{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:30:23Z","timestamp":1792017023402,"version":"4.4.0"},"reference-count":89,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T00:00:00Z","timestamp":1677024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"NIH","doi-asserted-by":"publisher","award":["P30MH062261 (Pilot Project)"],"award-info":[{"award-number":["P30MH062261 (Pilot Project)"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>HIV-1 infection in the era of combined antiretroviral therapy has been associated with premature aging. Among the various features of HIV-1 associated neurocognitive disorders, astrocyte senescence has been surmised as a potential cause contributing to HIV-1-induced brain aging and neurocognitive impairments. Recently, lncRNAs have also been implicated to play essential roles in the onset of cellular senescence. Herein, using human primary astrocytes (HPAs), we investigated the role of lncRNA TUG1 in HIV-1 Tat-mediated onset of astrocyte senescence. We found that HPAs exposed to HIV-1 Tat resulted in significant upregulation of lncRNA TUG1 expression that was accompanied by elevated expression of p16 and p21, respectively. Additionally, HIV-1 Tat-exposed HPAs demonstrated increased expression of senescence-associated (SA) markers\u2014SA-\u03b2-galactosidase (SA-\u03b2-gal) activity and SA-heterochromatin foci\u2014cell-cycle arrest, and increased production of reactive oxygen species and proinflammatory cytokines. Intriguingly, gene silencing of lncRNA TUG1 in HPAs also reversed HIV-1 Tat-induced upregulation of p21, p16, SA-\u03b2 gal activity, cellular activation, and proinflammatory cytokines. Furthermore, increased expression of astrocytic p16 and p21, lncRNA TUG1, and proinflammatory cytokines were observed in the prefrontal cortices of HIV-1 transgenic rats, thereby suggesting the occurrence of senescence activation in vivo. Overall, our data indicate that HIV-1 Tat-induced astrocyte senescence involves the lncRNA TUG1 and could serve as a potential therapeutic target for dampening accelerated aging associated with HIV-1\/HIV-1 proteins.<\/jats:p>","DOI":"10.3390\/ijms24054330","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T03:32:17Z","timestamp":1677036737000},"page":"4330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Involvement of lncRNA TUG1 in HIV-1 Tat-Induced Astrocyte Senescence"],"prefix":"10.3390","volume":"24","author":[{"given":"Prakash P.","family":"Pillai","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Division of Neurobiology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthukumar","family":"Kannan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susmita","family":"Sil","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7125-2289","authenticated-orcid":false,"given":"Annadurai","family":"Thangaraj","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Centre for Excellence in Nanobio Translational Research, Anna University, BIT Campus, Tiruchirappalli 600025, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest T.","family":"Chivero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Psychology, University of Nebraska Omaha, Omaha, NE 68182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9337-149X","authenticated-orcid":false,"given":"Raghubendra Singh","family":"Dagur","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0904-0650","authenticated-orcid":false,"given":"Ashutosh","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The University of Texas Health Science Centre at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4792-0416","authenticated-orcid":false,"given":"Guoku","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0386-5611","authenticated-orcid":false,"given":"Palsamy","family":"Periyasamy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpa","family":"Buch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a risk factor for neurodegenerative disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"R741","DOI":"10.1016\/j.cub.2012.07.024","article-title":"Ageing as a risk factor for disease","volume":"22","author":"Niccoli","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_3","first-page":"35","article-title":"Cognitive impairment in patients with AIDS\u2014Prevalence and severity","volume":"7","author":"Watkins","year":"2015","journal-title":"HIV AIDS"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1093\/gerona\/gly022","article-title":"Induction of a Senescence-Like Phenotype in Cultured Human Fetal Microglia During HIV-1 Infection","volume":"73","author":"Chen","year":"2018","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1093\/cid\/cir627","article-title":"Premature age-related comorbidities among HIV-infected persons compared with the general population","volume":"53","author":"Guaraldi","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","first-page":"451","article-title":"Inflammation in aging: Cause, effect, or both?","volume":"13","author":"Jenny","year":"2012","journal-title":"Discov. Med."},{"key":"ref_7","first-page":"137","article-title":"Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder","volume":"19","author":"Letendre","year":"2011","journal-title":"Top. Antivir. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41586-018-0543-y","article-title":"Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline","volume":"562","author":"Bussian","year":"2018","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/acel.12308","article-title":"The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation","volume":"14","author":"Beaupere","year":"2015","journal-title":"Aging Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1097\/QAD.0b013e328363bf7f","article-title":"Accelerated biological ageing in HIV-infected individuals in South Africa: A case-control study","volume":"27","author":"Pathai","year":"2013","journal-title":"AIDS"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chou, J.P., Ramirez, C.M., Wu, J.E., and Effros, R.B. (2013). Accelerated aging in HIV\/AIDS: Novel biomarkers of senescent human CD8+ T cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064702"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1097\/QAD.0000000000000471","article-title":"Relationships of pulmonary function, inflammation, and T-cell activation and senescence in an HIV-infected cohort","volume":"28","author":"Fitzpatrick","year":"2014","journal-title":"AIDS"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/glia.23081","article-title":"Fate of microglia during HIV-1 infection: From activation to senescence?","volume":"65","author":"Chen","year":"2017","journal-title":"Glia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1111\/acel.12593","article-title":"HIV and drug abuse mediate astrocyte senescence in a beta-catenin-dependent manner leading to neuronal toxicity","volume":"16","author":"Yu","year":"2017","journal-title":"Aging Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3389\/fnagi.2017.00281","article-title":"Astrocyte Senescence and Metabolic Changes in Response to HIV Antiretroviral Therapy Drugs","volume":"9","author":"Cohen","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13588","DOI":"10.1073\/pnas.1308673110","article-title":"Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein","volume":"110","author":"Johnson","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11362","DOI":"10.1523\/JNEUROSCI.1208-16.2016","article-title":"HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway","volume":"36","author":"Fan","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s13365-010-0002-5","article-title":"Genetic and functional heterogeneity of CNS-derived tat alleles from patients with HIV-associated dementia","volume":"17","author":"Cowley","year":"2011","journal-title":"J. Neurovirol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.2353\/ajpath.2010.090945","article-title":"Interactive comorbidity between opioid drug abuse and HIV-1 Tat: Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons","volume":"177","author":"Fitting","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12604","DOI":"10.1523\/JNEUROSCI.2958-08.2008","article-title":"Human immunodeficiency virus protein Tat induces synapse loss via a reversible process that is distinct from cell death","volume":"28","author":"Kim","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12640-011-9279-2","article-title":"Neurotoxicity of human immunodeficiency virus-1: Viral proteins and axonal transport","volume":"21","author":"Mocchetti","year":"2012","journal-title":"Neurotox. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17908","DOI":"10.1523\/JNEUROSCI.1312-13.2013","article-title":"Human immunodeficiency virus-1 Tat protein increases the number of inhibitory synapses between hippocampal neurons in culture","volume":"33","author":"Hargus","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.mcn.2012.12.005","article-title":"Human immunodeficiency virus-1 protein Tat induces excitotoxic loss of presynaptic terminals in hippocampal cultures","volume":"54","author":"Shin","year":"2013","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/ana.410200304","article-title":"Immunohistochemical identification of HTLV-III antigen in brains of patients with AIDS","volume":"20","author":"Gabuzda","year":"1986","journal-title":"Ann. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.3389\/fmicb.2015.01164","article-title":"The cross-talk of HIV-1 Tat and methamphetamine in HIV-associated neurocognitive disorders","volume":"6","author":"Mediouni","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E1896","DOI":"10.1073\/pnas.1800165115","article-title":"Normal aging induces A1-like astrocyte reactivity","volume":"115","author":"Clarke","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3389\/fnagi.2018.00337","article-title":"Astrocytes and Aging","volume":"10","author":"Palmer","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e12937","DOI":"10.1111\/acel.12937","article-title":"Astrocyte senescence: Evidence and significance","volume":"18","author":"Cohen","year":"2019","journal-title":"Aging Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3389\/fnagi.2019.00059","article-title":"Astrocyte Heterogeneity: Impact to Brain Aging and Disease","volume":"11","author":"Matias","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17887","DOI":"10.1038\/srep17887","article-title":"HIV-1 increases TLR responses in human primary astrocytes","volume":"5","author":"Serramia","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lutgen, V., Narasipura, S.D., Barbian, H.J., Richards, M., Wallace, J., Razmpour, R., Buzhdygan, T., Ramirez, S.H., Prevedel, L., and Eugenin, E.A. (2020). HIV infects astrocytes in vivo and egresses from the brain to the periphery. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008381"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.mcn.2004.07.003","article-title":"Astrocyte activation and dysfunction and neuron death by HIV-1 Tat expression in astrocytes","volume":"27","author":"Zhou","year":"2004","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Bhat, R., Crowe, E.P., Bitto, A., Moh, M., Katsetos, C.D., Garcia, F.U., Johnson, F.B., Trojanowski, J.Q., Sell, C., and Torres, C. (2012). Astrocyte senescence as a component of Alzheimer\u2019s disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045069"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.celrep.2017.12.092","article-title":"Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson\u2019s Disease","volume":"22","author":"Chinta","year":"2018","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e1600584","DOI":"10.1126\/sciadv.1600584","article-title":"Epigenetics and aging","volume":"2","author":"Pal","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.pneurobio.2015.05.002","article-title":"The epigenetics of aging and neurodegeneration","volume":"131","author":"Lardenoije","year":"2015","journal-title":"Prog. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1016\/j.bbadis.2019.02.005","article-title":"Genetics and Epigenetics in Aging and Longevity: Myths and Truths","volume":"1865","author":"Ren","year":"2019","journal-title":"Biochim. Biophys. Acta. Mol. Basis Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.molcel.2016.03.019","article-title":"Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA","volume":"62","author":"Gross","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.cell.2016.07.050","article-title":"Epigenetic Mechanisms of Longevity and Aging","volume":"166","author":"Sen","year":"2016","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1093\/infdis\/jiv277","article-title":"HIV-1 Infection Accelerates Age According to the Epigenetic Clock","volume":"212","author":"Horvath","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Puvvula, P.K. (2019). LncRNAs Regulatory Networks in Cellular Senescence. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112615"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/agm2.12030","article-title":"Role of lncRNAs in aging and age-related diseases","volume":"1","author":"He","year":"2018","journal-title":"Aging Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3389\/fendo.2016.00151","article-title":"Role of lncRNAs in Cellular Aging","volume":"7","author":"Degirmenci","year":"2016","journal-title":"Front. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/wrna.1297","article-title":"Noncoding RNA control of cellular senescence","volume":"6","author":"Abdelmohsen","year":"2015","journal-title":"Wiley Interdiscip Rev. RNA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"149","DOI":"10.14336\/AD.2016.0810","article-title":"Shining the Light on Senescence Associated LncRNAs","volume":"8","author":"Ghanam","year":"2017","journal-title":"Aging Dis."},{"key":"ref_46","first-page":"10327","article-title":"lncRNA TUG1 promotes cell growth and epithelial-mesenchymal transition in human cervical cancer","volume":"9","author":"Gao","year":"2016","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.gene.2017.01.024","article-title":"LncRNA, TUG1 regulates the oral squamous cell carcinoma progression possibly via interacting with Wnt\/beta-catenin signaling","volume":"608","author":"Liang","year":"2017","journal-title":"Gene"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"349","DOI":"10.4048\/jbc.2016.19.4.349","article-title":"LncRNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation by Inhibiting MicroRNA-9 in MCF-7 Cells","volume":"19","author":"Zhao","year":"2016","journal-title":"J. Breast Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3389\/fneur.2015.00045","article-title":"Long Non-Coding RNA Expression during Aging in the Human Subependymal Zone","volume":"6","author":"Barry","year":"2015","journal-title":"Front. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11667","DOI":"10.1073\/pnas.0904715106","article-title":"Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression","volume":"106","author":"Khalil","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s41419-018-0282-x","article-title":"Long non-coding RNAs in ischemic stroke","volume":"9","author":"Bao","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.brainresbull.2013.06.001","article-title":"Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases","volume":"97","author":"Wu","year":"2013","journal-title":"Brain Res. Bull."},{"key":"ref_53","first-page":"2422","article-title":"LncRNA TUG1 serves an important role in hypoxia-induced myocardial cell injury by regulating the miR1455pBinp3 axis","volume":"17","author":"Wu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.bbrc.2016.06.129","article-title":"Long non-coding RNA TUG1 acts as a miR-26a sponge in human glioma cells","volume":"477","author":"Li","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.bbrc.2017.02.043","article-title":"LncRNA TUG1 sponges microRNA-9 to promote neurons apoptosis by up-regulated Bcl2l11 under ischemia","volume":"485","author":"Chen","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e1243","DOI":"10.1038\/cddis.2014.201","article-title":"P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression","volume":"5","author":"Zhang","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/j.1749-6632.2009.05111.x","article-title":"Neurological complications of immune reconstitution in HIV-infected populations","volume":"1184","author":"Johnson","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1093\/gerona\/62.11.1279","article-title":"HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty","volume":"62","author":"Desquilbet","year":"2007","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5897298","DOI":"10.1155\/2017\/5897298","article-title":"Aging in HIV-Infected Subjects: A New Scenario and a New View","volume":"2017","author":"Negredo","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1086\/590150","article-title":"Aging and infectious diseases: Workshop on HIV infection and aging: What is known and future research directions","volume":"47","author":"Effros","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3389\/fcimb.2020.00061","article-title":"HIV-1 Tat: Role in Bystander Toxicity","volume":"10","author":"Ajasin","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrneurol.2016.27","article-title":"HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment","volume":"12","author":"Saylor","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6825493","DOI":"10.1155\/2017\/6825493","article-title":"HIV as a Cause of Immune Activation and Immunosenescence","volume":"2017","author":"Sokoya","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1007\/s11481-017-9730-0","article-title":"Tat-Mediated Induction of miRs-34a & -138 Promotes Astrocytic Activation via Downregulation of SIRT1: Implications for Aging in HAND","volume":"12","author":"Hu","year":"2017","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1128\/MCB.19.3.2109","article-title":"Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts","volume":"19","author":"Stein","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/nan.12559","article-title":"Expression of p16 and p21 in the frontal association cortex of ALS\/MND brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease","volume":"46","author":"Garwood","year":"2020","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_67","first-page":"e55533","article-title":"Techniques to Induce and Quantify Cellular Senescence","volume":"123","author":"Evans","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Tominaga, T., Shimada, R., Okada, Y., Kawamata, T., and Kibayashi, K. (2019). Senescence-associated-beta-galactosidase staining following traumatic brain injury in the mouse cerebrum. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0213673"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/978-1-62703-239-1_12","article-title":"Detection of senescence-associated heterochromatin foci (SAHF)","volume":"965","author":"Aird","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S0092-8674(03)00401-X","article-title":"Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence","volume":"113","author":"Narita","year":"2003","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1002\/j.1460-2075.1992.tb05135.x","article-title":"Cyclin A is required at two points in the human cell cycle","volume":"11","author":"Pagano","year":"1992","journal-title":"EMBO J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.3389\/fmicb.2015.01143","article-title":"HIV-1, methamphetamine and astrocytes at neuroinflammatory Crossroads","volume":"6","author":"Borgmann","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nrn3898","article-title":"Astrocyte barriers to neurotoxic inflammation","volume":"16","author":"Sofroniew","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jnr.10121","article-title":"Astrocytes in the aging brain","volume":"67","author":"Cotrina","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.mad.2007.01.005","article-title":"Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector","volume":"128","author":"Hayakawa","year":"2007","journal-title":"Mech. Ageing Dev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0197-4580(95)80008-F","article-title":"Increases of glial fibrillary acidic protein in the aging female mouse brain","volume":"16","author":"Kohama","year":"1995","journal-title":"Neurobiol. Aging"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/0197-4580(91)90056-P","article-title":"Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain","volume":"12","author":"Goss","year":"1991","journal-title":"Neurobiol. Aging"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1146\/annurev-genet-120213-092323","article-title":"Regulation of transcription by long noncoding RNAs","volume":"48","author":"Bonasio","year":"2014","journal-title":"Annu. Rev. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1093\/cvr\/cvr097","article-title":"Non-coding RNAs as regulators of gene expression and epigenetics","volume":"90","author":"Kaikkonen","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1089\/dna.2015.2966","article-title":"The Role of Long Intergenic Noncoding RNA p21 in Vascular Endothelial Cells","volume":"34","author":"He","year":"2015","journal-title":"DNA Cell Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e12870","DOI":"10.1111\/acel.12870","article-title":"LncRNAs regulating stemness in aging","volume":"18","author":"Rebelo","year":"2019","journal-title":"Aging Cell"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Lin, P.C., Huang, H.D., Chang, C.C., Chang, Y.S., Yen, J.C., Lee, C.C., Chang, W.H., Liu, T.C., and Chang, J.G. (2016). Long noncoding RNA TUG1 is downregulated in non-small cell lung cancer and can regulate CELF1 on binding to PRC2. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2569-6"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"6845","DOI":"10.2147\/OTT.S167900","article-title":"The lncRNA TUG1 promotes epithelial ovarian cancer cell proliferation and invasion via the WNT\/beta-catenin pathway","volume":"11","author":"Liu","year":"2018","journal-title":"Onco Targets Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12943-016-0575-6","article-title":"Long non-coding RNA TUG1 is involved in cell growth and chemoresistance of small cell lung cancer by regulating LIMK2b via EZH2","volume":"16","author":"Niu","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.carpath.2017.11.004","article-title":"TUG1 knockdown ameliorates atherosclerosis via up-regulating the expression of miR-133a target gene FGF1","volume":"33","author":"Zhang","year":"2018","journal-title":"Cardiovasc. Pathol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.4049\/jimmunol.1502146","article-title":"LincRNA-Cox2 Promotes Late Inflammatory Gene Transcription in Macrophages through Modulating SWI\/SNF-Mediated Chromatin Remodeling","volume":"196","author":"Hu","year":"2016","journal-title":"J. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s12035-014-8991-3","article-title":"HIV Tat-Mediated Induction of Human Brain Microvascular Endothelial Cell Apoptosis Involves Endoplasmic Reticulum Stress and Mitochondrial Dysfunction","volume":"53","author":"Ma","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e381","DOI":"10.1038\/cddis.2012.114","article-title":"Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction","volume":"3","author":"Hu","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4330\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:38:51Z","timestamp":1760121531000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4330"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,22]]},"references-count":89,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24054330"],"URL":"https:\/\/doi.org\/10.3390\/ijms24054330","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,22]]}}}