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Chilosi M, Piciucchi S, Ravaglia C, Spagnolo P, Sverzellati N, Tomassetti S, Wuyts W, Poletti V. "Alveolar stem cell exhaustion, fibrosis and bronchiolar proliferation" related entities. A narrative review. Pulmonology 2025; 31:2416847. [PMID: 39277539 DOI: 10.1016/j.pulmoe.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/11/2024] [Accepted: 05/27/2024] [Indexed: 09/17/2024] Open
Affiliation(s)
- M Chilosi
- Department of Medical Specialities/Pulmonology Ospedale GB Morgagni, Forlì I
| | - S Piciucchi
- Department of Radiology, Ospedale GB Morgagni, Forlì I
| | - C Ravaglia
- Department of Medical Specialities/Pulmonology Ospedale GB Morgagni, Forlì (I); DIMEC, Bologna University, Forlì Campus, Forlì I, Department
| | - P Spagnolo
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - N Sverzellati
- Scienze Radiologiche, Department of Medicine and Surgery, University Hospital Parma, Parma, Italy
| | - S Tomassetti
- Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy
| | - W Wuyts
- Pulmonology Department, UZ Leuven, Leuven, Belgium
| | - V Poletti
- Department of Medical Specialities/Pulmonology Ospedale GB Morgagni, Forlì (I); DIMEC, Bologna University, Forlì Campus, Forlì I, Department
- Department of Respiratory Diseases & Allergy, Aarhus University, Aarhus, Denmark
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2
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Liu S, Zheng Y, Cui B, Yang J, Yuan B, Cao Y, Zhao Z, Sun Z, Wang Q, Yang X, Pan W, He C. Gut microbiota-derived butyrate alleviates the impairment of mice intestinal integrity caused by Toxoplasma gondii infection. Life Sci 2025; 374:123709. [PMID: 40368048 DOI: 10.1016/j.lfs.2025.123709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 05/04/2025] [Accepted: 05/09/2025] [Indexed: 05/16/2025]
Abstract
Chronic infection with Toxoplasma gondii (T. gondii) results in severe damages to the integrity of intestinal barrier, however, both the underlying mechanism and feasible intervention strategies are still little known. Here, we found that both the chronic infection of T. gondii and transplanting gut microbiota from T. gondii-infected mice severely impaired the mice intestinal integrity, which was characterized by significantly decreased thickness of inner mucus layer and down-regulated expression of three tight junction proteins Occludin, ZO-1, and Claudin (p < 0.05). Moreover, T. gondii infection also led to mice intestinal microbiota dysbiosis, especially butyrate-producing bacteria, and significantly changed the expression of several senescence-associated markers, including 6- and 7- fold upregulation for P16, P21, and 6-fold downregulation for Lamin B1 at mRNA levels, and 2-fold downregulation for β-galactosidase at protein levels (p < 0.05). Interestingly, subsequent administration with dietary butyrate could alleviate T. gondii-induced intestinal integrity impairment and cell senescence, revealing a significant increase of the inner mucus layer thickness (p < 0.001), and a remarkable decrease in P16, P21, β-galactosidase expression levels while an upregulation of Lamin B1 expression (p < 0.05). Taken together, our study revealed that T. gondii-induced dysbiosis of gut microbiota, especially butyrate-producing bacteria, contributes to the intestinal impairment, potentially via promoting cell senescence. In addition, administration with the metabolite, butyrate, could be a promising therapeutic measure against T. gondii infection.
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Affiliation(s)
- Shuni Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, China; The First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yutao Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, China; School of Stomatology, Xuzhou Medical University, Xuzhou, China
| | - Bingqian Cui
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, China; The First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jiayi Yang
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, China; The First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Bohui Yuan
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, China
| | - Yuhan Cao
- The Second Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zimu Zhao
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zhuo Sun
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qingling Wang
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaoying Yang
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, China; Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, China
| | - Wei Pan
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, China; Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, China.
| | - Cheng He
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, China; Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, China.
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3
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Shin JW, Jang DH, Kim SY, Lee JJ, Gil TH, Shim E, Kim JY, Kim HS, Conboy MJ, Conboy IM, Wiley CD, Shin JS, Jeon OH. Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state. Metabolism 2025; 168:156259. [PMID: 40189139 DOI: 10.1016/j.metabol.2025.156259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/27/2025] [Accepted: 04/01/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND & PURPOSE Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence. METHODS We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both in vitro and in vivo. Senescence was determined by SA-β-gal & EdU staining, p16INK4a and p21 expression, RT-qPCR, and Western blot methods. Bulk RNA sequencing was performed to investigate ReHMGB1-driven transcriptional changes and underlying pathways. Cytokine arrays characterized SASP profiles from ReHMGB1-treated cells. In vivo, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade. RESULTS Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers in vivo, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration. CONCLUSION ReHMGB1 is a redox-dependent pro-geronic factor driving systemic senescence. Targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.
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Affiliation(s)
- Ji-Won Shin
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Dong-Hyun Jang
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - So Young Kim
- Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Je-Jung Lee
- Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Tae-Hwan Gil
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Eunha Shim
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Ji Yeon Kim
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Hyeon Soo Kim
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Michael J Conboy
- Department of Bioengineering and QB3 Institute, University of California, Berkeley, CA 94720, USA
| | - Irina M Conboy
- Department of Bioengineering and QB3 Institute, University of California, Berkeley, CA 94720, USA
| | - Christopher D Wiley
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA
| | - Jeon-Soo Shin
- Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Ok Hee Jeon
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea.
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4
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Liang Q, Huang Z, Wang D, Xin F, Xu J, He J, Luo R, Zeng Y, Ma Y. Study on the role of miR-10b-3p as SASP in exosomes of premature senescent hepatocytes induced by hexavalent chromium. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 298:118333. [PMID: 40373709 DOI: 10.1016/j.ecoenv.2025.118333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 05/11/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025]
Abstract
The exact mechanisms through which chronic, low-concentration exposure to Cr(VI) facilitates the development of related pathological conditions remain to be fully elucidated. Senescence-associated secretory phenotype (SASP) exhibits a bidirectional regulatory function in biological processes. Consequently, it is essential to identify the formulation and functional characteristics of the SASP released by Cr(VI)-triggered senescent L02 hepatocytes (S-L02). In this study, exosomes were extracted from the conditioned media of both normal L02 cells and their senescent counterparts (Senescent L02, S-L02 cells). Among the miRNAs identified in the exosomes, miR-10b-3p was found to be the most abundantly expressed in the exosomes derived from S-L02 cells. As part of the SASP, miR-10b-3p was shown to suppress the proliferation of both L02 and S-L02 cells. Simultaneously, it promoted the growth, migration, and invasive capabilities of hepatocellular carcinoma (HCC) cells. The next mechanistic analysis showed that miR-10b-3p reduces the regulatory influence of the protein PHLPP2 on Akt by downregulating its target gene, PHLPP2. This suppression led to lower levels of p27, FOXO3a and p21, thereby enhancing the proliferation of HCC cells by relieving the negative regulatory mechanisms of the cell cycle. This research offers significant understanding into the oncogenic pathways induced by Cr(VI), and provides laboratory evidence for mechanistic studies targeting hepatic carcinoma associated with Cr(VI) exposure.
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Affiliation(s)
- Qi Liang
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Zidi Huang
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Di Wang
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Fei Xin
- Dalian Health Development Center, Dalian 116011, China
| | - Jiaqi Xu
- School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
| | - Jiajia He
- School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
| | - Runnan Luo
- School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China
| | - Yuan Zeng
- Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 510440, China.
| | - Yu Ma
- School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China.
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5
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Isildar B, Ozkan S, Neccar D, Koyuturk M. Preconditioning and post-preconditioning states of mesenchymal stem cells with deferoxamine: A comprehensive analysis. Eur J Pharmacol 2025; 996:177574. [PMID: 40180273 DOI: 10.1016/j.ejphar.2025.177574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/17/2025] [Accepted: 03/31/2025] [Indexed: 04/05/2025]
Abstract
Mesenchymal stem cells (MSCs) derive their therapeutic potential from their secretomes, which can be modulated by external stimuli. Hypoxia is one such stimulus, and research on preconditioning MSCs with hypoxia-mimetic agents is rising. However, the effects of these preconditioning processes and the resulting metabolic status require further investigation. This study evaluated the effects of deferoxamine (DFX), a hypoxia-mimetic agent, preconditioning on MSCs in serum and serum-free environments. The influence of hypoxia on cell metabolism was examined during and after preconditioning by assessing cytotoxicity, proliferation, migration, secretomes, senescence, autophagy, and apoptosis mechanisms. The optimal DFX dose and duration for preconditioning were determined as 150 μM and 24 h based on cytotoxicity testing. Accordingly, DFX preconditioning significantly upregulated HIF-1α expression, increasing protein secretion and reducing total oxidant status. DFX appears to enhance the therapeutic potential of MSCs by increasing their secretome and antioxidant capacity. However, upon DFX removal, HIF-1α levels returned to normal, and the associated positive effects diminished. Autophagy was markedly enhanced during DFX preconditioning, potentially improving metabolic activity, preserving cellular integrity, and preparing MSCs for ischemic environments. Autophagy returned to baseline after DFX withdrawal, indicating a temporary hypoxia-mimetic response. In a serum-containing medium, specific effects of preconditioning were relatively weak to be observed. This study demonstrates that DFX-preconditioning increases MSCs' metabolic activity and enhances their adaptive cellular response. However, the effect may be transient, which provides insights into the behavior of MSCs in ischemic environments and emphasizes the need to evaluate the long-term effects of hypoxia-mimetic agents.
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Affiliation(s)
- Basak Isildar
- Balıkesir University, Histology and Embryology Department, Balıkesir, Turkey.
| | - Serbay Ozkan
- İzmir Katip Çelebi University, Histology and Embryology Department, Izmir, Turkey.
| | - Duygu Neccar
- İstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Department of Histology and Embryology, Istanbul, Turkey.
| | - Meral Koyuturk
- İstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Department of Histology and Embryology, Istanbul, Turkey.
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6
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Santos-Sousa DC, da Rosa S, Filippi-Chiela E. Molecular signatures of cellular senescence in cancer: a critical review of prognostic implications and therapeutic opportunities. Mech Ageing Dev 2025; 225:112052. [PMID: 40120861 DOI: 10.1016/j.mad.2025.112052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/01/2025] [Accepted: 03/15/2025] [Indexed: 03/25/2025]
Abstract
Cellular senescence is a state of permanent loss of proliferative capacity. Therefore, cells that reach a senescent state prevent tumor initiation, acting as an anti-tumor mechanism. However, despite not being proliferative, senescent cells have high secretory activity, constituting the Senescence-Associated Secretory Phenotype (SASP). SASP includes thousands of soluble molecules and extracellular vesicles, through which senescent cells can affect other cells and the extracellular matrix. In advanced tumors, the enrichment of senescent cells can have anti- or pro-tumor effects depending on features like SASP composition, tumor microenvironment (TME) composition, the anatomic site, histopathologic characteristics of malignancy, and tumor molecular background. We reviewed the studies assessing the impact of the senescence status, measured by mRNA or lncRNA molecular signatures, in the prognosis and other clinically relevant information in cancer, including anti-tumor immunity and response to therapy. We discussed the pros and cons of different strategies to define those molecular signatures and the main limitations of the studies. Finally, we also raised clinical challenges regarding the crossroad between cellular senescence and cancer prognosis, including some therapeutic opportunities in the field.
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Affiliation(s)
- Débora C Santos-Sousa
- Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 91501-970, Brazil; Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil.
| | - Solon da Rosa
- Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 91501-970, Brazil; Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil.
| | - Eduardo Filippi-Chiela
- Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 91501-970, Brazil; Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil; Department of Morphological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil.
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7
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Avelar RA, Palmer D, Kulaga AY, Fuellen G. Conserved biological processes in partial cellular reprogramming: Relevance to aging and rejuvenation. Ageing Res Rev 2025; 108:102737. [PMID: 40122394 DOI: 10.1016/j.arr.2025.102737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 03/05/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
Partial or transient cellular reprogramming is defined by the limited induction of pluripotency factors without full dedifferentiation of cells to a pluripotent state. Comparing in vitro and in vivo mouse studies, and in vitro studies in humans, supported by visualizations of data interconnections, we show consistent patterns in how such reprogramming modulates key biological processes. Generally, partial reprogramming drives dynamic chromatin remodelling, involving histone modifications that regulate accessibility and facilitate pluripotency gene activation while silencing somatic identity. These changes are accompanied by modifications in stress response programs, such as inflammation, autophagy, and cellular senescence, as well as improved mitochondrial activity and dysregulation of extracellular matrix pathways. We also underscore the challenges in evaluating complex processes like aging and cellular senescence, given the variability in biomarkers used across studies. Overall, we highlight biological processes consistently influenced by reprogramming while noting that some effects are context-dependent, varying according to cell type, species, sex, recovery time, and the reprogramming method employed. These insights inform future research and potential therapeutic applications in aging and regenerative medicine.
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Affiliation(s)
- Roberto A Avelar
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Germany.
| | - Daniel Palmer
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Germany.
| | - Anton Y Kulaga
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Germany; Systems Biology of Aging Group, Institute of Biochemistry of the Romanian Academy, Bucharest 060031, Romania.
| | - Georg Fuellen
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Germany; School of Medicine, University College Dublin, Dublin, Ireland.
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8
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Hartung F, Krutmann J, Haarmann-Stemmann T. Evidence that the aryl hydrocarbon receptor orchestrates oxinflammatory responses and contributes to airborne particulate matter-induced skin aging. Free Radic Biol Med 2025; 233:264-278. [PMID: 40157462 DOI: 10.1016/j.freeradbiomed.2025.03.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/14/2025] [Accepted: 03/27/2025] [Indexed: 04/01/2025]
Abstract
Exposure to airborne particulate matter (PM) is a substantial threat to public health, contributing to respiratory, cardiovascular, and skin-related diseases. Population-based studies strongly indicate that chronic exposure to airborne PM, especially combustion-derived PM2.5, accelerates skin aging and thus reduces the quality of life of those affected. There is increasing evidence that especially PM-bound polycyclic aromatic hydrocarbons (PAHs) critically contribute to the clinical manifestation of skin aging, i.e. the development of lentigines/pigment spots and coarse wrinkles. PAHs harm human skin primarily by activating the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor amongst others involved in orchestrating xenobiotic metabolism and immune responses. In this review, we summarize the available population-based data linking particulate air pollution exposure to skin aging. We explain in detail how PAH-rich PM induces the formation of oxidative stress, the release of pro-inflammatory mediators, the expression extracellular matrix degrading metalloproteases, and melanin synthesis, in an AHR-dependent manner, and how these events may culminate in the development of pigment spots and wrinkles, respectively. We also review the current data on the interaction of airborne PM with another factor of the skin aging exposome that exerts its deleterious effects in part through AHR-dependent signaling pathways, namely solar ultraviolet radiation.
