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Lei P, Walker T, Ayton S. Neuroferroptosis in health and diseases. Nat Rev Neurosci 2025:10.1038/s41583-025-00930-5. [PMID: 40389615 DOI: 10.1038/s41583-025-00930-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2025] [Indexed: 05/21/2025]
Abstract
Ferroptosis is a type of cell death process defined by iron-dependent peroxidation of phospholipids leading to the destruction of cellular membranes and death of the cell. Ferroptosis occurs throughout the body, but a considerable research focus on ferroptosis in the brain - neuroferroptosis - has been driven by the rich lipid and iron content of the brain as well as its high oxygen consumption. Neurons also have an exceptionally large surface area and metabolic demand, which necessitates specific mechanisms (such as lipid antioxidants) to engage constantly to protect the plasma membrane against lipid peroxidation. Ferroptosis has been extensively linked to neurodegeneration and ischaemia and is increasingly implicated in physiological processes such as neuronal reprogramming. Astrocytes provide metabolic support to neurons, enabling them to defend against ferroptosis, yet ferroptotic signals in microglia can propagate damage to astrocytes and neurons, highlighting the complex intercellular (patho)physiology of neuroferroptosis.
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Affiliation(s)
- Peng Lei
- Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
| | - Tara Walker
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, Queensland, Australia
| | - Scott Ayton
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
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2
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Saleh T, Greenberg EF, Faber AC, Harada H, Gewirtz DA. A Critical Appraisal of the Utility of Targeting Therapy-Induced Senescence for Cancer Treatment. Cancer Res 2025; 85:1755-1768. [PMID: 40036150 DOI: 10.1158/0008-5472.can-24-2219] [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: 09/25/2024] [Revised: 01/03/2025] [Accepted: 02/21/2025] [Indexed: 03/06/2025]
Abstract
Cancer chemotherapy and radiotherapy are rarely successful in eliminating the entire tumor population, often leaving behind a subpopulation of senescent cells that can contribute to disease recurrence. These senescent tumor cells also secrete various chemokines and cytokines that may be tumor promoting and immunosuppressive. Recognition of the deleterious impact of therapy-induced senescence has led to the preclinical development of senolytic compounds that eliminate senescent cells, representing a potential strategy to enhance the efficacy of conventional and targeted anticancer therapy. However, it remains uncertain whether this strategy can or will be translated to the clinic. This review provides a summary of the recent preclinical literature supporting the use of senolytics as an adjunct for cancer treatment, discusses the limitations associated with their use in the current preclinical models, and provides perspectives on the clinical development of senolytics in cancer treatment regimens. Overall, preclinical studies support the potential of senolytics to enhance efficacy and prolong the antitumor activity of current standard-of-care cancer therapies that promote senescence. However, further work is needed to develop optimal senolytic agents with the appropriate combination of properties for clinical testing, specifically, activity in the context of therapy-induced senescence with acceptable tolerability.
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Affiliation(s)
- Tareq Saleh
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | | | - Anthony C Faber
- Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia
- Department of Pediatrics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia
| | - Hisashi Harada
- Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia
| | - David A Gewirtz
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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3
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Wang Z, Chen C, Ai J, Gao Y, Wang L, Xia S, Jia Y, Qin Y. The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities. MedComm (Beijing) 2025; 6:e70048. [PMID: 39811803 PMCID: PMC11731108 DOI: 10.1002/mco2.70048] [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: 06/09/2024] [Revised: 11/30/2024] [Accepted: 12/10/2024] [Indexed: 01/16/2025] Open
Abstract
Cellular senescence is characterized by a stable cell cycle arrest and a hypersecretory, proinflammatory phenotype in response to various stress stimuli. Traditionally, this state has been viewed as a tumor-suppressing mechanism that prevents the proliferation of damaged cells while activating the immune response for their clearance. However, senescence is increasingly recognized as a contributing factor to tumor progression. This dual role necessitates a careful evaluation of the beneficial and detrimental aspects of senescence within the tumor microenvironment (TME). Specifically, senescent cells display a unique senescence-associated secretory phenotype that releases a diverse array of soluble factors affecting the TME. Furthermore, the impact of senescence on tumor-immune interaction is complex and often underappreciated. Senescent immune cells create an immunosuppressive TME favoring tumor progression. In contrast, senescent tumor cells could promote a transition from immune evasion to clearance. Given these intricate dynamics, therapies targeting senescence hold promise for advancing antitumor strategies. This review aims to summarize the dual effects of senescence on tumor progression, explore its influence on tumor-immune interactions, and discuss potential therapeutic strategies, alongside challenges and future directions. Understanding how senescence regulates antitumor immunity, along with new therapeutic interventions, is essential for managing tumor cell senescence and remodeling the immune microenvironment.
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Affiliation(s)
- Zehua Wang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Chen Chen
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jiaoyu Ai
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yaping Gao
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Lei Wang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Shurui Xia
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yongxu Jia
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yanru Qin
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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Shimizu K, Inuzuka H, Tokunaga F. The interplay between cell death and senescence in cancer. Semin Cancer Biol 2025; 108:1-16. [PMID: 39557316 DOI: 10.1016/j.semcancer.2024.11.001] [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: 08/15/2024] [Revised: 11/10/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer. ABBREVIATIONS: Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.
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Affiliation(s)
- Kouhei Shimizu
- Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan.
