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Macrophage Senescence in health and diseases

Acta Pharmaceutica Sinica B 2024年第4期14卷 1508-1524页

作者： Longling Wang Wenxiang Hong Hong Zhu Qiaojun He Bo Yang Jiajia Wang Qinjie Weng Center for Drug Safety Evaluation and Research Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Nanhu Brain-Computer Interface Institute Hangzhou 311100China Taizhou Institute of Zhejiang University Taizhou 318000China The Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310009China

Macrophage Senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like Senescence-associated secretory phenotype,has long been consid-ered harmful.Persistent Senescence of macrophages may lead to maladaptation,immune dysfunction,and finally the development of age-related diseases,infections,autoimmune diseases,and malignancies.However,it is a ubiquitous,multi-factorial,and dynamic complex phenomenon that also plays roles in remodeled processes,including wound repair and embryogenesis.In this review,we summarize some general molecular changes and several specific biomarkers during macrophage Senescence,which may bring new sight to recognize senescent macrophages in different conditions.Also,we take an in-depth look at the functional changes in senescent macrophages,including metabolism,autophagy,polarization,phagocytosis,antigen presentation,and infiltration or recruitment.Furthermore,some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated,not only emphasizing the possibility of regulating macrophage Senescence to benefit age-associated diseases but also has an implication on the finding of potential tar-gets ordrugs clinically.

关键词： Macrophages Senescence Molecular changes Functional alterations Aging tissues Age-associated diseases Drug treatment Genetic regulation

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Bone Research 2024年第1期12卷 122-136页

作者： Nan-Yu Zou Ran Liu Mei Huang Yu-Rui Jiao Jie Wei Yangzi Jiang Wen-Zhen He Min Huang Yi-Li Xu Ling Liu Yu-Chen Sun Mi Yang Qi Guo Yan Huang Tian Su Ye Xiao Wei-Shan Wang Chao Zeng Guang-Hua Lei Xiang-Hang Luo Chang-Jun Li Department of Endocrinology Endocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan 410008China Department of Orthopaedics Xiangya Hospital of Central South UniversityChangshaHunan 410008China Department of Epidemiology and Health Statistics Xiangya School of Public HealthCentral South UniversityChangshaChina Hunan Key Laboratory of Joint Degeneration and Injury ChangshaHunan 410008China Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment Ministry of EducationXiangya HospitalCentral South UniversityChangshaChina School of Biomedical Sciences Institute for Tissue Engineering and Regenerative MedicineFaculty of MedicineThe Chinese University of Hong KongHong Kong SARChina Department of Orthopaedics The First Affiliated Hospital of Shihezi UniversityShiheziXinjiangChina National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan 410008China

Skeletal stem/progenitor cell(SSPC)Senescence is a major cause of decreased bone regenerative potential with aging,but the causes of SSPC Senescence remain unclear.In this study,we revealed that macrophages in calluses secrete prosenescent factors,including grancalcin(GCA),during aging,which triggers SSPC Senescence and impairs fracture healing.Local injection of human rGCA in young mice induced SSPC Senescence and delayed fracture repair.Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC Senescence.Mechanistically,GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction,resulting in cellular Senescence.Depletion of Plxnb2 in SSPCs impaired fracture healing.Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice.Thus,our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary Senescence,and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

关键词： healing union Senescence

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Multiple characteristic alterations and available therapeutic strategies of cellular Senescence

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第2期24卷 101-114页

作者： YUNZI ZHAO HUI LI QINGLONG GUO HUI HUI State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Carcinogenesis and InterventionChina Pharmaceutical UniversityNanjing 210009China

Given its state of stable proliferative inhibition,cellular Senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis.Cells undergoing Senescence are often associated with the alteration of a series of specific features and functions,such as metabolic shifts,stemness induction,and microenvironment remodeling.However,recent research has revealed more complexity associated with Senescence,including adverse effects on both physiological and pathological processes.How organisms evade these harmful consequences and survive has become an urgent research issue.Several therapeutic strategies targeting Senescence,including senolytics,senomorphics,immunotherapy,and function restoration,have achieved initial success in certain scenarios.In this review,we describe in detail the characteristic changes associated with cellular Senescence and summarize currently available countermeasures.