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Affiliation(s)
- Frederick Hartung
- IUF - Leibniz-Research Institute for Environmental Medicine, 40225, Düsseldorf, Germany
| | - Jean Krutmann
- IUF - Leibniz-Research Institute for Environmental Medicine, 40225, Düsseldorf, Germany; Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225, Düsseldorf, Germany
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9
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Wang C, Jiang X, Li HY, Hu J, Ji Q, Wang Q, Liu X, Huang D, Yan K, Zhao L, Fan Y, Wang S, Ma S, Belmonte JCI, Qu J, Liu GH, Zhang W. RIG-I-driven CDKN1A stabilization reinforces cellular senescence. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1646-1661. [PMID: 40133712 DOI: 10.1007/s11427-024-2844-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/17/2025] [Indexed: 03/27/2025]
Abstract
The innate immune signaling network follows a canonical format for signal transmission. The innate immune pathway is crucial for defense against pathogens, yet its mechanistic crosstalk with aging processes remains largely unexplored. Retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity within this pathway, has an enigmatic role in stem cell senescence. Our study reveals that RIG-I levels increase in human genetic and physiological cellular aging models, and its accumulation drives cellular senescence. Conversely, CRISPR/Cas9-mediated RIG-I deletion or pharmacological inhibition in human mesenchymal stem cells (hMSCs) confers resistance to senescence. Mechanistically, RIG-I binds to endogenous mRNAs, with CDKN1A mRNA being a prominent target. Specifically, RIG-I stabilizes CDKN1A mRNA, resulting in elevated CDKN1A transcript levels and increased p21Cip1 protein expression, which precipitates senescence. Collectively, our findings establish RIG-I as a post-transcriptional regulator of senescence and suggest potential targets for the mitigation of aging-related diseases.
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Affiliation(s)
- Cui Wang
- China National Center for Bioinformation, Beijing, 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoyu Jiang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hong-Yu Li
- Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jianli Hu
- China National Center for Bioinformation, Beijing, 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qianzhao Ji
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qiaoran Wang
- China National Center for Bioinformation, Beijing, 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoqian Liu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Daoyuan Huang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Kaowen Yan
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Liyun Zhao
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Yanling Fan
- China National Center for Bioinformation, Beijing, 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
- Aging Biomarker Consortium, Beijing, 100101, China
| | - Shuai Ma
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Aging Biomarker Consortium, Beijing, 100101, China
| | | | - Jing Qu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Biomarker Consortium, Beijing, 100101, China.
| | - Guang-Hui Liu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Biomarker Consortium, Beijing, 100101, China.
| | - Weiqi Zhang
- China National Center for Bioinformation, Beijing, 100101, China.
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Aging Biomarker Consortium, Beijing, 100101, China.
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10
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Ji J, Zhang B, Zheng J, Zhang X, Hu X, Zhu H, Wang P, Lan Z. Epimedii Folium and Curculiginis Rhizoma ameliorate age-related cognitive decline and neuroinflammation through modulation of the NLRP3 inflammasome. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119883. [PMID: 40319931 DOI: 10.1016/j.jep.2025.119883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/15/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Age-related cognitive decline and neuroinflammation are significant contributors to neurodegenerative diseases. In Traditional Chinese Medicine, aging is often associated with "kidney deficiency," a concept linked to impaired bone marrow production and brain function. Epimedii Folium and Curculiginis Rhizoma (XY), a classic herbal pair used to tonify the kidney, are traditionally employed to enhance vitality, bone health, and cognitive function. While previous studies suggest XY's efficacy in pathological models, its impact on natural aging process requires further investigation. AIM OF THE STUDY This study aimed to investigate the neuroprotective effects of XY against cognitive impairment and neuroinflammation in naturally aged mice and to explore the underlying mechanisms. MATERIALS AND METHODS Network pharmacology was used to identify potential targets and pathways, while molecular docking assessed the binding interactions between active compounds from XY and key target proteins. Naturally aged mice were orally treated with XY (2.34, 4.68 g/kg/day) for 26 days. Cognitive function was assessed using behavioral tests. Histological analysis, ELISA, real-time PCR, and Western blotting were employed to evaluate hippocampal neuronal damage, inflammatory markers, senescence-related proteins, and NLRP3 inflammasome components. RESULTS Network pharmacology identified key targets and pathways associated with aging and neuroinflammation. Molecular docking confirmed strong binding affinities between active components (e.g., Icariin, Epimedin B, Epimedin C) and relevant protein targets. In vivo, XY treatment significantly improved cognitive performance, ameliorated hippocampal neuronal damage, and suppressed microglial activation in aged mice. Furthermore, XY downregulated the expression of senescence markers (p53, p21, p16, CDK6), pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IFN-γ), factors associated with the senescence-associated secretory phenotype (SASP), and key components indicative of NLRP3 inflammasome activation (ASC, Caspase-1, IL-1β). CONCLUSIONS XY alleviates age-related cognitive decline and neuroinflammation in naturally aged mice. These beneficial effects are mediated, at least in part, by reducing inflammatory mediators, modulating microglial activation, attenuating cellular senescence pathways, and suppressing NLRP3 inflammasome activity. These findings highlight the therapeutic potential of XY for managing age-related cognitive impairment and associated neuroinflammation.
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Affiliation(s)
- Jiaqi Ji
- School of Pharmacy, Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, 430065, PR China
| | - Biqun Zhang
- School of Pharmacy, Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, 430065, PR China
| | - Junzuo Zheng
- School of Pharmacy, Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, 430065, PR China
| | - Xuesong Zhang
- School of Pharmacy, Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, 430065, PR China
| | - Xiaosong Hu
- School of Pharmacy, Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, 430065, PR China
| | - He Zhu
- School of Pharmacy, Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, 430065, PR China
| | - Ping Wang
- Engineering Research Center of TCM Protection Technology and New Product Development for the Elderly Brain Health, Ministry of Education, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, PR China
| | - Zhou Lan
- School of Pharmacy, Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, 430065, PR China; Engineering Research Center of TCM Protection Technology and New Product Development for the Elderly Brain Health, Ministry of Education, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, PR China; Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, PR China.
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11
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Picos A, Seoane N, Campos-Toimil M, Viña D. Vascular senescence and aging: mechanisms, clinical implications, and therapeutic prospects. Biogerontology 2025; 26:118. [PMID: 40418230 DOI: 10.1007/s10522-025-10256-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Accepted: 05/11/2025] [Indexed: 05/27/2025]
Abstract
The aging vasculature is characterized by endothelial dysfunction, arterial stiffness, and increased susceptibility to vascular pathologies. Central to these changes is the process of cellular senescence, where endothelial and vascular smooth muscle cells lose their replicative and functional capacity and adopt a pro-inflammatory secretory phenotype. This review provides an overview of the key mechanisms underlying vascular senescence, including the p53/p21 and p16/Rb pathways, the senescence-associated secretory phenotype (SASP), and oxidative stress, examines its contribution to cardiovascular diseases in older adults, and highlights emerging therapeutic strategies aimed at delaying or reversing these age-related vascular changes. In vascular cells, DNA damage, oxidative stress, and chronic inflammation associated with aging converge to amplify senescence. Clinically, vascular senescence is linked with hypertension, atherosclerosis, and increased overall cardiovascular risk. Several interventions, ranging from senolytics to lifestyle factors, show promise in mitigating these changes; however, long-term studies are needed. Given that vascular senescence is a pivotal driver of cardiovascular pathology in aging, targeting senescent cells or their secretory phenotype may potentially offer new avenues for preventing or attenuating age-related vascular diseases. This review presents an updated and integrative overview of vascular senescence, connecting fundamental cellular mechanisms with their clinical manifestations and highlighting the most promising therapeutic interventions.
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Affiliation(s)
- Aitor Picos
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
- Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, Santiago de Compostela, Spain.
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
| | - Nuria Seoane
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
- Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, Santiago de Compostela, Spain
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
| | - Manuel Campos-Toimil
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
- Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, Santiago de Compostela, Spain.
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
| | - Dolores Viña
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
- Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, Santiago de Compostela, Spain
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
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12
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Sen I, Trzaskalski NA, Hsiao YT, Liu PP, Shimizu I, Derumeaux GA. Aging at the Crossroads of Organ Interactions: Implications for the Heart. Circ Res 2025; 136:1286-1305. [PMID: 40403108 DOI: 10.1161/circresaha.125.325637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/18/2025] [Accepted: 04/19/2025] [Indexed: 05/24/2025]
Abstract
Aging processes underlie common chronic cardiometabolic diseases such as heart failure and diabetes. Cross-organ/tissue interactions can accelerate aging through cellular senescence, tissue wasting, accelerated atherosclerosis, increased vascular stiffness, and reduction in blood flow, leading to organ remodeling and premature failure. This interorgan/tissue crosstalk can accelerate aging-related dysfunction through inflammation, senescence-associated secretome, and metabolic and mitochondrial changes resulting in increased oxidative stress, microvascular dysfunction, cellular reprogramming, and tissue fibrosis. This may also underscore the rising incidence and co-occurrence of multiorgan dysfunction in cardiometabolic aging in the population. Examples include interactions between the heart and the lungs, kidneys, liver, muscles, and brain, among others. However, this phenomenon can also present new translational opportunities for identifying diagnostic biomarkers to define early risks of multiorgan dysfunction, gain mechanistic insights, and help to design precision-directed therapeutic interventions. Indeed, this opens new opportunities for therapeutic development in targeting multiple organs simultaneously to disrupt the crosstalk-driven process of mutual disease acceleration. New therapeutic targets could provide synergistic benefits across multiple organ systems in the same at-risk patient. Ultimately, these approaches may together slow the aging process itself throughout the body. In the future, with patient-centered multisystem coordinated approaches, we can initiate a new paradigm of multiorgan early risk prediction and tailored intervention. With emerging tools including artificial intelligence-assisted risk profiling and novel preventive strategies (eg, RNA-based therapeutics), we may be able to mitigate multiorgan cardiometabolic dysfunction much earlier and, perhaps, even slow the aging process itself.
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Affiliation(s)
- Ilke Sen
- Department of Physiology, INSERM U955 (Institut national de la santé et de la recherche médicale, Unité 955), Assistance Publique-Hôpitaux de Paris (AP-HP), Henri Mondor Hospital, Fédération Hospitalo-Universitaire (FHU SENCODE), Ecole Universitaire de Recherche LIVE (EUR LIVE), Université Paris-Est Créteil, France (I. Sen, G.A.D.)
| | - Natasha A Trzaskalski
- University of Ottawa Heart Institute, Brain-Heart Interconnectome, University of Ottawa, Ontario, Canada (N.A.T., P.P.L.)
| | - Yung-Ting Hsiao
- Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (Y.-T.H., I. Shimizu)
| | - Peter P Liu
- University of Ottawa Heart Institute, Brain-Heart Interconnectome, University of Ottawa, Ontario, Canada (N.A.T., P.P.L.)
| | - Ippei Shimizu
- Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (Y.-T.H., I. Shimizu)
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (I. Shimizu)
| | - Geneviève A Derumeaux
- Department of Physiology, INSERM U955 (Institut national de la santé et de la recherche médicale, Unité 955), Assistance Publique-Hôpitaux de Paris (AP-HP), Henri Mondor Hospital, Fédération Hospitalo-Universitaire (FHU SENCODE), Ecole Universitaire de Recherche LIVE (EUR LIVE), Université Paris-Est Créteil, France (I. Sen, G.A.D.)
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13
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Grossi E, Marchese FP, González J, Goñi E, Fernández-Justel JM, Amadoz A, Herranz N, Puchades-Carrasco L, Montes M, Huarte M. A lncRNA-mediated metabolic rewiring of cell senescence. Cell Rep 2025; 44:115747. [PMID: 40408249 DOI: 10.1016/j.celrep.2025.115747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 03/21/2025] [Accepted: 05/06/2025] [Indexed: 05/25/2025] Open
Abstract
Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.
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Affiliation(s)
- Elena Grossi
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Francesco P Marchese
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Jovanna González
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Enrique Goñi
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - José Miguel Fernández-Justel
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Alicia Amadoz
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Nicolás Herranz
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
| | - Leonor Puchades-Carrasco
- Drug Discovery Unit, Instituto de Investigación Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain
| | - Marta Montes
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
| | - Maite Huarte
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
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14
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Salvarredi L, Agüero H, Millan ME, Marra MF, Callegari E, Castro C, Lopez L. Radiation-induced senescent melanoma cells secrete soluble factors that trigger bystander senescence. Int J Radiat Biol 2025:1-10. [PMID: 40397620 DOI: 10.1080/09553002.2025.2505525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 04/17/2025] [Accepted: 04/29/2025] [Indexed: 05/23/2025]
Abstract
PURPOSE Senescence is a key cellular response to ionizing radiation. Senescent cells experience irreversible growth arrest while remaining metabolically active and secrete a distinct set of proteins, collectively referred to as the senescence-associated secretory phenotype (SASP). These secreted factors influence neighboring non-irradiated cells through a mechanism known as the bystander effect. This study aimed to investigate and characterize the bystander effect in a melanoma cell model. MATERIAL AND METHODS Murine melanoma B16F0 cells were exposed to X-irradiation (10 Gy), and senescence was induced 3 days later. Conditioned media from the senescent cells was collected and used to culture non-irradiated B16F0 cells. Proliferation, viability, clonogenic capacity, DNA damage foci formation, apoptosis, and senescence were assessed. The composition of the senescence-associated secretory phenotype was analyzed using mass spectrometry and bioinformatics tools. RESULTS Conditioned media from senescent cells induced by radiation reduced growth and promoted senescence in tumor cell cultures not exposed to ionizing radiation. Mass spectrometry analysis revealed greater protein diversity and abundance in conditioned media from senescent cells compared to that from non-irradiated cells. Additionally, conditioned media from senescent cells contained higher concentrations of proteins related to immune response, cellular aging, and responses to oxidative stress. CONCLUSIONS Cells undergoing radiation-induced senescence promote bystander senescence by secreting soluble factors involved in the induction and maintenance of senescence.