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA02215, USA
| | - Fuminori Tokunaga
- Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
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De Leon-Oliva D, Boaru DL, Minaya-Bravo AM, De Castro-Martinez P, Fraile-Martinez O, Garcia-Montero C, Cobo-Prieto D, Barrena-Blázquez S, Lopez-Gonzalez L, Albillos A, Alvarez-Mon M, Saez MA, Diaz-Pedrero R, Ortega MA. Improving understanding of ferroptosis: Molecular mechanisms, connection with cellular senescence and implications for aging. Heliyon 2024; 10:e39684. [PMID: 39553553 PMCID: PMC11564042 DOI: 10.1016/j.heliyon.2024.e39684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/20/2024] [Accepted: 10/21/2024] [Indexed: 11/19/2024] Open
Abstract
In the face of cell damage, cells can initiate a response ranging from survival to death, the balance being crucial for tissue homeostasis and overall health. Cell death, in both accidental and regulated forms, plays a fundamental role in maintaining tissue homeostasis. Among the regulated mechanisms of cell death, ferroptosis has garnered attention for its iron-dependent phospholipid (PL) peroxidation and its implications in aging and age-related disorders, as well as for its therapeutic relevance. In this review, we provide an overview of the mechanisms, regulation, and physiological and pathological roles of ferroptosis. We present new insights into the relationship between ferroptosis, cellular senescence and aging, emphasizing how alterations in ferroptosis pathways contribute to aging-related tissue dysfunction. In addition, we examine the therapeutic potential of ferroptosis in aging-related diseases, offering innovative insights into future interventions aimed at mitigating the effects of aging and promoting longevity.
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Affiliation(s)
- Diego De Leon-Oliva
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Diego Liviu Boaru
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Ana M. Minaya-Bravo
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Patricia De Castro-Martinez
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Cielo Garcia-Montero
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - David Cobo-Prieto
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Immune System Diseases-Rheumatology Service, Central University Hospital of Defence-UAH Madrid, 28801, Alcala de Henares, Spain
| | - Silvestra Barrena-Blázquez
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of General and Digestive Surgery, General and Digestive Surgery, Príncipe de Asturias Universitary Hospital, Alcala de Henares, Spain
| | - Laura Lopez-Gonzalez
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Agustín Albillos
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Gastroenterology and Hepatology Service, Ramón y Cajal University Hospital, University of Alcalá, IRYCIS, Network Biomedical Research Center for Liver and Digestive Diseases (CIBERehd), Carlos III Health Institute, Madrid, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine (CIBEREHD), University Hospital Príncipe de Asturias, 28806, Alcala de Henares, Spain
| | - Miguel A. Saez
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Pathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, 28801, Alcala de Henares, Spain
| | - Raul Diaz-Pedrero
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of General and Digestive Surgery, General and Digestive Surgery, Príncipe de Asturias Universitary Hospital, Alcala de Henares, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Miguel A. Ortega
- Department of Medicine and Medical Specialities, (CIBERehd), Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
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Chen X, Yu T, Li S, Fang H. Inhibition of bromodomain regulates cellular senescence in pancreatic adenocarcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2024; 17:360-370. [PMID: 39544715 PMCID: PMC11558316 DOI: 10.62347/bknq9812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/23/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators that promote the transcription of genes in the chromatin region associated with acetylated histones. Small molecule BET inhibitor JQ1 suppresses the biologic function of BET proteins in a variety of tumors and inhibits their proliferation. METHODS We investigated the effect of JQ1 in the treatment of pancreatic cancer. In addition, we evaluated the expression level of BRD4 protein in pancreatic cancer tissues using the Gene Expression Profiling Interactive Analysis (GEPIA) and the Human protein Altas databases and analyzed the correlation between BRD4 and the clinicopathologic features and immune checkpoints of pancreatic adenocarcinoma using UALACN and TIMER databases. RESULTS JQ1 significantly inhibited the proliferation of pancreatic adenocarcinoma (PAAD) cells and induced cell senescence but had little effect on Senescence-associated secretory phenotype (SASP). Interestingly, JQ1 inhibited the epithelial-mesenchymal transition (EMT) and Wnt signaling pathways. CONCLUSIONS These results provide a theoretical basis for new targets in the treatment of pancreatic cancer.
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Affiliation(s)
- Xiang Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Tao Yu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Shu Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Hongcai Fang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
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Zhang LJ, Salekeen R, Soto-Palma C, Elsallabi O, Ye H, Hughes B, Zhang B, Nunes A, Lee K, Xu W, Mohamed A, Piepgras E, McGowan SJ, Angelini L, O’Kelly R, Han X, Niedernhofer LJ, Robbins PD. Identification of lipid senolytics targeting senescent cells through ferroptosis induction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.14.618023. [PMID: 39463954 PMCID: PMC11507694 DOI: 10.1101/2024.10.14.618023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice. Importantly, these novel lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic PUFAs and ROS levels in senescent cells. Mechanistic studies and computational analyses further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. This new class of ferroptosis-inducing lipid senolytics provides a novel approach to slow aging and treat age-related disease, targeting senescent cells that are primed for ferroptosis.
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Affiliation(s)
- Lei Justan Zhang
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Rahagir Salekeen
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Carolina Soto-Palma
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Osama Elsallabi
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
- Department of Medicine and Aging Sciences, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Hongping Ye
- Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA
| | - Brian Hughes
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Borui Zhang
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Allancer Nunes
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Kyooa Lee
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Wandi Xu
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Abdalla Mohamed
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Ellie Piepgras
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Sara J. McGowan
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Luise Angelini
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Ryan O’Kelly
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Xianlin Han
- Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Laura J. Niedernhofer
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Paul D. Robbins
- Institute on the Biology of Aging and Metabolism and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
- Lead contact
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Luo Y, Bai XY, Zhang L, Hu QQ, Zhang N, Cheng JZ, Hou MZ, Liu XL. Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches. Drug Des Devel Ther 2024; 18:2485-2529. [PMID: 38919962 PMCID: PMC11198730 DOI: 10.2147/dddt.s472178] [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: 04/04/2024] [Accepted: 06/13/2024] [Indexed: 06/27/2024] Open
Abstract
Ferroptosis, a unique form of programmed cell death, is initiated by an excess of iron accumulation and lipid peroxidation-induced damage. There is a growing body of evidence indicating that ferroptosis plays a critical role in the advancement of tumors. The increased metabolic activity and higher iron levels in tumor cells make them particularly vulnerable to ferroptosis. As a result, the targeted induction of ferroptosis is becoming an increasingly promising approach for cancer treatment. This review offers an overview of the regulatory mechanisms of ferroptosis, delves into the mechanism of action of traditional small molecule ferroptosis inducers and their effects on various tumors. In addition, the latest progress in inducing ferroptosis using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic therapy (SDT) and nanomaterials is summarized. Finally, this review discusses the challenges and opportunities in the development of ferroptosis-inducing agents, focusing on discovering new targets, improving selectivity, and reducing toxic and side effects.