关键词： Senescence Metabolism Stemness Microenvironment Senolytic Immune surveillance

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Inhibition of ASCT2 induces hepatic stellate cell Senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3618-3638页

作者： Feixia Wang Zhanghao Li Li Chen Ting Yang Baoyu Liang Zili Zhang Jiangjuan Shao Xuefen Xu Guoping Yin Shijun Wang Hai Ding Feng Zhang Shizhong Zheng Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of PharmacyNanjing University of Chinese MedicineNanjing 210023China Department of General Surgery Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjing 210003China Department of Anesthesiology Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjing 210003China College of Traditional Chinese Medicine Shandong University of Traditional Chinese MedicineJinan 250035China

Senescence of activated hepatic stellate cells(aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression.Senescent cells often accompanied by a multi-faceted Senescence-associated secretory phenotype(SASP).But little is known about how alanine-serine-cysteine transporter type-2(ASCT2),a high affinity glutamine transporter,affects HSC Senescence and SASP during liver fibrosis.Here,we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers.We first discovered ASCT2 inhibition induced HSCs to Senescence in vitro and in vivo.The proinflammatory SASP were restricted by ASCT2 inhibition at Senescence initiation to prevent paracrine migration.Mechanically,ASCT2 was a direct target of glutaminolysisdependent proinflammatory SASP,interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82.From a translational perspective,atractylenolide Ⅲ is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2.The presence of -OH group in atractylenolide Ⅲ is suggested to be favorable for the inhibition of ASCT2.Importantly,atractylenolide Ⅲ could be utilized to treat liver fibrosis mice.Taken together,ASCT2 controlled HSC Senescence while modifying the proinflammatory SASP.Targeting ASCT2 by atractylenolide Ⅲ could be a therapeutic candidate for liver fibrosis.

关键词： Hepatic stellate cells Senescence SASP ASCT2 Precursor IL-1α NF-κB Atractylenolide III Liver fibrosis

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Unveiling E2F4,TEAD1 and AP-1 as regulatory transcription factors of the replicative Senescence program by multi-omics analysis

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Protein & Cell 2022年第10期13卷 742-759页

作者： Yuting Wang Liping Liu Yifan Song Xiaojie Yu Hongkui Deng School of Basic Medical Sciences State Key Laboratory of Natural and Biomimetic DrugsPeking UniversityBeijing 100191China The MOE Key Laboratory of Cell Proliferation and Differentiation College of Life SciencesPeking-Tsinghua Center for Life SciencesPeking UniversityBeijing 100871China State Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China

Senescence,a stable state of growth arrest,affects many physiological and pathophysiological processes,especially aging.Previous work has indicated that transcription factors(TFs)play a role in regulating Senescence.However,a systematic study of regulatory TFs during replicative Senescence(RS)using multiomics analysis is still lacking.Here,we generated timeresolved RNA-seq,reduced representation bisulfite sequencing(RRBS)and ATAC-seq datasets during RS of mouse skin fibroblasts,which demonstrated that an enhanced inflammatory response and reduced proliferative capacity were the main characteristics of RS in both the transcriptome and epigenome.Through integrative analysis and genetic manipulations,we found that transcription factors E2F4,TEAD1 and AP-1 are key regulators of RS.Overexpression of E2f4 improved cellular proliferative capacity,attenuated SA-β-Gal activity and changed RS-associated differentially methylated sites(DMSs).Moreover,knockdown of Tead1 attenuated SA-β-Gal activity and partially altered the RS-associated transcriptome.In addition,knockdown of Atf3,one member of AP-1 superfamily TFs,reduced Cdkn2a(p16)expression in pre-senescent fibroblasts.Taken together,the results of this study identified transcription factors regulating the Senescence program through multi-omics analysis,providing potential therapeutic targets for anti-aging.

关键词： transcription factor Senescence multiomics

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RING-box proteins regulate leaf Senescence and stomatal closure via repression of ABA transporter gene ABCG40

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Journal of Integrative Plant Biology 2022年第5期64卷 979-994页

作者： Yun Qi Wei Jun Jie Yuan Chen Chen Xiao Gui Xin Li Jing Ying Yan Shao Jian Zheng Zhong Jie Ding State Key Laboratory of Plant Physiology and Biochemistry College of Life SciencesZhejiang UniversityHangzhou 310058China Guangdong Laboratory for Lingnan Modern Agriculture College of Natural Resources and EnvironmentSouth China Agricultural UniversityGuangzhou 510642China College of Agronomy and Biotechnology Zhejiang UniversityHangzhou 310058China Agricultural Experimental Station Zhejiang UniversityHangzhou 310058China