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Affiliation(s)
- Leonardo Salvarredi
- Nuclear Medicine School Foundation, Mendoza, Argentina
- National Commission of Atomic Energy (CNEA), Mendoza, Argentina
- Balseiro Institute, National Commission of Atomic Energy & National University of Cuyo, Mendoza, Argentina
- Faculty of Medical Sciences, Institute of Biochemistry and Biotechnology, National University of Cuyo, Mendoza, Argentina
| | - Héctor Agüero
- Nuclear Medicine School Foundation, Mendoza, Argentina
- Balseiro Institute, National Commission of Atomic Energy & National University of Cuyo, Mendoza, Argentina
| | - María Elisa Millan
- Institute of Histology and Embryology of Mendoza (IHEM), National Scientific and Technical Research Council (CONICET), Mendoza, Argentina
| | - María Fernanda Marra
- Institute of Histology and Embryology of Mendoza (IHEM), National Scientific and Technical Research Council (CONICET), Mendoza, Argentina
| | - Eduardo Callegari
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, USA
| | - Claudia Castro
- Faculty of Medical Sciences, Institute of Biochemistry and Biotechnology, National University of Cuyo, Mendoza, Argentina
- Institute of Experimental Medicine and Biology of Cuyo (IMBECU), National Scientific and Technical Research Council (CONICET), Mendoza, Argentina
| | - Luis Lopez
- Institute of Histology and Embryology of Mendoza (IHEM), National Scientific and Technical Research Council (CONICET), Mendoza, Argentina
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15
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Ryan P, Lee J. In vitro senescence and senolytic functional assays. Biomater Sci 2025. [PMID: 40375674 DOI: 10.1039/d4bm01684j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
A detailed understanding of aging biology and the development of anti-aging therapeutic strategies remain imperative yet inherently challenging due to the protracted nature of aging. Cellular senescence arises naturally through replicative exhaustion and is accelerated by clinical treatments or environmental stressors. The accumulation of senescent cells-defined by a loss of mitogenic potential, resistance to apoptosis, and acquisition of a pro-inflammatory secretory phenotype-has been implicated as a key driver of chronic disease, tissue degeneration, and organismal aging. Recent studies have highlighted the therapeutic promise of senolytic drugs, which selectively eliminate senescent cells. Compelling results from preclinical animal studies and ongoing clinical trials underscore this potential. However, the clinical translation of senolytics requires further pharmacological validation to refine selectivity, minimize toxicity, and determine optimal dosing. Equally important is the evaluation of senolytics' potential to restore tissue structure and function by reducing the senescent cell burden. In vitro tissue culture models offer a powerful platform to advance these efforts. This review summarizes the current landscape of in vitro systems used for inducing cellular senescence-referred to as "senescence assays"-and for screening senolytic drugs-referred to as "senolytic assays". We conclude by discussing key challenges to improving mechanistic insight, predictive accuracy, and clinical relevance in senolytic drug development, as well as emerging applications of senolytic therapies.
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Affiliation(s)
- Patrick Ryan
- Molecular & Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, 01003, USA.
| | - Jungwoo Lee
- Molecular & Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, 01003, USA.
- Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, 01003, USA
- Department of Biomedical Engineering, University of Massachusetts, Amherst, Massachusetts, 01003, USA
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16
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Adam N, Yang Y, Djamshidi M, Seifan S, Ting NSY, Glover J, Touret N, Gordon PMK, Vineetha Warriyar KV, Krowicki H, Garcia CK, Savage SA, Goodarzi AA, Baird DM, Beattie TL, Riabowol K. hTERT Increases TRF2 to Induce Telomere Compaction and Extend Cell Replicative Lifespan. Aging Cell 2025:e70105. [PMID: 40371663 DOI: 10.1111/acel.70105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 04/22/2025] [Accepted: 04/29/2025] [Indexed: 05/16/2025] Open
Abstract
Replicative senescence occurs in response to shortened telomeres and is triggered by ATM and TP53-mediated DNA damage signaling that blocks replication. hTERT lengthens telomeres, which is thought to block damage signaling and the onset of senescence. We find that normal diploid fibroblasts expressing hTERT mutants unable to maintain telomere length do not initiate DNA damage signaling and continue to replicate, despite having telomeres shorter than senescent cells. The TRF1 and TRF2 DNA binding proteins of the shelterin complex stabilize telomeres, and we find that expression of different mutant hTERT proteins decreases levels of the Siah1 E3 ubiquitin ligase that targets TRF2 to the proteasome, by increasing levels of the CDC20 and FBXO5 E3 ligases that target Siah1. This restores the TRF2:TRF1 ratio to block the activation of ATM and subsequent activation of TP53 that is usually associated with DNA damage-induced senescence signaling. All hTERT variants reduce DNA damage signaling, and this occurs concomitantly with telomeres assuming a more compact, denser conformation than senescent cells as measured by super-resolution microscopy. This indicates that hTERT variants induce TRF2-mediated telomere compaction that is independent of telomere length, and it plays a dominant role in regulating the DNA damage signaling that induces senescence and blocks replication of human fibroblasts. These observations support the idea that very short telomeres often seen in cancer cells may fail to induce senescence due to selective stabilization of components of the shelterin complex, increasing telomere density, rather than maintaining telomere length via the reverse transcriptase activity of hTERT.
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Affiliation(s)
- Nancy Adam
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Yang Yang
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Mahbod Djamshidi
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sara Seifan
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Nicholas S Y Ting
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Joel Glover
- Live Cell Imaging Laboratory, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Nicolas Touret
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Paul M K Gordon
- Centre for Health Genomics and Informatics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - K V Vineetha Warriyar
- Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Hokan Krowicki
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Aaron A Goodarzi
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Duncan M Baird
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Tara L Beattie
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Karl Riabowol
- Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and/or Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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17
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Graves SI, Meyer CF, Jeganathan KB, Baker DJ. p16-expressing microglia and endothelial cells promote tauopathy and neurovascular abnormalities in PS19 mice. Neuron 2025:S0896-6273(25)00303-4. [PMID: 40381614 DOI: 10.1016/j.neuron.2025.04.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 11/15/2024] [Accepted: 04/21/2025] [Indexed: 05/20/2025]
Abstract
Cellular senescence is characterized by irreversible cell-cycle exit, a pro-inflammatory secretory phenotype, macromolecular damage, and deregulated metabolism. Senescent cells are highly associated with age-related diseases. We previously demonstrated that targeted elimination of senescent cells prevents neurodegenerative disease in tau (MAPTP301S;PS19) mutant mice. Here, we show that genetic ablation of the senescence mediator p16Ink4a is sufficient to attenuate senescence signatures in PS19 mice. Disease phenotypes-including neuroinflammation, phosphorylated tau, neurodegeneration, and cognitive impairment-were blunted in the absence of p16Ink4a. Additionally, we found that PS19 mouse brains display p16Ink4-dependent neurovascular alterations such as vessel dilation, increased vessel density, deregulated endothelial cell extracellular matrix, and astrocytic endfoot depolarization. Finally, we show that p16Ink4a deletion in endothelial cells and microglia alone attenuates many of the same phenotypes. Altogether, these results indicate that neurodegenerative disease in PS19 mice is driven, at least in part, by p16Ink4a-expressing endothelial cells and microglia.
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Affiliation(s)
- Sara I Graves
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 1st ST., Rochester, MN 55905, USA
| | - Charlton F Meyer
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 1st ST., Rochester, MN 55905, USA
| | - Karthik B Jeganathan
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 1st ST., Rochester, MN 55905, USA
| | - Darren J Baker
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 1st ST., Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 1st ST., Rochester, MN 55905, USA; Paul F. Glenn Center for Biology of Aging Research, Mayo Clinic, 200 1st ST., Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 1st ST., Rochester, MN 55905, USA.
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18
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Yesilyurt-Dirican ZE, Qi C, Wang YC, Simm A, Deelen L, Hafiz Abbas Gasim A, Lewis-McDougall F, Ellison-Hughes GM. SGLT2 inhibitors as a novel senotherapeutic approach. NPJ AGING 2025; 11:35. [PMID: 40348751 PMCID: PMC12065912 DOI: 10.1038/s41514-025-00227-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 04/23/2025] [Indexed: 05/14/2025]
Abstract
Cellular senescence is the permanent cessation of cell proliferation and growth. Senescent cells accumulating in tissues and organs with aging contribute to many chronic diseases, mainly through the secretion of a pro-inflammatory senescence-associated secretory phenotype (SASP). Senotherapeutic (senolytic or senomorphic) strategies targeting senescent cells or/and their SASP are being developed to prolong healthy lifespan and treat age-related pathologies. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of anti-diabetic drugs that promote the renal excretion of glucose, resulting in lower blood glucose levels. Beyond their glucose-lowering effects, SGLT2 inhibitors have demonstrated protective effects against cardiovascular and renal events. Moreover, SGLT2 inhibitors have recently been associated with the inhibition of cell senescence, making them a promising therapeutic approach for targeting senescence and aging. This review examines the latest research on the senotherapeutic potential of SGLT2 inhibitors.
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Affiliation(s)
- Zeynep Elif Yesilyurt-Dirican
- Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara, Türkiye
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Ce Qi
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Yi-Chian Wang
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Annika Simm
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Laura Deelen
- Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, UK
- Centre for Microvascular Research, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Alia Hafiz Abbas Gasim
- Centre for Microvascular Research, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Fiona Lewis-McDougall
- Centre for Microvascular Research, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Georgina M Ellison-Hughes
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK.
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19
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Wei H, Liu Y, Huang C, Wang C, Jiang H, Wang L, Wang Y, Wang Z. Ginsenoside Rg1 targets TLR2 to inhibit the NF-κB signaling pathway and ameliorate hematopoietic support of mesenchymal stromal cells. JOURNAL OF ETHNOPHARMACOLOGY 2025; 349:119917. [PMID: 40348305 DOI: 10.1016/j.jep.2025.119917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/19/2025] [Accepted: 05/01/2025] [Indexed: 05/14/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ginsenoside Rg1 is a key bioactive compound in ginseng, a traditional herbal medicine known for tonifying qi and nourishing blood, traditionally used to replenish "qi" by regulating hematopoietic function. But its underlying mechanism remains to be elucidated. AIM OF THE STUDY This study aims to delve into the role of Rg1 on senescent hematopoiesis and its mechanisms. MATERIALS AND METHODS A model of D-galactose-induced hematopoietic injury was established with ginsenoside Rg1. The hematopoietic supportive effect of Rg1 was assessed by quantifying the levels of hematopoietic supportive factors VCAM1, CXCL12 and SCF, CFU-Mix formation and cellular senescence; and the levels of inflammatory factors and oxidative stress were measured by ELISA in the serum and cellular supernatant of mice. Co-culture technique was used to examine the ability of Rg1 to restore impaired hematopoiesis by improving the inflammatory hematopoietic microenvironment. For mechanism exploration, RNA-Seq was used to detect differential genes in Rg1-treated MSCs, GO- and KEGG-based enrichment analyses were used to screen the key pathways in which Rg1 exerts its effects, and molecular docking was used to demonstrate the feasibility of molecular interconnections between Rg1 and TLR2. To further explore the mechanism, pathway activators were further used and the expression levels of target proteins downstream of the TLR2 pathway were quantified using Western blotting. RESULTS Rg1 decreased the levels of inflammatory factors IL-1β, IL-6 and TNFα, while enhancing the expression of hematopoietic support factors in senescent MSCs, thereby improving the self-renewal and differentiation of aged HSPCs. Additionally, Rg1 also delayed HSPC senescence and reduced the level of oxidative stress. KEGG and GO were enriched for the Toll/NF-κB signaling pathway, based on differential genes obtained by transcriptional sequencing. Rg1 could inhibit the elevated levels of MyD88, NF-κB-p65 and IκBα proteins, and their phosphorylation levels by binding to TLR2 protein and inhibiting them. In conclusion, Rg1 ameliorates the inflammatory hematopoietic microenvironment induced by MSCs senescence via the TLR2/NF-κB-p65 signaling pathway, alleviating HSPCs senescence. CONCLUSIONS Our results reveal the mechanism by which Rg1 regulates HSPCs function and represent a potential therapeutic strategy for hematopoietic dysfunction, highlighting the potential value of traditional Chinese medicine extracts in clinical applications.
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Affiliation(s)
- Han Wei
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Yonggang Liu
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Caihong Huang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Cheng Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Honghui Jiang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Lu Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China
| | - Yaping Wang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, PR China.
| | - Ziling Wang
- Department of Pathology, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, PR China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, PR China.
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20
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Tejedor-Santamaria L, Marquez-Exposito L, Villacampa A, Marchant V, Battaglia-Vieni A, Rayego-Mateos S, Rodrigues-Diez RR, Santos FM, Valentijn FA, Knoppert SN, Broekhuizen R, Ruiz-Torres MP, Goldschmeding R, Ortiz A, Peiró C, Nguyen TQ, Ramos AM, Ruiz-Ortega M. CCN2 Activates Cellular Senescence Leading to Kidney Fibrosis in Folic Acid-Induced Experimental Nephropathy. Int J Mol Sci 2025; 26:4401. [PMID: 40362638 PMCID: PMC12072722 DOI: 10.3390/ijms26094401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/28/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025] Open
Abstract
Cellular communication network factor 2 (CCN2, also known as CTGF) is a complex protein that regulates numerous cellular functions. This biomolecule exhibits dual functions, depending on the context, and can act as a matricellular protein or as a growth factor. CCN2 is an established marker of fibrosis and a well-known mediator of kidney damage, involved in the regulation of inflammation, extracellular matrix remodeling, cell death, and activation of tubular epithelial cell (TECs) senescence. In response to kidney damage, cellular senescence mechanisms are activated, linked to regeneration failure and progression to fibrosis. Our preclinical studies using a total conditional CCN2 knockout mouse demonstrate that CCN2 plays a significant role in the development of a senescence phenotype after exposure to a nephrotoxic agent. CCN2 induces cell growth arrest in TECs, both in the early phase and in the chronic phase of folic acid nephropathy (FAN), associated with cell-death/necroinflammation and fibrosis, respectively. Renal CCN2 overexpression was found to be linked to excessive collagen accumulation in tubulointerstitial areas, microvascular rarefaction, and a decline in renal function, which were observed three weeks following the initial injury. All these findings were markedly diminished in conditional CCN2 knockout mice. In the FAN model, injured senescent TECs are associated with microvascular rarefaction, and both were modulated by CCN2. In primary cultured endothelial cells, as previously described in TECs, CCN2 directly induced senescence. The findings collectively demonstrate the complexity of CCN2, highlight the pivotal role of cellular senescence as an important mechanism in renal injury, and underscore the critical function of this biomolecule in kidney damage progression.
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Affiliation(s)
- Lucia Tejedor-Santamaria
- Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.T.-S.); (L.M.-E.); (V.M.); (A.B.-V.); (S.R.-M.); (F.M.S.)