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Affiliation(s)
- YiLin Luo
- Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of China
| | - Xin Yue Bai
- Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of China
| | - Lei Zhang
- Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of China
| | - Qian Qian Hu
- Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of China
| | - Ning Zhang
- Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of China
| | - Jun Zhi Cheng
- Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of China
| | - Ming Zheng Hou
- Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of China
| | - Xiao Long Liu
- Yan ‘an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan’an University, Yan’an, People’s Republic of China
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9
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Sfera A, Imran H, Sfera DO, Anton JJ, Kozlakidis Z, Hazan S. Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes. Int J Mol Sci 2024; 25:5904. [PMID: 38892092 PMCID: PMC11173215 DOI: 10.3390/ijms25115904] [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: 03/26/2024] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.
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Affiliation(s)
- Adonis Sfera
- Patton State Hospital, 3102 Highland Ave., Patton, CA 92369, USA; (H.I.)
- University of California Riverside, Riverside 900 University Ave., Riverside, CA 92521, USA
- Loma Linda University, 11139 Anderson St., Loma Linda, CA 92350, USA
| | - Hassan Imran
- Patton State Hospital, 3102 Highland Ave., Patton, CA 92369, USA; (H.I.)
- University of California Riverside, Riverside 900 University Ave., Riverside, CA 92521, USA
- Loma Linda University, 11139 Anderson St., Loma Linda, CA 92350, USA
| | - Dan O. Sfera
- Patton State Hospital, 3102 Highland Ave., Patton, CA 92369, USA; (H.I.)
- University of California Riverside, Riverside 900 University Ave., Riverside, CA 92521, USA
- Loma Linda University, 11139 Anderson St., Loma Linda, CA 92350, USA
| | | | - Zisis Kozlakidis
- International Agency for Research on Cancer, 69372 Lyon, France;
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Feng Y, Wei H, Lyu M, Yu Z, Chen J, Lyu X, Zhuang F. Iron retardation in lysosomes protects senescent cells from ferroptosis. Aging (Albany NY) 2024; 16:7683-7703. [PMID: 38683121 PMCID: PMC11131988 DOI: 10.18632/aging.205777] [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: 10/17/2023] [Accepted: 03/09/2024] [Indexed: 05/01/2024]
Abstract
Ferroptosis, an iron-triggered modality of cellular death, has been reported to closely relate to human aging progression and aging-related diseases. However, the involvement of ferroptosis in the development and maintenance of senescent cells still remains elusive. Here, we established a doxorubicin-induced senescent HSkM cell model and found that both iron accumulation and lipid peroxidation increase in senescent cells. Moreover, such iron overload in senescent cells has changed the expression panel of the ferroptosis-response proteins. Interestingly, the iron accumulation and lipid peroxidation does not trigger ferroptosis-induced cell death. Oppositely, senescent cells manifest resistance to the ferroptosis inducers, compared to the proliferating cells. To further investigate the mechanism of ferroptosis-resistance for senescent cells, we traced the iron flux in cell and found iron arrested in lysosome. Moreover, disruption of lysosome functions by chloroquine and LLOMe dramatically triggered the senescent cell death. Besides, the ferroitinophagy-related proteins FTH1/FTL and NCOA4 knockdown also increases the senescent cell death. Thus, we speculated that iron retardation in lysosome of senescent cells is the key mechanism for ferroptosis resistance. And the lysosome is a promising target for senolytic drugs to selectively clear senescent cells and alleviate the aging related diseases.
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Affiliation(s)
- Yujing Feng
- School of Laboratory Animal and Shandong Laboratory Animal Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Huaiqing Wei
- Biomedical Research College and Shandong Medicinal Biotechnology Centre, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Meng Lyu
- School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhiyuan Yu
- School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jia Chen
- School of Radiology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, Shandong, China
| | - Xinxing Lyu
- School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Fengfeng Zhuang
- School of Laboratory Animal and Shandong Laboratory Animal Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
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11
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Hall SA, Lesniewski LA. Targeting vascular senescence in cardiovascular disease with aging. THE JOURNAL OF CARDIOVASCULAR AGING 2024; 4:16. [PMID: 39119148 PMCID: PMC11309369 DOI: 10.20517/jca.2023.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
Aging is a major risk factor for atherosclerosis and cardiovascular disease (CVD). Two major age-associated arterial phenotypes, endothelial dysfunction and large elastic arterial stiffness, are autonomous predictors of future CVD diagnosis and contribute to the progression of CVD in older adults. Senescent cells lose the capacity to proliferate but remain metabolically active and secrete inflammatory factors termed senescence-associated secretory phenotype (SASP), leading to an increase in inflammation and oxidative stress. Accumulation of senescent cells is linked with the progression of age-related diseases and has been known to play a role in cardiovascular disease. In this brief review, we describe the characteristics and mechanisms of senescent cell accumulation and how senescent cells promote endothelial dysfunction and arterial stiffness. We focus on a range of novel therapeutic strategies aimed at reducing the burden of endothelial dysfunction leading to atherosclerosis through targeting senescent cells. Studies have begun to investigate a specific class of drugs that are able to selectively eliminate senescent cells, termed senolytics, which have shown great promise in reversing the aging phenotype and ameliorating pathologies in age-related disorders, creating a new opportunity for aging research. Generating therapies targeting the elimination of senescent cells would improve health span and increase longevity, making senolytics a promising therapy for cardiovascular diseases.