Plant hormone abscisic acid(ABA)plays an indispensable role in the control of leaf Senescence,during which ABA signaling depends on its biosynthesis.Nevertheless,the role of ABA transport in leaf Senescence remains unknown.Here,we identified two novel RING-box protein-encoding genes UBIQUITIN LIGASE of Senescence 1 and2(ULS1 and ULS2)involved in leaf Senescence.Lack of ULS1 and ULS2 accelerates leaf Senescence,which is specifically promoted by ABA treatment.Furthermore,the expression of Senescence-related genes is significantly affected in mature leaves of uls1/uls2 double mutant(versus wild type(WT))in an ABA-dependent manner,and the ABA content is substantially increased.ULS1 and ULS2 are mainly expressed in the guard cells and aging leaves,and the expression is induced by ABA.Further RNA-seq and quantitative proteomics of ubiquitination reveal that ABA transporter ABCG40 is highly expressed in uls1/uls2 mutant versus WT,though it is not the direct target of ULS1/2.Finally,we show that the acceleration of leaf Senescence,the increase of leaf ABA content,and the promotion of stomatal closure in uls1/usl2 mutant are suppressed by abcg40 loss-of-function mutation.These results indicate that ULS1 and ULS2 function in feedback inhibition of ABCG40-dependent ABA transport during ABA-induced leaf Senescence and stomatal closure.

关键词： ABA Arabidopsis E3 ligase leaf Senescence stomata transport

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Inhibition of Cyclin F Promotes Cellular Senescence through Cyclin-dependent Kinase 1-mediated Cell Cycle Regulation

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Current Medical Science 2023年第2期43卷 246-254页

作者： Xun LI You-jian LI Meng-jie WANG Ke-peng OU Ya-qi CHEN GI Cancer Research Institute Tongji HospitalHuazhong University of Science and TechnologyWuhan430030China College of Pharmacy National&Local Joint Engineering Research Center of Targeted and Innovative TherapeuticsChongqing Key Laboratory of Kinase Modulators as Innovative MedicineChongqing University of Arts and SciencesChongqing402160China Department of Obstetrics and Gynecology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China College of Pharmaceutical Sciences and Chinese Medicine Southwest UniversityChongqing400715China

Objective Kidney renal clear cell carcinoma(KIRC)is a common renal malignancy that has a poor prognosis.As a member of the F box family,cyclin F(CCNF)plays an important regulatory role in normal tissues and tumors.However,the underlying mechanism by which CCNF promotes KIRC proliferation still remains unclear.Methods Bioinformatics methods were used to analyze The Cancer Genome Atlas(TCGA)database to obtain gene expression and clinical prognosis data.The CCK8 assay,EdU assay,and xenograft assay were used to detect cell proliferation.The cell Senescence and potential mechanism were assessed by SA-β-gal staining,Western blotting,as well as ELISA.Results Our data showed that CCNF was highly expressed in KIRC patients.Meanwhile,downregulation of CCNF inhibited cell proliferation in vivo and in vitro.Further studies showed that the reduction of CCNF promoted cell Senescence by decreasing cyclin-dependent kinase 1(CDK1),increasing the proinflammatory factors interleukin(IL)-6 and IL-8,and then enhancing the expression of p21 and p53.Conclusion We propose that the high expression of CCNF in KIRC may play a key role in tumorigenesis by regulating cell Senescence.Therefore,CCNF shows promise as a new biomarker to predict the clinical prognosis of KIRC patients and as an effective therapeutic target.

关键词： cyclin F kidney renal clear cell carcinoma clinical outcome cyclin-dependent kinase 1 Senescence

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Insulin-like growth factor binding proteins 7 prevents dental pulp-derived mesenchymal stem cell Senescence via metabolic downregulation of p21

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Science China(Life Sciences) 2022年第11期65卷 2218-2232页

作者： Xiaoyu Li Liang Feng Chunmei Zhang Jinsong Wang Songlin Wang Lei Hu Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function ReconstructionBeijing Laboratory of Oral HealthCapital Medical University School of StomatologyBeijing 100050China Immunology Research Center for Oral and Systemic Health Beijing Friendship HospitalCapital Medical UniversityBeijing 100050China Department of Biochemistry and Molecular Biology Capital Medical University School of Basic MedicineBeijing 100069China Laboratory for Oral and General Health Integration and Translation Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Research Unit of Tooth Development and Regeneration Chinese Academy of Medical SciencesBeijing 100700China Department of Prosthodontics Capital Medical University School of StomatologyBeijing 100050China