- Instituto de Salud Carlos III., 28029 Madrid, Spain; (A.O.); (A.M.R.)
| | - Laura Marquez-Exposito
- Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.T.-S.); (L.M.-E.); (V.M.); (A.B.-V.); (S.R.-M.); (F.M.S.)
- Instituto de Salud Carlos III., 28029 Madrid, Spain; (A.O.); (A.M.R.)
| | - Alicia Villacampa
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain; (A.V.); (C.P.)
- Vascular Pharmacology and Metabolism (FARMAVASM) Group, IdiPAZ, 28029 Madrid, Spain
| | - Vanessa Marchant
- Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.T.-S.); (L.M.-E.); (V.M.); (A.B.-V.); (S.R.-M.); (F.M.S.)
- Instituto de Salud Carlos III., 28029 Madrid, Spain; (A.O.); (A.M.R.)
| | - Antonio Battaglia-Vieni
- Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.T.-S.); (L.M.-E.); (V.M.); (A.B.-V.); (S.R.-M.); (F.M.S.)
| | - Sandra Rayego-Mateos
- Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.T.-S.); (L.M.-E.); (V.M.); (A.B.-V.); (S.R.-M.); (F.M.S.)
- Instituto de Salud Carlos III., 28029 Madrid, Spain; (A.O.); (A.M.R.)
| | - Raul R. Rodrigues-Diez
- Department of Cell Biology, School of Medicine, Complutense University, 28040 Madrid, Spain;
| | - Fatima Milhano Santos
- Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.T.-S.); (L.M.-E.); (V.M.); (A.B.-V.); (S.R.-M.); (F.M.S.)
- Instituto de Salud Carlos III., 28029 Madrid, Spain; (A.O.); (A.M.R.)
| | - Floris A. Valentijn
- Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (F.A.V.); (S.N.K.); (R.B.); (R.G.); (T.Q.N.)
| | - Sebastian N. Knoppert
- Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (F.A.V.); (S.N.K.); (R.B.); (R.G.); (T.Q.N.)
| | - Roel Broekhuizen
- Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (F.A.V.); (S.N.K.); (R.B.); (R.G.); (T.Q.N.)
| | | | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (F.A.V.); (S.N.K.); (R.B.); (R.G.); (T.Q.N.)
| | - Alberto Ortiz
- Instituto de Salud Carlos III., 28029 Madrid, Spain; (A.O.); (A.M.R.)
- Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28049 Madrid, Spain
| | - Concepción Peiró
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain; (A.V.); (C.P.)
- Vascular Pharmacology and Metabolism (FARMAVASM) Group, IdiPAZ, 28029 Madrid, Spain
| | - Tri Q. Nguyen
- Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (F.A.V.); (S.N.K.); (R.B.); (R.G.); (T.Q.N.)
| | - Adrián M. Ramos
- Instituto de Salud Carlos III., 28029 Madrid, Spain; (A.O.); (A.M.R.)
- Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28049 Madrid, Spain
| | - Marta Ruiz-Ortega
- Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.T.-S.); (L.M.-E.); (V.M.); (A.B.-V.); (S.R.-M.); (F.M.S.)
- Instituto de Salud Carlos III., 28029 Madrid, Spain; (A.O.); (A.M.R.)
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21
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Huang Y, Qiu Z, Jiang C, Fang Q, Wang J, Han M, Liu Y, Li Z. ANXA2 regulates mitochondrial function and cellular senescence of PDLCs via AKT/eNOS signaling pathway under high glucose conditions. Sci Rep 2025; 15:15843. [PMID: 40328825 PMCID: PMC12056103 DOI: 10.1038/s41598-025-00950-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 05/02/2025] [Indexed: 05/08/2025] Open
Abstract
Diabetes mellitus is one of the risk factors for periodontitis. Patients with diabetes mellitus possess higher prevalence of periodontitis, more severe periodontal destruction, yet the underlying mechanisms of action are not yet clear. Annexin A2 (ANXA2) is a calcium-dependent phospholipid-binding protein widely involved in membrane repair, cytokinesis, and endocytosis. In this study, we explore whether ANXA2 is one of the associative links between diabetes and periodontitis and find out its underlying mechanisms. Cellular senescence and mitochondrial functions (ROS, mitochondrial morphology, mitochondrial autophagy) were observed. We observed that ANXA2 expression was down-regulated in Periodontal ligament cells (PDLCs) under high glucose conditions. Furthermore, overexpression of ANXA2 delayed high glucose-induced cellular senescence and mitochondrial dysfunction. β-galactosidase activity and the mRNA levels of the senescence-relative genes(p21,p16) were decreased, mitochondrial fracture and ROS release were reduced, and the expression of mitochondrial autophagy-related proteins (LC3,p62,Parkin) was enhanced. expression was enhanced. Mechanistically, we demonstrated that it can regulate the AKT/eNOS signaling pathway by knockdown and overexpression of ANXA2 which was measured using Western blotting (WB) assay to measure the expression of eNOS, p-eNOS Ser1177, Akt and p-Akt Ser473 proteins in PDLCs. After that, we used AKT and eNOS inhibitors to demonstrate the protective effect of ANXA2 on PDLCs under high glucose conditions. The above results suggest that ANXA2 has an anti-aging protective effect, attenuates high glucose-induced cellular senescence in PDLCs, and maintains mitochondrial homeostasis. Therefore, it would be valuable to further explore its role in the link between diabetes and periodontitis in future experiments.
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Affiliation(s)
- Yanlin Huang
- Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of stomatology, The People's Hospital of Sanshui District, Foshan, Guangdong, China
| | - Zejing Qiu
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Chunhui Jiang
- Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
- Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Qian Fang
- Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
- Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jiaye Wang
- Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
- Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Mingfang Han
- Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
- Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yizhao Liu
- Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
- Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zehui Li
- Department of stomatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
- Hangzhou Normal University, Hangzhou, Zhejiang, China.
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22
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Athar F, Zheng Z, Riquier S, Zacher M, Lu JY, Zhao Y, Volobaev V, Alcock D, Galazyuk A, Cooper LN, Schountz T, Wang LF, Teeling EC, Seluanov A, Gorbunova V. Limited cell-autonomous anticancer mechanisms in long-lived bats. Nat Commun 2025; 16:4125. [PMID: 40319021 PMCID: PMC12049446 DOI: 10.1038/s41467-025-59403-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 04/22/2025] [Indexed: 05/07/2025] Open
Abstract
Several bat species live >20-40 years, suggesting that they possess efficient anti-aging and anti-cancer defenses. Here we investigate the requirements for malignant transformation in primary fibroblasts from four bat species Myotis lucifugus, Eptesicus fuscus, Eonycteris spelaea, and Artibeus jamaicensis - spanning the bat evolutionary tree and including the longest-lived genera. We show that bat fibroblasts do not undergo replicative senescence, express active telomerase, and show attenuated SIPs with dampened secretory phenotype. Unexpectedly, unlike other long-lived mammals, bat fibroblasts are readily transformed by two oncogenic "hits": inactivation of p53 or pRb and activation of HRASG12V. Bat fibroblasts exhibit increased TP53 and MDM2 transcripts and elevated p53-dependent apoptosis. M. lucifugus shows a genomic duplication of TP53. We hypothesize that some bat species have evolved enhanced p53 activity as an additional anti-cancer strategy, similar to elephants. Further, the absence of unique cell-autonomous tumor suppressive mechanisms may suggest that in vivo bats may rely on enhanced immunosurveillance.
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Affiliation(s)
- Fathima Athar
- Department of Biology, University of Rochester, Rochester, NY, USA
| | - Zhizhong Zheng
- Department of Biology, University of Rochester, Rochester, NY, USA
| | - Sebastien Riquier
- School of Biology and Environmental Science, Belfield, University College Dublin, Dublin, Ireland
| | - Max Zacher
- Department of Biology, University of Rochester, Rochester, NY, USA
| | - J Yuyang Lu
- Department of Biology, University of Rochester, Rochester, NY, USA
| | - Yang Zhao
- Department of Biology, University of Rochester, Rochester, NY, USA
| | | | - Dominic Alcock
- School of Biology and Environmental Science, Belfield, University College Dublin, Dublin, Ireland
| | - Alex Galazyuk
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Lisa Noelle Cooper
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Tony Schountz
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Lin-Fa Wang
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore; SingHealth Duke-NUS Global Health Institute, Singapore, Singapore
| | - Emma C Teeling
- School of Biology and Environmental Science, Belfield, University College Dublin, Dublin, Ireland
| | - Andrei Seluanov
- Department of Biology, University of Rochester, Rochester, NY, USA.
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
| | - Vera Gorbunova
- Department of Biology, University of Rochester, Rochester, NY, USA.
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
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23
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Xiong J, Guo Q, Luo X. Cellular senescence in age-related musculoskeletal diseases. Front Med 2025:10.1007/s11684-025-1125-7. [PMID: 40314896 DOI: 10.1007/s11684-025-1125-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 12/16/2024] [Indexed: 05/03/2025]
Abstract
Aging is typically associated with decreased musculoskeletal function, leading to reduced mobility and increased frailty. As a hallmark of aging, cellular senescence plays a crucial role in various age-related musculoskeletal diseases, including osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. The detrimental effects of senescence are primarily due to impaired regenerative capacity of stem cells and the pro-inflammatory environment created by accumulated senescent cells. The secreted senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, further amplifying senescent signals. Although the removal of senescent cells and the suppression of SASP factors have shown promise in alleviating disease progression and restoring musculoskeletal health in mouse models, clinical trials have yet to demonstrate significant efficacy. This review summarizes the mechanisms of cellular senescence in age-related musculoskeletal diseases and discusses potential therapeutic strategies targeting cellular senescence.
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Affiliation(s)
- Jinming Xiong
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China
| | - Qiaoyue Guo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China.
| | - Xianghang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China.
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24
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Kamii M, Kamata R, Saito H, Yamamoto G, Mashima C, Yamauchi T, Nakao T, Sakae Y, Yamamori-Morita T, Nakai K, Hakozaki Y, Takenaka M, Okamoto A, Ohashi A. PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells. Sci Rep 2025; 15:15458. [PMID: 40316566 PMCID: PMC12048520 DOI: 10.1038/s41598-025-00336-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 04/28/2025] [Indexed: 05/04/2025] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors have improved the prognosis of homologous recombination deficient (HRD) ovarian cancer (OC), while effective therapeutic strategies for HR-proficient (HRP) OC still need to be established. This study investigates senescence-mediated inflammation as a novel mechanism of action for PARP inhibitors in HRP cancers. Transcriptome analyses were performed in olaparib-treated HeLa cells as a HRP model. Interferon regulatory factor-Lucia luciferase (IRF-Luc) reporter activity was assessed. The effects of PARP inhibitors on senescence-like phenotypes were assessed in seven HRP cancer cell lines, based on morphological changes, senescence-associated β-galactosidase (SA-β-GAL) activity, cellular granularity, and senescence-associated secretory phenotype (SASP)-related gene expression. Peripheral blood mononuclear cell (PBMC) migration assays were also performed with the conditioned medium in treatment with the PARP inhibitor. Transcriptome analyses revealed numbers of inflammatory cytokine- and chemokine-related pathways were significantly upregulated in olaparib-treated HeLa cells, which were confirmed by IRF-Luc reporter assays. The PARP inhibitors induced senescent phenotypes in HRP cancer cell lines: flattened and enlarged morphology, increased SA-β-GAL activity, elevated cellular granularity, and upregulated expressions of SASP-related genes (e.g., IL1B, IL6, and CXCL10). Furthermore, in vitro migration assays revealed that PARP inhibitor-treated HRP cancer cells attracted PBMCs more abundantly, suggesting the potential for recruiting immune cells to HRP cancer cells through senescence-mediated immunological activation. Our findings suggest that PARP inhibitors recruit immune cells to HRP cancer cells, potentially activating immune responses in the tumor microenvironment, providing new insights into the clinical benefits of PARP inhibitors in immunotherapy for patients with HRP OC.
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Affiliation(s)
- Misato Kamii
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Ryo Kamata
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
| | - Hitoshi Saito
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Gaku Yamamoto
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Chiaki Mashima
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Toyohiro Yamauchi
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Integrated Bioscience, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-0882, Japan
| | - Takehiro Nakao
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yuta Sakae
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Tomoko Yamamori-Morita
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Kazuki Nakai
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yumi Hakozaki
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Masataka Takenaka
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Aikou Okamoto
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Akihiro Ohashi
- Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
- Department of Integrated Bioscience, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-0882, Japan.
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25
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Khalaf F, Barayan D, Saldanha S, Jeschke MG. Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction. Metabolism 2025; 166:156158. [PMID: 39947519 DOI: 10.1016/j.metabol.2025.156158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/31/2025] [Accepted: 02/09/2025] [Indexed: 02/16/2025]
Abstract
With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of "metabolaging." This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, "metabolaging" provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.
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Affiliation(s)
- Fadi Khalaf
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; David Braley Research Institute, Hamilton, Ontario, Canada; Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Dalia Barayan
- David Braley Research Institute, Hamilton, Ontario, Canada; Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Sean Saldanha
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; David Braley Research Institute, Hamilton, Ontario, Canada; Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Marc G Jeschke
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; David Braley Research Institute, Hamilton, Ontario, Canada; Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
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Nguyen HH, Gupta I, Cellini A, Papadimitriou JC, Mehra R, Gaykalova DA, Witek ME. Comprehensive Analysis Reveals No Significant Correlation Between p16/ CDKN2A Expression and Treatment Outcomes in Laryngeal Squamous Cell Carcinoma. Head Neck 2025; 47:1315-1328. [PMID: 39714101 DOI: 10.1002/hed.28044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 11/16/2024] [Accepted: 12/10/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND The p16/CDKN2A protein is being explored as an independent prognostic marker in laryngeal cancer, with studies suggesting that p16-positive patients may have a better prognosis. While its role is well-established in oropharyngeal squamous cell carcinoma (OPSCC) related to HPV, ongoing research indicates its potential prognostic value in laryngeal cancer, even in HPV-negative cases. METHODS In this study, we investigated the association between survival outcomes and p16 expression in a cohort of 310 laryngeal cancer patients from the Cancer Genome Atlas (TCGA) Program and the University of Maryland Medical Center (UMMC). RESULTS In the TCGA cohort, patients with high p16 protein expression had a significantly higher probability of disease-free survival (DFS) at 89%, compared to 51% in the low p16 protein group (p = 0.0266). Additionally, the mean relative p16 protein expression decreased significantly with advancing TNM stage, measured at 1.116 for stage II, 1.075 for stage III, and 0.6204 for stage IV (p = 0.7871 for stage II vs. stage III, p = 0.0065 for stage III vs. stage IV, p = 0.0031 for stage I vs. stage IV). Protein expression for p16 also correlated with CDKN2A retention/deletion status (p = 0.0077), where the DFS was higher in patients with retained CDKN2A than those with deleted CDKN2A (p = 0.0187). Multivariate analysis of the UMMC and TCGA cohorts revealed that both an increase in the patient's age and higher T stage significantly increased the risk of mortality (p = 0.05, p = 0.01, respectively). CONCLUSION While this study observes trends suggesting that low p16 protein expression is associated with longer DFS and advanced TNM stage in laryngeal cancer, the multivariate analysis did not establish p16 as an independent prognostic factor. These findings suggest that while p16 may have a biological role in tumor progression, its utility as a standalone prognostic marker in clinical outcomes requires further validation.