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Affiliation(s)
- Shelby A Hall
- Department of Nutrition and Integrated Physiology, University of Utah, Salt Lake City, UT 84112, USA
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Lisa A Lesniewski
- Department of Nutrition and Integrated Physiology, University of Utah, Salt Lake City, UT 84112, USA
- Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA
- Geriatric Research Education and Clinical Centers, Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA
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12
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Rad AN, Grillari J. Current senolytics: Mode of action, efficacy and limitations, and their future. Mech Ageing Dev 2024; 217:111888. [PMID: 38040344 DOI: 10.1016/j.mad.2023.111888] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/11/2023] [Accepted: 11/21/2023] [Indexed: 12/03/2023]
Abstract
Senescence is a cellular state characterized by its near-permanent halted cell cycle and distinct secretory phenotype. Although senescent cells have a variety of beneficial physiological functions, progressive accumulation of these cells due to aging or other conditions has been widely shown to provoke deleterious effects on the normal functioning of the same or higher-level biological organizations. Recently, erasing senescent cells in vivo, using senolytics, could ameliorate diseases identified with an elevated number of senescent cells. Since then, researchers have struggled to develop new senolytics each with different selectivity and potency. In this review, we have gathered and classified the proposed senolytics and discussed their mechanisms of action. Moreover, we highlight the heterogeneity of senolytics regarding their effect sizes, and cell type specificity as well as comment on the exploited strategies to improve these features. Finally, we suggest some prospective routes for the novel methods for ablation of senescent cells.
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Affiliation(s)
- Amirhossein Nayeri Rad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 71468-64685, Shiraz, Iran.
| | - Johannes Grillari
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria; Institute of Molecular Biotechnology, University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190 Vienna, Austria.
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13
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Crescenzi E, Leonardi A, Pacifico F. Iron Metabolism in Cancer and Senescence: A Cellular Perspective. BIOLOGY 2023; 12:989. [PMID: 37508419 PMCID: PMC10376531 DOI: 10.3390/biology12070989] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/06/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023]
Abstract
Iron participates in a number of biological processes and plays a crucial role in cellular homeostasis. Alterations in iron metabolism are considered hallmarks of cancer and drivers of aggressive behaviors, such as uncontrolled proliferation, resistance to apoptosis, enhanced metastatic ability, increased cell plasticity and stemness. Furthermore, a dysregulated iron metabolism has been associated with the development of an adverse tumor microenvironment. Alterations in iron metabolism have been described in cellular senescence and in aging. For instance, iron has been shown to accumulate in aged tissues and in age-related diseases. Furthermore, in vitro studies demonstrate increases in iron content in both replicative and stress-induced senescent cells. However, the role, the mechanisms of regulation and dysregulation and the effects of iron metabolism on senescence remain significantly less characterized. In this review, we first provide an overview of iron metabolism and iron regulatory proteins. Then, we summarize alterations in iron homeostasis in cancer and senescence from a cellular point of view.
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Affiliation(s)
- Elvira Crescenzi
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, CNR, Via S. Pansini, 5, 80131 Naples, Italy
| | - Antonio Leonardi
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, "Federico II" University of Naples, Via S. Pansini, 5, 80131 Naples, Italy
| | - Francesco Pacifico
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, CNR, Via S. Pansini, 5, 80131 Naples, Italy
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14
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Smer-Barreto V, Quintanilla A, Elliott RJR, Dawson JC, Sun J, Campa VM, Lorente-Macías Á, Unciti-Broceta A, Carragher NO, Acosta JC, Oyarzún DA. Discovery of senolytics using machine learning. Nat Commun 2023; 14:3445. [PMID: 37301862 PMCID: PMC10257182 DOI: 10.1038/s41467-023-39120-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin and oleandrin in human cell lines under various modalities of senescence. The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives. Our approach led to several hundred-fold reduction in drug screening costs and demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data, paving the way for new open science approaches to early-stage drug discovery.
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Affiliation(s)
- Vanessa Smer-Barreto
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK.
| | - Andrea Quintanilla
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-SODERCAN. C/ Albert Einstein 22, Santander, 39011, Spain
| | - Richard J R Elliott
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK
| | - John C Dawson
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK
| | - Jiugeng Sun
- School of Informatics, University of Edinburgh, 10 Crichton St, Edinburgh, EH8 9AB, UK
| | - Víctor M Campa
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-SODERCAN. C/ Albert Einstein 22, Santander, 39011, Spain
| | - Álvaro Lorente-Macías
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK
| | - Asier Unciti-Broceta
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK
| | - Neil O Carragher
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK
| | - Juan Carlos Acosta
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK.
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-SODERCAN. C/ Albert Einstein 22, Santander, 39011, Spain.
| | - Diego A Oyarzún
- School of Informatics, University of Edinburgh, 10 Crichton St, Edinburgh, EH8 9AB, UK.
- School of Biological Sciences, University of Edinburgh, Max Born Crescent, Edinburgh, EH9 3BF, UK.
- The Alan Turing Institute, 96 Euston Road, London, NW1 2DB, UK.