Cellular Senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic differentiation and the Senescence of MSCs,but its exact function and mechanism remain unclear.We found IGFBP7 promoted the osteogenic differentiation and prevented the Senescence of dental pulp-derived MSCs(DPSCs),as observed in the gain-of-function and lossof-function analyses,the Senescence-associated marker p21 showed the most pronounced expression changes.We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism,resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter,thereby reducing the transcription of p21,which ultimately prevents DPSCs Senescence and promotes tissue regeneration.The activation of the mitochondrial electron transport chain(ETC)by Coenzyme Q10 could rescue the promotion of DPSC Senescence induced by the knockdown of IGFBP7,whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC Senescence induced by IGFBP7 overexpression.In conclusion,our present results reveal a novel function of IGFBP7 in preventing DPSC Senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription,suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.

关键词： dental pulp-derived mesenchymal stem cells insulin-like growth factor binding protein 7 Senescence metabolism SIRT1 p21

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Melatonin delays leaf Senescence in pak choi(Brassica rapa subsp.chinensis)by regulating biosynthesis of the second messenger cGMP

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Horticultural Plant Journal 2024年第1期10卷 145-155页

作者： Xuesong Liu Ronghui An Guofeng Li Shufen Luo Huali Hu Pengxia Li Institute of Agricultural Facilities and Equipment Jiangsu Academy of Agricultural SciencesNanjingJiangsu 210014China School of Food and Biological Engineering Jiangsu UniversityZhenjiangJiangsu 212013China Jiangsu Key Laboratory for Horticultural Crop Genetic Improvement NanjingJiangsu 210014China Key Laboratory of Cold Chain Logistics Technology for Agro-Products Ministry of Agriculture and Rural AffairsNanjingJiangsu 210014China Jinan Fruit Research Institute All China Federation of Supply and Marketing CooperativesJinanShandong 250220China

Melatonin(MT)is a low molecular weight compound with multiple biological functions in plants.It is known to delay leaf Senescence in various species.However,no data are available on the MT signaling pathway in postharvest vegetables.This study demonstrates that MT increases cGMP concentration and the expression of the cGMP synthesis gene BcGC1 in pak choi.The c GMP inhibitor LY83583 destroys effect of MT delaying the leaf Senescence.LY83583 also prevents MT treatment from reducing the expression of chlorophyll metabolism-related genes(BcNYC1,BcNOL,BcPPH1/2,BcSGR1/2,and BcPAO)and Senescence genes(BcSAG12 and BcSAG21).It also inhibits MT from reducing the activity of the key chlorophyll catabolism enzymes Mg-dechelatase,pheophytinase,and pheide a oxygenase.Thus,the ability of MT to maintain high levels of chlorophyll metabolites is also destroyed.The Arabidopsis c GMP synthetic gene mutant atgc1 was used to confirm that delayed leaf Senescence caused by MT is mediated,at least in part,by the second messenger c GMP.

关键词： Pak choi Melatonin cGMP Chlorophyll degradation Senescence

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CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell Senescence

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Science China(Life Sciences) 2024年第3期67卷 460-474页

作者： Daoyuan Huang Qian Zhao Kuan Yang Jinghui Lei Ying Jing Hongyu Li Chen Zhang Shuai Ma Shuhui Sun Yusheng Cai Guibin Wang Jing Qu Weiqi Zhang Si Wang Guang-Hui Liu Advanced Innovation Centerfor Human Brain Protection National Clinical Research Centerfor Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational MedicineCenter International Centerfor Aging and CancerBejing Municipal GeriatricMedical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative Medicine Beijing100101China CAS Key Laboratory of Genomic and Precision Medicine Bejing Institute of Genomics and China National Center for BioinformationChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Sino-Danish Cllege University of Chinese Academy of SciencesBeijing101408China National Laboratory of Biomacromolecules CAS Center for Excelence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and Senescence.To this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three Senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome hMSCs.Among all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to Senescence.To investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC Senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays Senescence.Our work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC Senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关键词： Cullins stem cell Senescence aging proteostasis ubiquitination APPBP2 TSPYL2

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