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Affiliation(s)
| | - Ishita Gupta
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Ashley Cellini
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - John C Papadimitriou
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Ranee Mehra
- Department of Medical Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Daria A Gaykalova
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Matthew E Witek
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Medstar Georgetown University Hospital, Washington, DC, USA
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Klier S, Dananberg J, Masaki L, Bhisitkul RB, Khanani AM, Maturi R, Salehi-Had H, Mallinckrodt CH, Rathmell JM, Ghosh A, Sapieha P. Safety and Efficacy of Senolytic UBX1325 in Diabetic Macular Edema. NEJM EVIDENCE 2025; 4:EVIDoa2400009. [PMID: 40261111 DOI: 10.1056/evidoa2400009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
BACKGROUND We tested the ability of a single intravitreal injection of foselutoclax (hereafter UBX1325), a novel senolytic small molecule inhibitor of antiapoptotic protein B-cell lymphoma-extra large, to mitigate the impact of diabetic macular edema. METHODS Patients with diabetic macular edema with prior suboptimal response to anti-vascular endothelial growth factor treatment were randomly assigned (1:1) to either a single intravitreal injection of 10 μg of UBX1325 or sham and were followed for up to 48 weeks. The primary trial objective was to evaluate the safety and side-effect profile of UBX1325 as assessed by ocular and systemic treatment-emergent adverse events (TEAEs). Our secondary objective was to probe efficacy, defined as mean changes from baseline for UBX1325 versus sham in best corrected visual acuity measured in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (range, 0-100 letters, higher scores indicate better vision) and retinal structure. RESULTS Between June 2021 and April 2022, 65 participants (32.3% women) were randomly assigned to either UBX1325 (n=32) or sham (n=33). There were four TEAEs of Grade 3 or greater in the sham group, of which three were considered serious, while there were five in the UBX1325 group of Grade 3 or greater and considered serious. There were no apparent between-group differences with respect to vital signs, electrocardiograms, or routine blood chemistries. For the secondary outcome of efficacy, the difference between UBX1325 and sham in mean change to week 48 in best corrected visual acuity was 5.6 more ETDRS letters (95% confidence interval, -1.5 to 12.7). CONCLUSIONS In this sham-controlled trial there were no TEAEs that led to discontinuation of treatment with UBX1325 compared with sham. There were trends suggestive of potential efficacy; larger trials are needed to further evaluate these findings. (Funded by UNITY Biotechnology; ClinicalTrials.gov number, NCT04857996.).
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Affiliation(s)
| | | | | | | | - Arshad M Khanani
- Sierra Eye Associates, Reno, NV, and Reno School of Medicine, The University of Nevada, Reno, NV
| | - Raj Maturi
- Midwest Eye Institute, Indianapolis
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis
| | - Hani Salehi-Had
- Retina Associates of Southern California, Huntington Beach, CA
| | | | | | | | - Przemyslaw Sapieha
- UNITY Biotechnology, San Francisco
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal
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Admasu TD, Yu JS. Harnessing Immune Rejuvenation: Advances in Overcoming T Cell Senescence and Exhaustion in Cancer Immunotherapy. Aging Cell 2025; 24:e70055. [PMID: 40178455 PMCID: PMC12073907 DOI: 10.1111/acel.70055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/15/2025] [Accepted: 03/14/2025] [Indexed: 04/05/2025] Open
Abstract
Immunotherapy has transformed the landscape of cancer treatment, with T cell-based strategies at the forefront of this revolution. However, the durability of these responses is frequently undermined by two intertwined phenomena: T cell exhaustion and senescence. While exhaustion is driven by chronic antigen exposure in the immunosuppressive tumor microenvironment, leading to a reversible state of diminished functionality, senescence reflects a more permanent, age- or stress-induced arrest in cellular proliferation and effector capacity. Together, these processes represent formidable barriers to sustained anti-tumor immunity. In this review, we dissect the molecular underpinnings of T cell exhaustion and senescence, revealing how these dysfunctions synergistically contribute to immune evasion and resistance across a range of solid tumors. We explore cutting-edge therapeutic approaches aimed at rewiring the exhausted and senescent T cell phenotypes. These include advances in immune checkpoint blockade, the engineering of "armored" CAR-T cells, senolytic therapies that selectively eliminate senescent cells, and novel interventions that reinvigorate the immune system's capacity for tumor eradication. By spotlighting emerging strategies that target both exhaustion and senescence, we provide a forward-looking perspective on the potential to harness immune rejuvenation. This comprehensive review outlines the next frontier in cancer immunotherapy: unlocking durable responses by overcoming the immune system's intrinsic aging and exhaustion, ultimately paving the way for transformative therapeutic breakthroughs.
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Affiliation(s)
| | - John S. Yu
- Department of NeurosurgeryCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
- Kairos PharmaLos AngelesCaliforniaUSA
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Watkins BA, Mitchell AE, Shin AC, Dehghani F, Shen CL. Dietary flavonoid actions on senescence, aging, and applications for health. J Nutr Biochem 2025; 139:109862. [PMID: 39929283 DOI: 10.1016/j.jnutbio.2025.109862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/04/2025] [Accepted: 02/06/2025] [Indexed: 03/18/2025]
Abstract
Fruits and vegetables contain biologically active phenolic compounds that show mitigating effects against free radical damage and inflammation. The unique properties of phenolic compounds are protection against oxidative stress, and inception and potentiating of inflammation in the body. Aging is manifest with changes in epigenetic modifications and as with living systems undergo entropy. The gradual decline of body functions and in many cases with aging the cellular processes of senescence are contributors to age-related diseases. Herein the focus is on phenolic compounds as a diet approach to delay the negative consequences of aging. The actions of phenolic compounds on the biology of aging and senescence are presented. The phenolic compounds called flavonoids which are found in many fruits are potential antisenescence factors that benefit health by reducing damage to DNA and the senescence-associated phenotypic cell changes in healthy cells during aging. Flavonoids are proposed to delay and palliate aging where senescence is involved. The dietary sources of natural phenolic compounds afford protection in the aging process and include as some examples naringenin, hesperidin, quercetin, kaempferol, luteolin, genistein, epigallocatechin gallate, and resveratrol. Many of these compounds possess antisenescence effects. The purpose of the review is to discuss where food flavonoids interact with the targets of senescence and how these compounds can attenuate aging-related events. The goal is to provide greater insight into dietary flavonoids and how they improve health and lower the consequences of aging. A novel aspect of this review is the application of flavonoids to neuroprotective effects in brain to reduce pain and improve health with aging.
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Affiliation(s)
- Bruce A Watkins
- Department of Nutrition, University of California, Davis, Davis CA.
| | - Alyson E Mitchell
- Department of Food Science and Technology, University of California, Davis, Davis CA
| | - Andrew C Shin
- Department of Nutritional Sciences, Neurobiology of Nutrition Laboratory, College of Health & Human Sciences, Texas Tech University, Lubbock, TX
| | - Fereshteh Dehghani
- Department of Nutritional Sciences, Neurobiology of Nutrition Laboratory, College of Health & Human Sciences, Texas Tech University, Lubbock, TX
| | - Chwan-Li Shen
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430; Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX 79430; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430
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30
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Marmisolle I, Chacón E, Mansilla S, Ruiz S, Bresque M, Martínez J, Martínez-Zamudio RI, Herbig U, Liu J, Finkel T, Escande C, Castro L, Quijano C. Oncogene-induced senescence mitochondrial metabolism and bioenergetics drive the secretory phenotype: further characterization and comparison with other senescence-inducing stimuli. Redox Biol 2025; 82:103606. [PMID: 40158257 PMCID: PMC11997345 DOI: 10.1016/j.redox.2025.103606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/19/2025] [Accepted: 03/19/2025] [Indexed: 04/02/2025] Open
Abstract
Cellular senescence is characterized by proliferation arrest and a senescence-associated secretory phenotype (SASP), that plays a role in aging and the progression of various age-related diseases. Although various metabolic alterations have been reported, no consensus exists regarding mitochondrial bioenergetics. Here we compared mitochondrial metabolism of human fibroblasts after inducing senescence with different stimuli: the oxidant hydrogen peroxide (H2O2), the genotoxic doxorubicin, serial passage, or expression of the H-RASG12V oncogene (RAS). In senescence induced by H2O2, doxorubicin or serial passage a decrease in respiratory control ratio (RCR) and coupling efficiency was noted, in relation to control cells. On the contrary, oncogene-induced senescent cells had an overall increase in respiration rates, RCR, spare respiratory capacity and coupling efficiency. In oncogene-induced senescence (OIS) the increase in respiration rates was accompanied by an increase in fatty acid catabolism, AMPK activation, and a persistent DNA damage response (DDR), that were not present in senescent cells induced by either H2O2 or doxorubicin. Inhibition of AMPK reduced mitochondrial oxygen consumption and secretion of proinflammatory cytokines in OIS. Assessment of enzymes involved in acetyl-CoA metabolism in OIS showed a 3- to 7.5-fold increase in pyruvate dehydrogenase complex (PDH), a 40% inhibition of mitochondrial aconitase, increased phosphorylation and activation of ATP-citrate lyase (ACLY), and inhibition of acetyl-CoA carboxylase (ACC). There was also a significant increase in expression and nuclear levels of the deacetylase sirtuin 6 (SIRT6). These changes can influence the sub-cellular distribution of acetyl-CoA and modulate protein acetylation reactions in the cytoplasm and nuclei. In fact, ACLY inhibition reduced histone 3 acetylation (H3K9Ac) in OIS and secretion of SASP components. In summary, our data show marked heterogeneity in mitochondrial energy metabolism of senescent cells, depending on the inducing stimulus, reveal new metabolic features of oncogene-induced senescent cells and identify AMPK and ACLY as potential targets for SASP modulation.
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Affiliation(s)
- Inés Marmisolle
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Uruguay
| | - Eliana Chacón
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Uruguay
| | - Santiago Mansilla
- Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Uruguay; Departamento de Métodos Cuantitativos, Facultad de Medicina, Universidad de la República, Uruguay
| | - Santiago Ruiz
- Laboratorio de Patologías del Metabolismo y el Envejecimiento, Institut Pasteur de Montevideo, Uruguay
| | - Mariana Bresque
- Laboratorio de Patologías del Metabolismo y el Envejecimiento, Institut Pasteur de Montevideo, Uruguay
| | - Jennyfer Martínez
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Uruguay
| | | | - Utz Herbig
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ, 07103, USA
| | - Jie Liu
- Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Toren Finkel
- Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Carlos Escande
- Laboratorio de Patologías del Metabolismo y el Envejecimiento, Institut Pasteur de Montevideo, Uruguay
| | - Laura Castro
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Uruguay
| | - Celia Quijano
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Uruguay.
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31
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Lavarti R, Alvarez-Diaz T, Marti K, Kar P, Raju RP. The context-dependent effect of cellular senescence: From embryogenesis and wound healing to aging. Ageing Res Rev 2025; 109:102760. [PMID: 40318767 DOI: 10.1016/j.arr.2025.102760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 04/20/2025] [Accepted: 04/26/2025] [Indexed: 05/07/2025]
Abstract
Aging is characterized by a steady loss of physiological integrity, leading to impaired function and increased vulnerability to death. Cell senescence is a biological process that progresses with aging and is believed to be a key driver of age-related diseases. Senescence, a hallmark of aging, also demonstrates its beneficial physiological aspects as an anti-cancer, pro-regenerative, homeostatic, and developmental mechanism. A transitory response in which the senescent cells are quickly formed and cleared may promote tissue regeneration and organismal fitness. At the same time, senescence-related secretory phenotypes associated with extended senescence can have devastating effects. The fact that the interaction between senescent cells and their surroundings is very context-dependent may also help to explain this seemingly opposing pleiotropic function. Further, mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence and figures prominently in multiple feedback loops that induce and maintain the senescent phenotype. This review summarizes the mechanism of cellular senescence and the significance of acute senescence. We concisely introduced the context-dependent role of senescent cells and SASP, aspects of mitochondrial biology altered in the senescent cells, and their impact on the senescent phenotype. Finally, we conclude with recent therapeutic advancements targeting cellular senescence, focusing on acute injuries and age-associated diseases. Collectively, these insights provide a future roadmap for the role of senescence in organismal fitness and life span extension.
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Affiliation(s)
- Rupa Lavarti
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Tatiana Alvarez-Diaz
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Kyarangelie Marti
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Parmita Kar
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Raghavan Pillai Raju
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States; Charlie Norwood VA Medical Center, Augusta, GA, United States.
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32
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Gwak H, Hong S, Lee SH, Kim IW, Kim Y, Kim H, Pahk KJ, Kim SY. Low-Intensity Pulsed Ultrasound Treatment Selectively Stimulates Senescent Cells to Promote SASP Factors for Immune Cell Recruitment. Aging Cell 2025; 24:e14486. [PMID: 39821933 PMCID: PMC12073891 DOI: 10.1111/acel.14486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 12/20/2024] [Accepted: 12/26/2024] [Indexed: 01/19/2025] Open
Abstract
As emerging therapeutic strategies for aging and age-associated diseases, various biochemical approaches have been developed to selectively remove senescent cells, but how physical stimulus influences senescent cells and its possible application in senolytic therapy has not been reported yet. Here we developed a physical method to selectively stimulate senescent cells via low-intensity pulsed ultrasound (LIPUS) treatment. LIPUS stimulation did not affect the cell cycle, but selectively enhanced secretion of specific cytokines in senescent cells, known as the senescence-associated secretory phenotype (SASP), resulting in enhanced migration of monocytes/macrophages and upregulation of phagocytosis of senescent cells by M1 macrophage. We found that LIPUS stimulation selectively perturbed the cellular membrane structure in senescent cells, which led to activation of the intracellular reactive oxygen species-dependent p38-NF-κB signaling pathway. Using a UV-induced skin aging mouse model, we confirmed enhanced macrophage infiltration followed by reduced senescent cells after LIPUS treatment. Due to the advantages of ultrasound treatment, such as non-invasiveness, deep penetration capability, and easy application in clinical settings, we expect that our method can be applied to treat various senescence-associated diseases or combined with other established biochemical therapies to enhance efficacy.