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15
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Vielee ST, Wise JP. Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence. Brain Sci 2023; 13:500. [PMID: 36979310 PMCID: PMC10046019 DOI: 10.3390/brainsci13030500] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/10/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023] Open
Abstract
Advancements in modern medicine have improved the quality of life across the globe and increased the average lifespan of our population by multiple decades. Current estimates predict by 2030, 12% of the global population will reach a geriatric age and live another 3-4 decades. This swelling geriatric population will place critical stress on healthcare infrastructures due to accompanying increases in age-related diseases and comorbidities. While much research focused on long-lived individuals seeks to answer questions regarding how to age healthier, there is a deficit in research investigating what aspects of our lives accelerate or exacerbate aging. In particular, heavy metals are recognized as a significant threat to human health with links to a plethora of age-related diseases, and have widespread human exposures from occupational, medical, or environmental settings. We believe heavy metals ought to be classified as a class of gerontogens (i.e., chemicals that accelerate biological aging in cells and tissues). Gerontogens may be best studied through their effects on the "Hallmarks of Aging", nine physiological hallmarks demonstrated to occur in aged cells, tissues, and bodies. Evidence suggests that cellular senescence-a permanent growth arrest in cells-is one of the most pertinent hallmarks of aging and is a useful indicator of aging in tissues. Here, we discuss the roles of heavy metals in brain aging. We briefly discuss brain aging in general, then expand upon observations for heavy metals contributing to age-related neurodegenerative disorders. We particularly emphasize the roles and observations of cellular senescence in neurodegenerative diseases. Finally, we discuss the observations for heavy metals inducing cellular senescence. The glaring lack of knowledge about gerontogens and gerontogenic mechanisms necessitates greater research in the field, especially in the context of the global aging crisis.
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Affiliation(s)
- Samuel T. Vielee
- Pediatrics Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - John P. Wise
- Pediatrics Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
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16
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Admasu TD, Kim K, Rae M, Avelar R, Gonciarz RL, Rebbaa A, Pedro de Magalhães J, Renslo AR, Stolzing A, Sharma A. Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis. Cell Rep 2023; 42:112058. [PMID: 36753419 DOI: 10.1016/j.celrep.2023.112058] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 11/29/2022] [Accepted: 01/17/2023] [Indexed: 02/08/2023] Open
Abstract
Senescent cells can spread the senescent phenotype to other cells by secreting senescence-associated secretory phenotype factors. The resulting paracrine senescent cells make a significant contribution to the burden of senescent cell accumulation with age. Previous efforts made to characterize paracrine senescence are unreliable due to analyses being based on mixed populations of senescent and non-senescent cells. Here, we use dipeptidyl peptidase-4 (DPP4) as a surface maker to isolate senescent cells from mixed populations. Using this technique, we enrich the percentage of paracrine senescence from 40% to 85%. We then use this enriched culture to characterize DPP4+ primary and paracrine senescent cells. We observe ferroptosis dysregulation and ferrous iron accumulation as a common phenomenon in both primary and paracrine senescent cells. Finally, we identify ferroptosis induction and ferrous iron-activatable prodrug as a broad-spectrum senolytic approach to ablate multiple types of primary and paracrine senescent cells.
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Affiliation(s)
| | - Kristie Kim
- SENS Research Foundation, Mountain View, CA 94041, USA
| | - Michael Rae
- SENS Research Foundation, Mountain View, CA 94041, USA
| | - Roberto Avelar
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
| | - Ryan L Gonciarz
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
| | | | - João Pedro de Magalhães
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
| | - Adam R Renslo
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
| | - Alexandra Stolzing
- Loughborough University, Centre for Biological Engineering, School of Mechanical, Electrical and Manufacturing Engineering, Epinal Way, Loughborough LE113TU, UK
| | - Amit Sharma
- SENS Research Foundation, Mountain View, CA 94041, USA.
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17
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Chibaya L, Snyder J, Ruscetti M. Senescence and the tumor-immune landscape: Implications for cancer immunotherapy. Semin Cancer Biol 2022; 86:827-845. [PMID: 35143990 PMCID: PMC9357237 DOI: 10.1016/j.semcancer.2022.02.005] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/03/2022] [Indexed: 01/27/2023]
Abstract
Cancer therapies, including conventional chemotherapy, radiation, and molecularly targeted agents, can lead to tumor eradication through a variety of mechanisms. In addition to their effects on tumor cell growth and survival, these regimens can also influence the surrounding tumor-immune microenvironment in ways that ultimately impact therapy responses. A unique biological outcome of cancer therapy is induction of cellular senescence. Senescence is a damage-induced stress program that leads to both the durable arrest of tumor cells and remodeling the tumor-immune microenvironment through activation of a collection pleiotropic cytokines, chemokines, growth factors, and proteinases known as the senescence-associated secretory phenotype (SASP). Depending on the cancer context and the mechanism of action of the therapy, the SASP produced following therapy-induced senescence (TIS) can promote anti-tumor immunity that enhances therapeutic efficacy, or alternatively chronic inflammation that leads to therapy failure and tumor relapse. Thus, a deeper understanding of the mechanisms regulating the SASP and components necessary for robust anti-tumor immune surveillance in different cancer and therapy contexts are key to harnessing senescence for tumor control. Here we draw a roadmap to modulate TIS and its immune-stimulating features for cancer immunotherapy.
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Affiliation(s)
- Loretah Chibaya
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jarin Snyder
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Marcus Ruscetti
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA; Immunology and Microbiology Program, University of Massachusetts Chan Medical School, Worcester, MA, USA; Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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18
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L'Hôte V, Mann C, Thuret JY. From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biol 2022; 12:220171. [PMID: 36128715 PMCID: PMC9490338 DOI: 10.1098/rsob.220171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Senescence is a cellular stress response that involves prolonged cell survival, a quasi-irreversible proliferative arrest and a modification of the transcriptome that sometimes includes inflammatory gene expression. Senescent cells are resistant to apoptosis, and if not eliminated by the immune system they may accumulate and lead to chronic inflammation and tissue dysfunction. Senolytics are drugs that selectively induce cell death in senescent cells, but not in proliferative or quiescent cells, and they have proved a viable therapeutic approach in multiple mouse models of pathologies in which senescence is implicated. As the catalogue of senolytic compounds is expanding, novel survival strategies of senescent cells are uncovered, and variations in sensitivity to senolysis between different types of senescent cells emerge. We propose herein a mechanistic classification of senolytic drugs, based on the level at which they target senescent cells: directly disrupting BH3 protein networks that are reorganized upon senescence induction; downregulating survival-associated pathways essential to senescent cells; or modulating homeostatic processes whose regulation is challenged in senescence. With this approach, we highlight the important diversity of senescent cells in terms of physiology and pathways of apoptosis suppression, and we describe possible avenues for the development of more selective senolytics.
