new senescence-related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multitarget mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescent cell antiapoptotic pathways (SCAPs). The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAP development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new antiapoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively., (© 2025 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Aging is often characterized by chronic inflammation, immune system dysregulation, and cellular senescence with chronically elevated levels of pro-inflammatory cytokines. These small glycoproteins are mainly secreted by immune cells, mediating intercellular communication and immune system modulation through inflammatory signaling. Their pro- and anti-inflammatory effects make them a noteworthy research topic as well as a promising ally in combating inflammation and the aging process. Cytokines exert a synergistic role in aging and disease and may prove useful biomarkers of tissue-specific dysregulation, disease diagnosis and monitoring, presenting potential therapeutic options as anti-inflammatory and senolytic medications. In this review, we address the cellular and molecular mechanisms implicating cytokines in the aging process and related diseases, highlighting their biomarker potential. We focus on the current therapeutic strategies, including specific pharmaceutical agents, supplements, a balanced diet, and healthy habits such as exercise, stress management, and caloric restriction., (Copyright © 2025 Elsevier B.V. All rights reserved.)

As the global population continues to age, understanding the complex role of cellular senescence and its implications in healthy lifespans has gained increasing prominence. Cellular senescence is defined as the irreversible cessation of cell proliferation, accompanied by the secretion of a range of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP), in response to various cellular stresses. While the accumulation of senescent cells has been strongly implicated in the aging process and the pathogenesis of age-related diseases owing to their pro-inflammatory properties, recent research has also highlighted their essential roles in processes such as tumour suppression, tissue development, and repair. This review provides a comprehensive examination of the dual nature of senescent cells, evaluating their deleterious contributions to chronic inflammation, tissue dysfunction, and disease, as well as their beneficial roles in maintaining physiological homeostasis. Additionally, we explored the therapeutic potential of senolytic agents designed to selectively eliminate detrimental senescent cells while considering the delicate balance between transient and beneficial senescence and the persistence of pathological senescence. A deeper understanding of these dynamics is critical to develop novel interventions aimed at mitigating age-related dysfunctions and enhancing healthy life expectancies., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Senescence, caused by cell-cycle arrest, is a hallmark of aging. Senescence has also been described in embryogenesis, wound healing, and acute injuries. Sepsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and mortality. Most of the pathophysiology of human sepsis is recapitulated in the mouse model of polymicrobial sepsis, developed by cecal ligation and puncture (CLP). In this report, we demonstrate a rapid onset of cellular senescence in the liver of mice subjected to CLP-induced sepsis, characterized by the upregulation of p21, p53, and other senescence markers, including SA-βgal. Using RNAscope, confocal microscopy, and flow cytometry, we further confirm the emergence of p21-expressing senescence phenotype in the liver 24 h after sepsis induction. Senescence was observed in several cell types in the liver, including hepatocytes, endothelial cells, and macrophages. We determined the landscape of senescence phenotype in murine sepsis by single-cell sequencing, which further ascertained that this cell fate is not confined to any particular cell type but displays a heterogeneous distribution. Furthermore, we observed a significant reduction in mortality following sepsis when mice were treated with senolytics, a combination of dasatinib and quercetin, before the CLP surgery. Our experiments unequivocally demonstrated a rapid development of cellular senescence with sepsis and, for the first time, described the senescence landscape in the sepsis liver and the possible role of senescent cells in the worsening outcome following sepsis., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)