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Affiliation(s)
- HyeRan Gwak
- Chemical and Biological Integrative Research Center, Biomedical Research DivisionKorea Institute of Science and TechnologySeoulRepublic of Korea
| | - Seoyoung Hong
- Chemical and Biological Integrative Research Center, Biomedical Research DivisionKorea Institute of Science and TechnologySeoulRepublic of Korea
| | - Su Hyun Lee
- Chemical and Biological Integrative Research Center, Biomedical Research DivisionKorea Institute of Science and TechnologySeoulRepublic of Korea
| | - In Woo Kim
- Chemical and Biological Integrative Research Center, Biomedical Research DivisionKorea Institute of Science and TechnologySeoulRepublic of Korea
| | - Yonghan Kim
- Chemical and Biological Integrative Research Center, Biomedical Research DivisionKorea Institute of Science and TechnologySeoulRepublic of Korea
| | - Hyungmin Kim
- Bionics Research Center, Biomedical Research DivisionKorea Institute of Science and TechnologySeoulRepublic of Korea
- Division of Bio‐Medical Science and Technology, KIST SchoolKorea University of Science and Technology (UST)SeoulRepublic of Korea
- KHU‐KIST Department of Converging Science and TechnologyKyung Hee UniversitySeoulRepublic of Korea
| | - Ki Joo Pahk
- KHU‐KIST Department of Converging Science and TechnologyKyung Hee UniversitySeoulRepublic of Korea
- Department of Biomedical EngineeringKyung Hee UniversityYonginRepublic of Korea
| | - So Yeon Kim
- Chemical and Biological Integrative Research Center, Biomedical Research DivisionKorea Institute of Science and TechnologySeoulRepublic of Korea
- Division of Bio‐Medical Science and Technology, KIST SchoolKorea University of Science and Technology (UST)SeoulRepublic of Korea
- KHU‐KIST Department of Converging Science and TechnologyKyung Hee UniversitySeoulRepublic of Korea
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Zhang H, Xu Q, Jiang Z, Sun R, Wang Q, Liu S, Luan X, Campisi J, Kirkland JL, Zhang W, Sun Y. Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age-Related Conditions in Mice. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412950. [PMID: 40265973 PMCID: PMC12120719 DOI: 10.1002/advs.202412950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 03/16/2025] [Indexed: 04/24/2025]
Abstract
Cellular senescence is a cell fate triggered by stressful stimuli and displays a hypersecretory feature, the senescence-associated secretory phenotype (SASP). Senescent cell burden increases with aging and contributes to age-related organ dysfunction and multiple chronic disorders. In this study, a large scale screening of a natural product library for senotherapeutic candidates is performed. Apigenin, a dietary flavonoid previously reported with antioxidant and anti-inflammatory activities, exhibits capacity for targeting senescent cells as a senomorphic agent. This compound blocks the interactions between ATM/p38MAPK and HSPA8, preventing the transition of an acute stress-associated phenotype (ASAP) toward the SASP. Mechanistically, apigenin targets peroxiredoxin 6 (PRDX6), an intracellular redox-active molecule, suppressing the iPLA2 activity of PRDX6 and disrupting downstream reactions underlying SASP development. Apigenin reduces the severity of cancer cell malignancy promoted by senescent stromal cells in culture, while restraining chemoresistance when combined with chemotherapy in anticancer regimens. In preclinical trials, apigenin improves the physical function of animals with a premature aging-like state, alleviating physical frailty and cognitive impairment. Together, the study demonstrates the feasibility of exploiting a natural compound with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing a baseline for future exploration of natural agents for alleviating age-related conditions.
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Affiliation(s)
- Hongwei Zhang
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203P. R. China
| | - Qixia Xu
- CAS Key Laboratory of Tissue Microenvironment and TumorShanghai Institute of Nutrition and HealthChinese Academy of SciencesShanghai200031P. R. China
| | - Zhirui Jiang
- CAS Key Laboratory of Tissue Microenvironment and TumorShanghai Institute of Nutrition and HealthChinese Academy of SciencesShanghai200031P. R. China
| | - Rong Sun
- Department of Discovery BiologyBioduro‐SundiaZhangjiang Hi‐Tech ParkShanghai201210P. R. China
| | - Qun Wang
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203P. R. China
| | - Sanhong Liu
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203P. R. China
| | - Xin Luan
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203P. R. China
| | | | - James L. Kirkland
- Center for Advanced GerotherapeuticsCedars‐Sinai Medical CenterPacific Design CenterWest HollywoodCA90069USA
- Division of EndocrinologyDiabetes and MetabolismCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Weidong Zhang
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203P. R. China
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao‐di HerbsInstitute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100193P. R. China
| | - Yu Sun
- CAS Key Laboratory of Tissue Microenvironment and TumorShanghai Institute of Nutrition and HealthChinese Academy of SciencesShanghai200031P. R. China
- Department of Medicine and VAPSHCSUniversity of WashingtonSeattleWA98195USA
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MacDonald JA, Bradshaw GA, Jochems F, Bernards R, Letai A. Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies. Cell Death Differ 2025; 32:802-817. [PMID: 39762561 DOI: 10.1038/s41418-024-01431-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 11/20/2024] [Accepted: 12/04/2024] [Indexed: 05/21/2025] Open
Abstract
Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found little univariate predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT-263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT-263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT-263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the senolytics ABT-263 or the combination of dasatinib and quercetin (D + Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-XL was significantly correlated to senescent cell killing by both ABT-263 and D + Q, despite no significant changes in the gene or protein expression of BCL-XL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.
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Affiliation(s)
- Julie A MacDonald
- Dana Farber Cancer Institute, Boston, MA, USA
- Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Gary A Bradshaw
- Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Fleur Jochems
- Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, CX, Amsterdam, The Netherlands
| | - René Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, CX, Amsterdam, The Netherlands
| | - Anthony Letai
- Dana Farber Cancer Institute, Boston, MA, USA.
- Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
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Pan P, Cao S, Gao H, Qu X, Ma Y, Yang J, Pei X, Yang Y. Immp2l gene knockout induces granulosa cell senescence by activation of cGAS-STING pathway via TFAM-mediated mtDNA leakage. Int J Biol Macromol 2025; 307:142368. [PMID: 40120895 DOI: 10.1016/j.ijbiomac.2025.142368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/18/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Abstract
Granulosa cell-produced inflammatory factors may be key contributors to ovarian dysfunction, and Immp2l deficiency accelerates ovarian aging via granulosa cell senescence; however, the role of inflammation in granulosa cell senescence is largely unknown. Therefore, in this study, cGAS-STING-mediated inflammation was explored in Immp2l deficiency-induced granulosa cell senescence. Immp2l deficiency led to senescence-associated secretory phenotype (SASP) and granulosa cell senescence. Immp2l knockout caused mitochondrial dysfunction and mitochondrial DNA (mtDNA) leakage into the cytoplasm. The cytoplasmic mtDNA was recognized by the DNA-sensing molecule cGAS-STING, which activates cGAS-STING and key downstream interferon-stimulated genes (ISGs) and then promotes the secretion of proinflammatory factors, leading to SASP in senescent granulosa cells. Interestingly, the mitochondrial inner membrane pore protein (Cyclophilin D40) CyPD40 and the outer membrane pore protein voltage-dependent-anion channel 1 (VDAC1) were markedly increased in senescent granulosa cells, accompanied by significantly increased expression of the mtDNA stability protein mitochondrial transcription factor A (TFAM). Downregulation of TFAM with siRNA in senescent granulosa cells improved mitochondrial function, significantly decreased mtDNA in the cytoplasm, inhibited the cGAS-STING pathway and markedly decreased CyPD40 and VDAC1 protein levels in TFAM-treated senescent granulosa cells. The SASP phenotype was also alleviated. In addition, senescent granulosa cells were treated with procyanidin B2 (PCB2), which has anti-inflammatory effects, and the TFAM-mediated mtDNA-cGAS-STING pathway was inhibited, accompanied by a markedly reduced SASP phenotype and granulosa cell senescence. In conclusion, Immp2l gene knockout induced granulosa cell senescence by activation of the cGAS-STING pathway via TFAM-mediated mtDNA leakage into the cytoplasm through the CyPD40 and the VDAC1.
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Affiliation(s)
- Pengge Pan
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Sinan Cao
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Hui Gao
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Xiaoya Qu
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Yan Ma
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Jinyi Yang
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Xiuying Pei
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
| | - Yanzhou Yang
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Emergency Department, The First People's Hospital of Yinchuan, The Second Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China.
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Zhou Y, Zhu H, Zhao L, Zhao G, Sun J. Bidirectional Mendelian randomization and potential mechanistic insights into the causal relationship between gut microbiota and malignant mesothelioma. Medicine (Baltimore) 2025; 104:e42245. [PMID: 40295238 PMCID: PMC12040020 DOI: 10.1097/md.0000000000042245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 04/30/2025] Open
Abstract
Malignant mesothelioma (MM) is a rare but aggressive cancer originating from mesothelial cells, which presents significant challenges to patients' physical and psychological well-being. The gut-lung axis underscores the connection between gut microbiota and respiratory diseases, with emerging evidence suggesting a strong association between gut microbiota and the development of MM. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between gut microbiota and MM, while also exploring the underlying mechanisms through bioinformatics approaches. Gut microbiota summary data were obtained from the MiBioGen consortium, while MM data were sourced from the FinnGen R11 dataset. Causality was examined using the inverse variance weighted method as the primary analysis. Additional methods, including the weighted median, simple mode, MR-Egger, and weighted mode, were also employed. The robustness of the findings was validated through sensitivity analyses, and reverse causality was considered to further strengthen the MR results. Moreover, bioinformatics analyses were conducted on genetic loci associated with both gut microbiota and MM to explore potential underlying mechanisms. Our study suggests that genetically predicted increases in class.Bacilli, family.Rikenellaceae, genus.Clostridium innocuum group, and order.Lactobacillales were suggestively associated with a higher risk of MM, whereas increases in genus.Ruminococcaceae UCG004, genus.Flavonifractor, phylum.Firmicutes, genus.Anaerofilum, genus.Clostridium sensu stricto 1, and genus.Lactobacillus appeared to confer protective effects. Bioinformatics analysis indicated that differentially expressed genes near loci associated with gut microbiota might affect MM by modulating pathways and the tumor microenvironment. The results of this study point to a potential genetic predisposition linking gut microbiota to MM. Further experimental validation is crucial to confirm these candidate microbes, establish causality, and elucidate the underlying mechanisms.
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Affiliation(s)
- Yinjie Zhou
- Department of Thoracic Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Huangkai Zhu
- Department of Thoracic Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Long Zhao
- Department of Cardiovascular Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Guofang Zhao
- Department of Thoracic Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Jiaen Sun
- Department of Cardiovascular Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
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Kerek R, Sawma Awad J, Bassam M, Hajjar C, Ghantous F, Rizk K, Rima M. The multifunctional protein CCN1/CYR61: Bridging physiology and disease. Exp Mol Pathol 2025; 142:104969. [PMID: 40286773 DOI: 10.1016/j.yexmp.2025.104969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
The matricellular protein CYR61/CCN1 is a member of the CCN protein family that plays significant roles in a broad range of physiological processes, including development, tissue repair, and inflammation, among others. CCN1 is also implicated in pathological conditions such as cancer and fibrosis. The diverse functions of CCN1 arise from its ability to bind different receptors located on many cell types, thereby activating diverse signaling pathways. The diverse, yet contradictory, functions mediated by CCN1 makes it a compelling target for investigation, as it offers the prospect of understanding fundamental cellular topics and their possible implications in various diseases. Recently, new cellular functions were attributed to CCN1, including senescence, pro-/anti- fibrosis, and rejuvenation. In this review, we discuss all these new findings along with the basic knowledge about CCN1 to provide an overall understanding of its conflicting roles and their potential corresponding mechanisms of action.
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Affiliation(s)
- Racha Kerek
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Joe Sawma Awad
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Mariam Bassam
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Carla Hajjar
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Fouad Ghantous
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Karelle Rizk
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Mohamad Rima
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon.
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Casanova V, Rodríguez-Agustín A, Ayala-Suárez R, Moraga E, Maleno MJ, Mallolas J, Martínez E, Sánchez-Palomino S, Miró JM, Alcamí J, Climent N. HIV-Tat upregulates the expression of senescence biomarkers in CD4 + T-cells. Front Immunol 2025; 16:1568762. [PMID: 40342418 PMCID: PMC12058733 DOI: 10.3389/fimmu.2025.1568762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 03/31/2025] [Indexed: 05/11/2025] Open
Abstract
Introduction Current antiretroviral therapy (ART) for HIV infection reduces plasma viral loads to undetectable levels and has increased the life expectancy of people with HIV (PWH). However, this increased lifespan is accompanied by signs of accelerated aging and a higher prevalence of age-related comorbidities. Tat (Trans-Activator of Transcription) is a key protein for viral replication and pathogenesis. Tat is encoded by 2 exons, with the full-length Tat ranging from 86 to 101 aa (Tat101). Introducing a stop codon in position 73 generates a 1 exon, synthetic 72aa Tat (Tat72). Intracellular, full-length Tat activates the NF-κB pro-inflammatory pathway and increases antiapoptotic signals and ROS generation. These effects may initiate a cellular senescence program, characterized by cell cycle arrest, altered cell metabolism, and increased senescence-associated secretory phenotype (SASP) mediator release However, the precise role of HIV-Tat in inducing a cellular senescence program in CD4+ T-cells is currently unknown. Methods Jurkat Tetoff cell lines stably transfected with Tat72, Tat101, or an empty vector were used. Flow cytometry and RT-qPCR were used to address senescence biomarkers, and 105 mediators were assessed in cell supernatants with an antibody-based membrane array. Key results obtained in Jurkat-Tat cells were addressed in primary, resting CD4+ T-cells by transient electroporation of HIV-Tat-FLAG plasmid DNA. Results In the Jurkat cell model, expression of Tat101 increased the levels of the senescence biomarkers BCL-2, CD87, and p21, and increased the release of sCD30, PDGF-AA, and sCD31, among other factors. Tat101 upregulated CD30 and CD31 co-expression in the Jurkat cell surface, distinguishing these cells from Tat72 and Tetoff Jurkats. The percentage of p21+, p16+, and γ-H2AX+ cells were higher in Tat-expressing CD4+ T-cells, detected as a FLAG+ population compared to their FLAG- (Tat negative) counterparts. Increased levels of sCD31 and sCD26 were also detected in electroporated CD4+ T-cell supernatants. Discussion Intracellular, full-length HIV-Tat expression increases several senescence biomarkers in Jurkat and CD4+ T-cells, and SASP/Aging mediators in cell supernatants. Intracellular HIV-Tat may initiate a cellular senescence program, contributing to the premature aging phenotype observed in PWH.