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Affiliation(s)
- Valentin L'Hôte
- CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette cedex, France
| | - Carl Mann
- CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette cedex, France
| | - Jean-Yves Thuret
- CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette cedex, France
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19
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Liao CM, Wulfmeyer VC, Chen R, Erlangga Z, Sinning J, von Mässenhausen A, Sörensen-Zender I, Beer K, von Vietinghoff S, Haller H, Linkermann A, Melk A, Schmitt R. Induction of ferroptosis selectively eliminates senescent tubular cells. Am J Transplant 2022; 22:2158-2168. [PMID: 35607817 DOI: 10.1111/ajt.17102] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 04/27/2022] [Accepted: 05/22/2022] [Indexed: 01/25/2023]
Abstract
The accumulation of senescent cells is an important contributor to kidney aging, chronic renal disease, and poor outcome after kidney transplantation. Approaches to eliminate senescent cells with senolytic compounds have been proposed as novel strategies to improve marginal organs. While most existing senolytics induce senescent cell clearance by apoptosis, we observed that ferroptosis, an iron-catalyzed subtype of regulated necrosis, might serve as an alternative way to ablate senescent cells. We found that murine kidney tubular epithelial cells became sensitized to ferroptosis when turning senescent. This was linked to increased expression of pro-ferroptotic lipoxygenase-5 and reduced expression of anti-ferroptotic glutathione peroxidase 4 (GPX4). In tissue slice cultures from aged kidneys low dose application of the ferroptosis-inducer RSL3 selectively eliminated senescent cells while leaving healthy tubular cells unaffected. Similar results were seen in a transplantation model, in which RSL3 reduced the senescent cell burden of aged donor kidneys and caused a reduction of damage and inflammatory cell infiltration during the early post-transplantation period. In summary, these data reveal an increased susceptibility of senescent tubular cells to ferroptosis with the potential to be exploited for selective reduction of renal senescence in aged kidney transplants.
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Affiliation(s)
- Chieh M Liao
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany
| | - Vera C Wulfmeyer
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany
| | - Rongjun Chen
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Medical School Hannover, Hannover, Germany
| | - Zulrahman Erlangga
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Medical School Hannover, Hannover, Germany
| | - Julius Sinning
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany
| | - Anne von Mässenhausen
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische University of Dresden, Dresden, Germany
| | - Inga Sörensen-Zender
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany
| | - Kristina Beer
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische University of Dresden, Dresden, Germany
| | - Sibylle von Vietinghoff
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.,Nephrology Section, First Medical Clinic, University Clinic and Rheinische Friedrich-Wilhelms Universität Bonn, Bonn, Germany
| | - Hermann Haller
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische University of Dresden, Dresden, Germany
| | - Anette Melk
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Medical School Hannover, Hannover, Germany
| | - Roland Schmitt
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany
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20
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Diwan B, Sharma R. Nutritional components as mitigators of cellular senescence in organismal aging: a comprehensive review. Food Sci Biotechnol 2022; 31:1089-1109. [PMID: 35756719 PMCID: PMC9206104 DOI: 10.1007/s10068-022-01114-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 11/06/2022] Open
Abstract
The process of cellular senescence is rapidly emerging as a modulator of organismal aging and disease. Targeting the development and removal of senescent cells is considered a viable approach to achieving improved organismal healthspan and lifespan. Nutrition and health are intimately linked and an appropriate dietary regimen can greatly impact organismal response to stress and diseases including during aging. With a renewed focus on cellular senescence, emerging studies demonstrate that both primary and secondary nutritional elements such as carbohydrates, proteins, fatty acids, vitamins, minerals, polyphenols, and probiotics can influence multiple aspects of cellular senescence. The present review describes the recent molecular aspects of cellular senescence-mediated understanding of aging and then studies available evidence of the cellular senescence modulatory attributes of major and minor dietary elements. Underlying pathways and future research directions are deliberated to promote a nutrition-centric approach for targeting cellular senescence and thus improving human health and longevity.
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Affiliation(s)
- Bhawna Diwan
- Faculty of Applied Sciences & Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, 173229 India
| | - Rohit Sharma
- Faculty of Applied Sciences & Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, 173229 India
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21
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Kim C, Lee SG, Lim S, Jung M, Kwon SP, Hong J, Kang M, Sohn HS, Go S, Moon S, Lee SJ, Kim JS, Kim BS. A Senolytic-Eluting Coronary Stent for the Prevention of In-Stent Restenosis. ACS Biomater Sci Eng 2022; 8:1921-1929. [PMID: 35416659 DOI: 10.1021/acsbiomaterials.1c01611] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The vast majority of drug-eluting stents (DES) elute either sirolimus or one of its analogues. While limus drugs stymie vascular smooth muscle cell (VSMC) proliferation to prevent in-stent restenosis, their antiproliferative nature is indiscriminate and limits healing of the endothelium in stented vessels, increasing the risk of late-stent thrombosis. Oxidative stress, which is associated with vascular injury from stent implantation, can induce VSMCs to undergo senescence, and senescent VSMCs can produce pro-inflammatory cytokines capable of inducing proliferation of neighboring nonsenescent VSMCs. We explored the potential of senolytic therapy, which involves the selective elimination of senescent cells, in the form of a senolytic-eluting stent (SES) for interventional cardiology. Oxidative stress was modeled in vitro by exposing VSMCs to H2O2, and H2O2-mediated senescence was evaluated by cytochemical staining of senescence-associated β-galactosidase activity and qRT-PCR. Quiescent VSMCs were then treated with the conditioned medium (CM) of H2O2-treated VSMCs. Proliferative effects of CM were analyzed by staining for proliferating cell nuclear antigen. Senolytic effects of the first-generation senolytic ABT263 were observed in vitro, and the effects of ABT263 on endothelial cells were also investigated through an in vitro re-endothelialization assay. SESs were prepared by dip coating. Iliofemoral arteries of hypercholesteremic rabbits were implanted with SES, everolimus-eluting stents (EESs), or bare-metal stents (BMSs), and the area of stenosis was measured 4 weeks post-implantation using optical coherence tomography. We found that a portion of H2O2-treated VSMCs underwent senescence, and that CM of H2O2-treated senescent VSMCs triggered the proliferation of quiescent VSMCs. ABT263 reverted H2O2-mediated senescence and the proliferative capacity of senescent VSMC CM. Unlike everolimus, ABT263 did not affect endothelial cell migration and/or proliferation. SES, but not EES, significantly reduced stenosis area in vivo compared with bare-metal stents (BMSs). This study shows the potential of SES as an alternative to current forms of DES.
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Affiliation(s)
- Cheesue Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Seul-Gee Lee
- Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Songhyun Lim
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Mungyo Jung
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Sung Pil Kwon
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Jihye Hong
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Mikyung Kang
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Hee Su Sohn
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Seokhyeong Go
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Sangjun Moon
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Seung-Jun Lee
- Cardiology Division, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jung-Sun Kim
- Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.,Cardiology Division, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea.,Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 08826, Republic of Korea.,Institute of Chemical Processes, Institute of Engineering Research, and BioMAX, Seoul National University, Seoul 08826, Republic of Korea
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22
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Tian Y, Tian Y, Yuan Z, Zeng Y, Wang S, Fan X, Yang D, Yang M. Iron Metabolism in Aging and Age-Related Diseases. Int J Mol Sci 2022; 23:3612. [PMID: 35408967 PMCID: PMC8998315 DOI: 10.3390/ijms23073612] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 02/06/2023] Open
Abstract
Iron is a trace metal element necessary to maintain life and is also involved in a variety of biological processes. Aging refers to the natural life process in which the physiological functions of the various systems, organs, and tissues decline, affected by genetic and environmental factors. Therefore, it is imperative to investigate the relationship between iron metabolism and aging-related diseases, including neurodegenerative diseases. During aging, the accumulation of nonheme iron destroys the stability of the intracellular environment. The destruction of iron homeostasis can induce cell damage by producing hydroxyl free radicals, leading to mitochondrial dysfunction, brain aging, and even organismal aging. In this review, we have briefly summarized the role of the metabolic process of iron in the body, then discussed recent developments of iron metabolism in aging and age-related neurodegenerative diseases, and finally, explored some iron chelators as treatment strategies for those disorders. Understanding the roles of iron metabolism in aging and neurodegenerative diseases will fill the knowledge gap in the field. This review could provide new insights into the research on iron metabolism and age-related neurodegenerative diseases.
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Affiliation(s)
- Yao Tian
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Y.T.); (Z.Y.); (Y.Z.); (S.W.); (X.F.); (D.Y.)
| | - Yuanliangzi Tian
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Y.T.); (Z.Y.); (Y.Z.); (S.W.); (X.F.); (D.Y.)
| | - Zhixiao Yuan
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Y.T.); (Z.Y.); (Y.Z.); (S.W.); (X.F.); (D.Y.)
| | - Yutian Zeng
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Y.T.); (Z.Y.); (Y.Z.); (S.W.); (X.F.); (D.Y.)
| | - Shuai Wang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Y.T.); (Z.Y.); (Y.Z.); (S.W.); (X.F.); (D.Y.)
| | - Xiaolan Fan
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Y.T.); (Z.Y.); (Y.Z.); (S.W.); (X.F.); (D.Y.)
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Deying Yang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Y.T.); (Z.Y.); (Y.Z.); (S.W.); (X.F.); (D.Y.)
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Mingyao Yang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Y.T.); (Z.Y.); (Y.Z.); (S.W.); (X.F.); (D.Y.)
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
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23
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Logie E, Van Puyvelde B, Cuypers B, Schepers A, Berghmans H, Verdonck J, Laukens K, Godderis L, Dhaenens M, Deforce D, Vanden Berghe W. Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence. Int J Mol Sci 2021; 22:12234. [PMID: 34830117 PMCID: PMC8618106 DOI: 10.3390/ijms222212234] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/29/2021] [Accepted: 11/08/2021] [Indexed: 12/20/2022] Open
Abstract
Disease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated cell death, are appealing alternative treatment strategies for multiple myeloma and other malignancies. Both ferroptosis and the epigenetic machinery are heavily influenced by oxidative stress and iron metabolism changes. Yet, only a limited number of epigenetic enzymes and modifications have been identified as ferroptosis regulators. In this study, we found that MM1 multiple myeloma cells are sensitive to ferroptosis induction and epigenetic reprogramming by RSL3, irrespective of their glucocorticoid-sensitivity status. LC-MS/MS analysis revealed the formation of non-heme iron-histone complexes and altered expression of histone modifications associated with DNA repair and cellular senescence. In line with this observation, EPIC BeadChip measurements of significant DNA methylation changes in ferroptotic myeloma cells demonstrated an enrichment of CpG probes located in genes associated with cell cycle progression and senescence, such as Nuclear Receptor Subfamily 4 Group A member 2 (NR4A2). Overall, our data show that ferroptotic cell death is associated with an epigenomic stress response that might advance the therapeutic applicability of ferroptotic compounds.