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Affiliation(s)
- Víctor Casanova
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Department of Medicine, Universitat de Barcelona (UB), Barcelona, Spain
| | - Andrea Rodríguez-Agustín
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Department of Medicine, Universitat de Barcelona (UB), Barcelona, Spain
| | - Rubén Ayala-Suárez
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
| | - Elisa Moraga
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
| | - María José Maleno
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
| | - Josep Mallolas
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Infectious Diseases Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Esteban Martínez
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Infectious Diseases Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Reial Academia de Medicina de Catalunya (RAMC), Barcelona, Spain
| | - Sonsoles Sánchez-Palomino
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Department of Medicine, Universitat de Barcelona (UB), Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - José M. Miró
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Infectious Diseases Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Reial Academia de Medicina de Catalunya (RAMC), Barcelona, Spain
| | - José Alcamí
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Department of Medicine, Universitat de Barcelona (UB), Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- AIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Núria Climent
- AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Department of Medicine, Universitat de Barcelona (UB), Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Komaki Y, Ibuki Y. Cigarette sidestream smoke-induced cellular senescence and the protective role of histone H2AX. Toxicol In Vitro 2025; 107:106076. [PMID: 40286947 DOI: 10.1016/j.tiv.2025.106076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 04/29/2025]
Abstract
Cigarette smoke imposes serious health hazards such as cancer and cardiovascular diseases but is also associated with cellular senescence. Recently, histone loss and modifications are reported as one of the characteristics of cellular senescence. In this study, we examined the relationship between cigarette smoke-induced cellular senescence and histone H2A variant H2AX, an important player in DNA damage response. We exposed normal human skin diploid fibroblast ASF-4-1 to cigarette sidestream smoke (CSS) extract and successfully induced premature senescence. Persistent DNA damages are known to induce cellular senescence. Double strand breaks (DSBs) formation was detected in CSS-treated cells, indicating DSBs could be the cause for the CSS-induced cellular senescence. In the senescent cells, persistent phosphorylation of histone H2AX (γ-H2AX) and unexpected increase of H2AX protein expression was observed. To elucidate the role of H2AX in CSS-induced cellular senescence, we depleted H2AX in ASF-4-1 cells with siRNA. In H2AX-depleted cells, CSS-induced elevated β-galactosidase activity was more prominent. CSS concentration-dependent increase of reactive oxygen species and DSBs formation was also facilitated by H2AX depletion. These results suggest that histone H2AX may have a protective role against DNA damage-induced premature senescence.
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Affiliation(s)
- Yukako Komaki
- Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526, Japan.
| | - Yuko Ibuki
- Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526, Japan.
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40
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Zafar A, Khatoon S, Khan MJ, Abu J, Naeem A. Advancements and limitations in traditional anti-cancer therapies: a comprehensive review of surgery, chemotherapy, radiation therapy, and hormonal therapy. Discov Oncol 2025; 16:607. [PMID: 40272602 PMCID: PMC12021777 DOI: 10.1007/s12672-025-02198-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 03/20/2025] [Indexed: 04/25/2025] Open
Abstract
Cancer remains a major global health challenge, consistently ranking as the second leading cause of mortality worldwide. Despite significant advancements in research and technology, the need to deepen our understanding of tumor biology and improve therapeutic strategies persists. This review focuses on the progress and challenges of four traditional cancer treatment modalities: surgery, chemotherapy, radiation therapy, and hormonal therapy. Surgery, the primary method for tumor removal, has evolved with the integration of fluorescence-based technology and robotic systems, enhancing precision and minimizing collateral damage. Radiation therapy has progressed with improved focus, intensity control, and 3D technology, refining both diagnosis and treatment. Chemotherapy has advanced from natural extracts to synthesized derivatives with amplified cytotoxicity against cancer cells. Hormonal therapy has emerged as a crucial strategy for hormone-dependent cancers, restraining growth or inducing regression. Despite these advancements, each approach faces ongoing challenges. Surgery struggles with complete tumor removal due to heterogeneity. Chemotherapy contends with drug resistance and side effects. Radiation therapy grapples with precision issues and limited access in some regions. Hormonal therapy faces resistance development and quality of life impacts. This study provides a comprehensive analysis of the evolution of these traditional anti-cancer therapies, offering insights into their progress and highlighting areas for future research. By examining these modalities, we aim to underscore their relevance in the current oncology landscape and identify opportunities for improvement in cancer treatment strategies.
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Affiliation(s)
- Aasma Zafar
- Department of Biosciences, COMSATS University, Islamabad, 45550, Pakistan
| | - Summaiya Khatoon
- College of Health Sciences, QU Health Sector, Qatar University, P.O. Box 2713, Doha, Qatar
| | | | - Junaid Abu
- Aisha bint Hamad al-Attiyah hospital, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Aisha Naeem
- Research and Graduate Studies, QU Health Sector, Qatar University, P.O. Box 2713, Doha, Qatar.
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Niklasson M, Dalmo E, Segerman A, Rendo V, Westermark B. p21-Dependent Senescence Induction by BMP4 Renders Glioblastoma Cells Vulnerable to Senolytics. Int J Mol Sci 2025; 26:3974. [PMID: 40362216 PMCID: PMC12071447 DOI: 10.3390/ijms26093974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
Glioblastoma (GBM) is a highly malignant brain tumor with extensive cellular heterogeneity and plasticity. Bone morphogenetic protein 4 (BMP4) has shown potential as a therapeutic agent by promoting differentiation, but its effects are complex and context dependent. While BMP4's role in differentiation is well established, its impact on senescence remains unclear. This study investigates BMP4's ability to induce senescence in GBM cells. Primary GBM cultures were treated with BMP4 and analyzed for senescence markers, including cell enlargement, p21 expression, senescence-related gene enrichment, and senescence-associated-β-galactosidase activity. A p21 knockout model was used to determine its role in BMP4-induced senescence, and sensitivity to the senolytic agent navitoclax was evaluated. BMP4 induced senescence in the GBM cultures, particularly in mesenchymal (MES)-like GBM cells with high baseline p21 levels. The knockout of p21 nearly abolished BMP4-induced senescence, maintaining cell size and proliferation. Furthermore, navitoclax effectively eliminated BMP4-induced senescent cells through apoptosis, while sparing cells with normal p21 expression. Our findings highlight BMP4 as an inducer of p21-dependent senescence in GBM, particularly in MES-like cells. This study clarifies BMP4's dual roles in differentiation and senescence, emphasizing their context dependence. Given the strong link between MES-like cells and therapy resistance, their heightened susceptibility to senescence may aid in developing targeted therapies for GBM and potentially other cancers with similar cellular dynamics.
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Affiliation(s)
- Mia Niklasson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; (E.D.); (A.S.); (V.R.); (B.W.)
| | - Erika Dalmo
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; (E.D.); (A.S.); (V.R.); (B.W.)
| | - Anna Segerman
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; (E.D.); (A.S.); (V.R.); (B.W.)
- Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University Hospital, 751 85 Uppsala, Sweden
| | - Veronica Rendo
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; (E.D.); (A.S.); (V.R.); (B.W.)
| | - Bengt Westermark
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; (E.D.); (A.S.); (V.R.); (B.W.)
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Yan Z, Shi X, Ding R, Xia F, Du Y, Wang X, Peng Q. Validation of Senescence of the Role of ATM/P53 Pathway in Myocardial Senescence in Mice with Sepsis. Infect Drug Resist 2025; 18:1961-1974. [PMID: 40271227 PMCID: PMC12017271 DOI: 10.2147/idr.s505836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/09/2025] [Indexed: 04/25/2025] Open
Abstract
Background Sepsis induces multi-organ damage, including myocardial dysfunction, which is often reversible. However, the role of cell senescence in sepsis-induced myocardial dysfunction (SIMD) remains understudied. This study aimed to investigate gene expression changes related to myocardial aging in sepsis. Methods Transcriptomic datasets (GSE79962 and GSE141864) were analyzed to identify senescence-related genes (SRGs) by intersecting differentially expressed genes (DEGs) with the CellAge database. Functional enrichment and protein-protein interaction (PPI) network analysis were performed to identify key pathways and hub genes. A murine sepsis model was established via intraperitoneal lipopolysaccharide (LPS) injection, and the Ataxia Telangiectasia Mutated Protein (ATM) inhibitor KU60019 was used to assess the effects on cardiac function and cellular aging. Results Bioinformatics analysis revealed 15 aging-related genes, including MYC, TP53, CXCL1, and SERPINE1, which were upregulated in septic myocardial tissue. Functional enrichment analysis highlighted pathways related to DNA damage repair, cell senescence, and immune response. In vivo validation using murine LPS-induced sepsis models confirmed significant myocardial damage, which was alleviated by treatment with KU60019, an inhibitor of the DNA damage response pathway. Conclusion Cellular senescence and immune dysregulation play critical roles in SIMD. Targeting DDR pathways, as demonstrated by KU60019 treatment, provides novel insights into the role of cellular senescence in severe sepsis and its potential therapeutic implications for improving cardiovascular prognosis in septic patients.
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Affiliation(s)
- Zhonghan Yan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Xuemei Shi
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Ruilin Ding
- Institute of Drug Clinical Trial/GCP Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Fenfen Xia
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Yan Du
- Department of Cardiology, Deyang People’s Hospital, Deyang, Sichuan, People’s Republic of China
| | - Xiaojie Wang
- Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Qing Peng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
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Alqahtani S, Alqahtani T, Venkatesan K, Sivadasan D, Ahmed R, Sirag N, Elfadil H, Abdullah Mohamed H, T.A. H, Elsayed Ahmed R, Muralidharan P, Paulsamy P. SASP Modulation for Cellular Rejuvenation and Tissue Homeostasis: Therapeutic Strategies and Molecular Insights. Cells 2025; 14:608. [PMID: 40277933 PMCID: PMC12025513 DOI: 10.3390/cells14080608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/09/2025] [Accepted: 04/15/2025] [Indexed: 04/26/2025] Open
Abstract
Cellular senescence regulates aging, tissue maintenance, and disease progression through the Senescence-Associated Secretory Phenotype (SASP), a secretory profile of cytokines, chemokines, growth factors, and matrix-remodeling enzymes. While transient SASP aids wound healing, its chronic activation drives inflammation, fibrosis, and tumorigenesis. This review examines SASP's molecular regulation, dual roles in health and pathology, and therapeutic potential. The following two main strategies are explored: senescence clearance, which eliminates SASP-producing cells, and SASP modulation, which refines secretion to suppress inflammation while maintaining regenerative effects. Key pathways, including NF-κB, C/EBPβ, and cGAS-STING, are discussed alongside pharmacological, immunotherapeutic, gene-editing, and epigenetic interventions. SASP heterogeneity necessitates tissue-specific biomarkers for personalized therapies. Challenges include immune interactions, long-term safety, and ethical considerations. SASP modulation emerges as a promising strategy for aging, oncology, and tissue repair, with future advancements relying on multi-omics and AI-driven insights to optimize clinical outcomes.
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Affiliation(s)
- Saud Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62521, Saudi Arabia
| | - Taha Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62521, Saudi Arabia
| | - Krishnaraju Venkatesan
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62521, Saudi Arabia
| | - Durgaramani Sivadasan
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - Rehab Ahmed
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.); (H.E.)
| | - Nizar Sirag
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Hassabelrasoul Elfadil
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.); (H.E.)
| | - Hanem Abdullah Mohamed
- Pediatric Nursing, College of Nursing, King Khalid University, Abha 62521, Saudi Arabia;
- Faculty of Nursing, Cairo University, Giza 12613, Egypt
| | - Haseena T.A.
- College of Nursing, Mahalah Branch for Girls, King Khalid University, Abha 62521, Saudi Arabia; (H.T.); (P.P.)
| | - Rasha Elsayed Ahmed
- Medical Surgical Nursing, Tanta University, Tanta 31527, Egypt;
- College of Nursing, King Khalid University, Khamis Mushait 61421, Saudi Arabia
| | - Pooja Muralidharan
- Undergraduate Program, PSG College of Pharmacy, Peelamedu, Coimbatore 641004, India;
| | - Premalatha Paulsamy
- College of Nursing, Mahalah Branch for Girls, King Khalid University, Abha 62521, Saudi Arabia; (H.T.); (P.P.)
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Li X, Bao Y, Zhang N, Lin C, Xie Y, Wei Y, Luo Q, Liu J, Sha Z, Wu G, Zhou T, Chen Q, Ling T, Pan W, Lu L, Wu L, Dai Y, Jin Q. Senescent CD8+ T cells: a novel risk factor in atrial fibrillation. Cardiovasc Res 2025; 121:97-112. [PMID: 39382426 DOI: 10.1093/cvr/cvae222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/24/2024] [Accepted: 08/16/2024] [Indexed: 10/10/2024] Open
Abstract
AIMS Immune cell alterations may play a role in the development of atrial fibrillation (AF). Our objective was to comprehensively characterize immune cells in AF, and investigate the potential mechanisms. METHODS AND RESULTS Single-cell RNA sequencing and multicolour flow cytometry revealed that T cells constituted the most significant subset alterations in AF, and senescent CD8+ T cells were AF-associated subset. Senescent CD8+ T cells increased in both peripheral veins (P < 0.0001) and the left atria (P < 0.05) in patients with AF compared to non-AF control. Senescent CD8+ T cells were independently associated with AF prevalence (odds ratio = 2.876, P < 0.05) and postprocedural recurrence (hazard ratio = 22.955, P < 0.0001) using a cross-sectional study and a subsequent prospective cohort study. Senescent CD8+ T cells secreted an increased amount of interferon (IFN)-γ, which induces Ca2+ handling abnormalities in human induced pluripotent stem cell-derived atrial cardiomyocytes, and translated into an increased susceptibility to AF assessed by heart optical mapping. CONCLUSIONS An increased amount of senescent CD8+ T cells may be a hallmark of the immune senescence phenotype in AF and potentially serve as a valid biomarker for assessing prevalence and postprocedural recurrence of AF. By connecting immune senescence with electrophysiological disturbances in AF, this research provides a potential mechanism for the involvement of senescent CD8+ T cells in proarrhythmic calcium disorders and suggests novel avenues for developing new immune-modulatory and senolytic therapies for AF.
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Affiliation(s)
- Xiang Li
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Yangyang Bao
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Ning Zhang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Changjian Lin
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Yun Xie
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Yue Wei
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Qingzhi Luo
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Jingmeng Liu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Zimo Sha
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Guanhua Wu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Taojie Zhou
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Qiujing Chen
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Tianyou Ling
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Wenqi Pan
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Lin Lu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Liqun Wu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Yang Dai
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
| | - Qi Jin
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road Number Two, Shanghai 200025, China
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Liu Z, Mao Y, Wang S, Zheng H, Yang K, Yang L, Huang P. A bibliometric and visual analysis of the impact of senescence on tumor immunotherapy. Front Immunol 2025; 16:1566227. [PMID: 40292294 PMCID: PMC12021824 DOI: 10.3389/fimmu.2025.1566227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Background Recently, many studies have focused on the relationship between senescence and immunotherapy in cancer treatment. However, relatively few studies have examined the intrinsic links between the three. Whether these studies can act synergistically in the fight against cancer and the specific links between them are still unclear. Methods We extracted, quantified, and visualized data from the literature (n = 2396) for the period 2004-2023 after rigorous quality control using citespace, GraphPad Prism, the R software package, and VOSviewer. Results Linear fit analyses were generated to predict the number of annual publications and citations as a function of the top-performing authors, journals, countries, and affiliations academically over the past two decades such as Weiwei, Aging-us, China, and the UT MD Anderson Cancer Center. Vosviewer-based hierarchical clustering further categorized study characteristics into six clusters, including two major clusters of immunotherapy research, immunosenescence-related research factors, and timeline distributions suggesting that cellular senescence and tumor progression is a relatively new research cluster that warrants further exploration and development. Study characterization bursts and linear regression analyses further confirmed these findings and revealed other important results, such as aging (a = 1.964, R² = 0.6803) and immunotherapy (a = 16.38, R² = 0.8812). Furthermore, gene frequency analysis in this study revealed the most abundant gene, APOE, and SIRT1-7 proteins. Conclusion The combination of aging therapies with tumor immunotherapies is currently in its preliminary stages. Although senescence has the greatest impact on ICB therapies, mechanistic investigations, and drug development for APOE and sirt1-7 (Sirtuins family) targets may be the key to combining senescence therapies with immunotherapies in the treatment of tumors.
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Affiliation(s)
- Zixu Liu
- Center for Evidence-Based Medicine, School of Public Health, Jiangxi Medical College. Nanchang University, Nanchang, China
- Jiangxi Province Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, Nanchang, China
- First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Yuchen Mao
- First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Shukai Wang
- First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Haoyu Zheng
- School of Stomatology, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Kangping Yang
- Department of Gastroenterological Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Liang Yang
- Department of Gastroenterological Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Peng Huang
- Center for Evidence-Based Medicine, School of Public Health, Jiangxi Medical College. Nanchang University, Nanchang, China
- Jiangxi Province Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, Nanchang, China
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Liu Z, Li S, Yang Q, Cao G, Yan W, Jiang S, Qiao R, Cai B, Wu Z, Lin C, Zhu N. LncRNA H19 inhibited dermal papilla cell senescence process through miR-29a by targeting Wnt/β-catenin signaling pathway. Arch Dermatol Res 2025; 317:688. [PMID: 40204984 DOI: 10.1007/s00403-025-04128-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 04/11/2025]
Abstract
Androgenetic alopecia is a common type of hair loss disease. As the most promising seeder for cell-based therapy, dermal papilla cells are prone to undergo premature senescence during passaging in vitro. Our previous studies revealed high expression of lncRNA H19 in early-passage dermal papilla cells and the maintenance of hair follicle-inducing ability upon prolonged culture. However, the exact mechanism of H19 regulating Wnt signaling pathway related to hair follicle regeneration has not been fully elucidated. Here, a cell senescence model was constructed by continuous cultivation in vitro to investigate the molecular mechanism of H19 in human dermal papilla cells. Animal hair follicle inductivity, cell proliferation and molecular experiments were performed to evaluate the cell inductivity, proliferation, senescence, expression of Wnt signaling key factors in early- and late-passage dermal papilla cells. Ectopic expression and silencing experiments were conducted to estimate effects of H19 on the proliferation and senescence of dermal papilla cells and the possible mechanism. Hair follicles from frontal baldness-prone and occipital non-balding areas of patients with androgenetic alopecia were exploited to detect the expression of H19 and relevant factors. Results showed late-passage DP8 cells exhibited lost hair follicle inductive properties, attenuated cell proliferation, elevated senescent marker and key Wnt factor levels, decreased inducing marker levels. Furthermore, overexpression of H19 inhibited senescence marker expression by binding to SAHH to upregulate miR-29, thus activating the Wnt signaling pathway to maintain inducing ability of DP cells. Knockdown of H19 showed opposite experimental results. Consistently, H19 together with miR-29a levels were lower and the expression levels of miR-29a target genes (DKK1, SFRP2) increased in the dermal papilla cells from frontal baldness-prone and occipital non-balding areas. Conclusively, our data provide a novel insight into the regulation and mechanism of H19 in inhibiting dermal papilla cell senescence, suggesting a potential therapy strategy for androgenetic alopecia.
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Affiliation(s)
- Zhenyu Liu
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, 541004, P. R. China
| | - Shenyu Li
- Department of Neurosurgery, Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541100, P. R. China
| | - Qilin Yang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, 541004, P. R. China
| | - Guiyuan Cao
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, 541004, P. R. China
| | - Wenjie Yan
- Department of Dermatology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, P. R. China
| | - Siyuan Jiang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, 541004, P. R. China
| | - Ruilong Qiao
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, 541004, P. R. China
| | - Bozhi Cai
- Tissue Engineering Laboratory, First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, 515000, P. R. China
| | - Zhihao Wu
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, 541004, P. R. China
| | - Changmin Lin
- Department of Histology and Embryology, Shantou University Medical College, No. 22, Xinling Road, Shantou, Guangdong, 515041, P. R. China.
| | - Ningxia Zhu
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, 541004, P. R. China.
- Institute of Basic Medicine, Guilin Medical University, Guilin, Guangxi, 541004, P. R. China.
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47
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Liu B, Peng Z, Zhang H, Zhang N, Liu Z, Xia Z, Huang S, Luo P, Cheng Q. Regulation of cellular senescence in tumor progression and therapeutic targeting: mechanisms and pathways. Mol Cancer 2025; 24:106. [PMID: 40170077 PMCID: PMC11963325 DOI: 10.1186/s12943-025-02284-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/26/2025] [Indexed: 04/03/2025] Open
Abstract
Cellular senescence, a stable state of cell cycle arrest induced by various stressors or genomic damage, is recognized as a hallmark of cancer. It exerts a context-dependent dual role in cancer initiation and progression, functioning as a tumor suppressor and promoter. The complexity of senescence in cancer arises from its mechanistic diversity, potential reversibility, and heterogeneity. A key mediator of these effects is the senescence-associated secretory phenotype (SASP), a repertoire of bioactive molecules that influence tumor microenvironment (TME) remodeling, modulate cancer cell behavior, and contribute to therapeutic resistance. Given its intricate role in cancer biology, senescence presents both challenges and opportunities for therapeutic intervention. Strategies targeting senescence pathways, including senescence-inducing therapies and senolytic approaches, offer promising avenues for cancer treatment. This review provides a comprehensive analysis of the regulatory mechanisms governing cellular senescence in tumors. We also discuss emerging strategies to modulate senescence, highlighting novel therapeutic opportunities. A deeper understanding of these processes is essential for developing precision therapies and improving clinical outcomes.
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Affiliation(s)
- Bowei Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China
- National Clinical Research Central for Geriatric Disorders. Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Jiangxi (National Regional Center for Neurological Diseases), Nanchang, Jiangxi, China
| | - Zhigang Peng
- Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China
- National Clinical Research Central for Geriatric Disorders. Xiangya Hospital, Central South University, Changsha, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Jiangxi (National Regional Center for Neurological Diseases), Nanchang, Jiangxi, China
| | - Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Nan Zhang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiwei Xia
- Department of Neurology, Hunan Aerospace Hospital, Hunan Normal University, Changsha, Hunan, China.
| | - Shaorong Huang
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China.
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China.
- National Clinical Research Central for Geriatric Disorders. Xiangya Hospital, Central South University, Changsha, China.
- Department of Neurosurgery, Xiangya Hospital, Central South University, Jiangxi (National Regional Center for Neurological Diseases), Nanchang, Jiangxi, China.
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48
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Zhou H, Gizlenci M, Xiao Y, Martin F, Nakamori K, Zicari EM, Sato Y, Tullius SG. Obesity-associated Inflammation and Alloimmunity. Transplantation 2025; 109:588-596. [PMID: 39192462 PMCID: PMC11868468 DOI: 10.1097/tp.0000000000005183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
Obesity is a worldwide health problem with a rapidly rising incidence. In organ transplantation, increasing numbers of patients with obesity accumulate on waiting lists and undergo surgery. Obesity is in general conceptualized as a chronic inflammatory disease, potentially impacting alloimmune response and graft function. Here, we summarize our current understanding of cellular and molecular mechanisms that control obesity-associated adipose tissue inflammation and provide insights into mechanisms affecting transplant outcomes, emphasizing on the beneficial effects of weight loss on alloimmune responses.
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Affiliation(s)
- Hao Zhou
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Merih Gizlenci
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany
| | - Yao Xiao
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Friederike Martin
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of Surgery, CVK/CCM, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Keita Nakamori
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Elizabeth M. Zicari
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Faculté de Pharmacie, Université Paris Cité, Paris, France
| | - Yuko Sato
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Stefan G. Tullius
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
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Tomimatsu N, Di Cristofaro LFM, Kanji S, Samentar L, Jordan BR, Kittler R, Habib AA, Espindola-Netto JM, Tchkonia T, Kirkland JL, Burns TC, Sarkaria JN, Gilbert A, Floyd JR, Hromas R, Zhao W, Zhou D, Sung P, Mukherjee B, Burma S. Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy. EMBO Mol Med 2025; 17:645-678. [PMID: 39972068 PMCID: PMC11982261 DOI: 10.1038/s44321-025-00201-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 01/28/2025] [Accepted: 02/05/2025] [Indexed: 02/21/2025] Open
Abstract
Glioblastomas (GBM) are routinely treated with high doses of ionizing radiation (IR), yet these tumors recur quickly, and the recurrent tumors are highly therapy resistant. Here, we report that IR-induced senescence of tumor cells counterintuitively spurs GBM recurrence, driven by the senescence-associated secretory phenotype (SASP). We find that irradiated GBM cell lines and patient derived xenograft (PDX) cultures senesce rapidly in a p21-dependent manner. Senescent glioma cells upregulate SASP genes and secrete a panoply of SASP factors, prominently interleukin IL-6, an activator of the JAK-STAT3 pathway. These SASP factors collectively activate the JAK-STAT3 and NF-κB pathways in non-senescent GBM cells, thereby promoting tumor cell proliferation and SASP spreading. Transcriptomic analyses of irradiated GBM cells and the TCGA database reveal that the cellular inhibitor of apoptosis protein 2 (cIAP2), encoded by the BIRC3 gene, is a potential survival factor for senescent glioma cells. Senescent GBM cells not only upregulate BIRC3 but also induce BIRC3 expression and promote radioresistance in non-senescent tumor cells. We find that second mitochondria-derived activator of caspases (SMAC) mimetics targeting cIAP2 act as novel senolytics that trigger apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells. Finally, using both PDX and immunocompetent mouse models of GBM, we show that the SMAC mimetic birinapant, administered as an adjuvant after radiotherapy, can eliminate senescent GBM cells and prevent the emergence of recurrent tumors. Taken together, our results clearly indicate that significant improvement in GBM patient survival may become possible in the clinic by eliminating senescent cells arising after radiotherapy.
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Affiliation(s)
- Nozomi Tomimatsu
- Department of Neurosurgery, University of Texas Health, San Antonio, TX, USA
| | | | - Suman Kanji
- Department of Neurosurgery, University of Texas Health, San Antonio, TX, USA
| | - Lorena Samentar
- Department of Neurosurgery, University of Texas Health, San Antonio, TX, USA
| | - Benjamin Russell Jordan
- Department of Neurosurgery, University of Texas Health, San Antonio, TX, USA
- Department of Biochemistry and Structural Biology, University of Texas Health, San Antonio, TX, USA
| | - Ralf Kittler
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Amyn A Habib
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Tamara Tchkonia
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | | | - Terry C Burns
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Andrea Gilbert
- Department of Pathology, University of Texas Health, San Antonio, TX, USA
| | - John R Floyd
- Department of Neurosurgery, University of Texas Health, San Antonio, TX, USA
| | - Robert Hromas
- Department of Medicine, University of Texas Health, San Antonio, TX, USA
| | - Weixing Zhao
- Department of Biochemistry and Structural Biology, University of Texas Health, San Antonio, TX, USA
| | - Daohong Zhou
- Department of Biochemistry and Structural Biology, University of Texas Health, San Antonio, TX, USA
| | - Patrick Sung
- Department of Biochemistry and Structural Biology, University of Texas Health, San Antonio, TX, USA
| | - Bipasha Mukherjee
- Department of Neurosurgery, University of Texas Health, San Antonio, TX, USA.
| | - Sandeep Burma
- Department of Neurosurgery, University of Texas Health, San Antonio, TX, USA.
- Department of Biochemistry and Structural Biology, University of Texas Health, San Antonio, TX, USA.
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50
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Babakhani K, Kucinskas AL, Ye X, Giles ED, Sun Y. Aging immunity: unraveling the complex nexus of diet, gut microbiome, and immune function. IMMUNOMETABOLISM (COBHAM, SURREY) 2025; 7:e00061. [PMID: 40352822 PMCID: PMC12063687 DOI: 10.1097/in9.0000000000000061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/28/2025] [Indexed: 05/14/2025]
Abstract
Aging is associated with immune senescence and gut dysbiosis, both of which are heavily influenced by the diet. In this review, we summarize current knowledge regarding the impact of diets high in fiber, protein, or fat, as well as different dietary components (tryptophan, omega-3 fatty acids, and galacto-oligosaccharides) on the immune system and the gut microbiome in aging. Additionally, this review discusses how aging alters tryptophan metabolism, contributing to changes in immune function and the gut microbiome. Understanding the relationship between diet, the gut microbiome, and immune function in the context of aging is critical to formulate sound dietary recommendations for older individuals, and these personalized nutritional practices will ultimately improve the health and longevity of the elderly.
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Affiliation(s)
| | - Amanda L. Kucinskas
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Xiangcang Ye
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Erin D. Giles
- School of Kinesiology, University of Michigan, Ann Arbor, MI, USA
| | - Yuxiang Sun
- Department of Nutrition, Texas A&M University, College Station, TX, USA
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