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Affiliation(s)
- Emilie Logie
- Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (E.L.); (H.B.)
| | - Bart Van Puyvelde
- Laboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, Belgium; (B.V.P.); (M.D.); (D.D.)
| | - Bart Cuypers
- Biomedical Informatics Network Antwerp (Biomina), Department of Computer Science, University of Antwerp, 2610 Antwerp, Belgium; (B.C.); (K.L.)
| | - Anne Schepers
- Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, 2650 Edegem, Belgium;
| | - Herald Berghmans
- Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (E.L.); (H.B.)
| | - Jelle Verdonck
- Center for Environment and Health, Department of Public Health and Primary Care, KU Leuven, 3000 Leuven, Belgium; (J.V.); (L.G.)
| | - Kris Laukens
- Biomedical Informatics Network Antwerp (Biomina), Department of Computer Science, University of Antwerp, 2610 Antwerp, Belgium; (B.C.); (K.L.)
| | - Lode Godderis
- Center for Environment and Health, Department of Public Health and Primary Care, KU Leuven, 3000 Leuven, Belgium; (J.V.); (L.G.)
- IDEWE, External Service for Prevention and Protection at Work, 3001 Heverlee, Belgium
| | - Maarten Dhaenens
- Laboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, Belgium; (B.V.P.); (M.D.); (D.D.)
| | - Dieter Deforce
- Laboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, Belgium; (B.V.P.); (M.D.); (D.D.)
| | - Wim Vanden Berghe
- Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (E.L.); (H.B.)
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24
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Lim S, Kim TJ, Kim YJ, Kim C, Ko SB, Kim BS. Senolytic Therapy for Cerebral Ischemia-Reperfusion Injury. Int J Mol Sci 2021; 22:ijms222111967. [PMID: 34769397 PMCID: PMC8584561 DOI: 10.3390/ijms222111967] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 10/30/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022] Open
Abstract
Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.
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Affiliation(s)
- Songhyun Lim
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Korea; (S.L.); (C.K.)
| | - Tae Jung Kim
- Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea; (T.J.K.); (Y.-J.K.)
- Department of Critical Care Medicine, Seoul National University Hospital, Seoul 03080, Korea
| | - Young-Ju Kim
- Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea; (T.J.K.); (Y.-J.K.)
| | - Cheesue Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Korea; (S.L.); (C.K.)
| | - Sang-Bae Ko
- Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea; (T.J.K.); (Y.-J.K.)
- Department of Critical Care Medicine, Seoul National University Hospital, Seoul 03080, Korea
- Correspondence: (S.-B.K.); (B.-S.K.); Tel.: +82-2-2072-2278 (S.-B.K.); +82-2-880-1509 (B.-S.K.)
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Korea; (S.L.); (C.K.)
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 08826, Korea
- Institute of Chemical Processes, Seoul National University, Seoul 08826, Korea
- Institute of Engineering Research, Seoul National University, Seoul 08826, Korea
- Bio-MAX Institute, Seoul National University, Seoul 08826, Korea
- Correspondence: (S.-B.K.); (B.-S.K.); Tel.: +82-2-2072-2278 (S.-B.K.); +82-2-880-1509 (B.-S.K.)
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25
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Sfera A, Osorio C, Rahman L, Zapata-Martín del Campo CM, Maldonado JC, Jafri N, Cummings MA, Maurer S, Kozlakidis Z. PTSD as an Endothelial Disease: Insights From COVID-19. Front Cell Neurosci 2021; 15:770387. [PMID: 34776871 PMCID: PMC8586713 DOI: 10.3389/fncel.2021.770387] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022] Open
Abstract
SARS-CoV-2 virus, the etiologic agent of COVID-19, has affected almost every aspect of human life, precipitating stress-related pathology in vulnerable individuals. As the prevalence rate of posttraumatic stress disorder in pandemic survivors exceeds that of the general and special populations, the virus may predispose to this disorder by directly interfering with the stress-processing pathways. The SARS-CoV-2 interactome has identified several antigens that may disrupt the blood-brain-barrier by inducing premature senescence in many cell types, including the cerebral endothelial cells. This enables the stress molecules, including angiotensin II, endothelin-1 and plasminogen activator inhibitor 1, to aberrantly activate the amygdala, hippocampus, and medial prefrontal cortex, increasing the vulnerability to stress related disorders. This is supported by observing the beneficial effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in both posttraumatic stress disorder and SARS-CoV-2 critical illness. In this narrative review, we take a closer look at the virus-host dialog and its impact on the renin-angiotensin system, mitochondrial fitness, and brain-derived neurotrophic factor. We discuss the role of furin cleaving site, the fibrinolytic system, and Sigma-1 receptor in the pathogenesis of psychological trauma. In other words, learning from the virus, clarify the molecular underpinnings of stress related disorders, and design better therapies for these conditions. In this context, we emphasize new potential treatments, including furin and bromodomains inhibitors.
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Affiliation(s)
- Adonis Sfera
- Department of Psychiatry, Loma Linda University, Loma Linda, CA, United States
- Patton State Hospital, San Bernardino, CA, United States
| | - Carolina Osorio
- Department of Psychiatry, Loma Linda University, Loma Linda, CA, United States
| | - Leah Rahman
- Patton State Hospital, San Bernardino, CA, United States
| | | | - Jose Campo Maldonado
- Department of Medicine, The University of Texas Rio Grande Valley, Edinburg, TX, United States
| | - Nyla Jafri
- Patton State Hospital, San Bernardino, CA, United States
| | | | - Steve Maurer
- Patton State Hospital, San Bernardino, CA, United States
| | - Zisis Kozlakidis
- International Agency For Research On Cancer (IARC), Lyon, France
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