{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:16:42Z","timestamp":1790997402245,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,6,11]],"date-time":"2020-06-11T00:00:00Z","timestamp":1591833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT)","award":["2017R1A2B2007209"],"award-info":[{"award-number":["2017R1A2B2007209"]}]},{"name":"Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI)","award":["HI17C0659"],"award-info":[{"award-number":["HI17C0659"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL\/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-\u03b3+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL\/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.<\/jats:p>","DOI":"10.3390\/ijms21114169","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T03:17:32Z","timestamp":1592191052000},"page":"4169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL\/6 Male Mouse Model"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2203-5709","authenticated-orcid":false,"given":"Chang Ho","family":"Yoon","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul 03080, Korea"},{"name":"Department of Ophthalmology, Seoul National University Hospital, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Suk","family":"Ryu","sequence":"additional","affiliation":[{"name":"Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Sik","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, College of Medicine, The Catholic University of Korea, Seoul 07345, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7850-6894","authenticated-orcid":false,"given":"Mee Kum","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul 03080, Korea"},{"name":"Department of Ophthalmology, Seoul National University Hospital, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nature13193","article-title":"The role of senescent cells in ageing","volume":"509","year":"2014","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-981-13-3681-2_2","article-title":"The Immune System and Its Dysregulation with Aging","volume":"91","author":"Muller","year":"2019","journal-title":"Subcell. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S0002-9394(03)00218-6","article-title":"Prevalence of dry eye syndrome among US women","volume":"136","author":"Schaumberg","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/s41385-018-0127-z","article-title":"Age-associated antigen-presenting cell alterations promote dry-eye inducing Th1 cells","volume":"12","author":"Bian","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.4110\/in.2019.19.e3","article-title":"Age-related Autoimmune Changes in Lacrimal Glands","volume":"19","author":"Alves","year":"2019","journal-title":"Immune Netw."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/IIO.0000000000000170","article-title":"Effects of Aging in Dry Eye","volume":"57","year":"2017","journal-title":"Int. Ophthalmol. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1001\/archophthalmol.2011.69","article-title":"Effects of age and dysfunction on human meibomian glands","volume":"129","author":"Nien","year":"2011","journal-title":"Arch. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1097\/ICO.0b013e31826a05a8","article-title":"The antiaging approach for the treatment of dry eye","volume":"31","author":"Tsubota","year":"2012","journal-title":"Cornea"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/path.1711430104","article-title":"Post-mortem prevalence of lymphocytic infiltration of the lacrymal gland: A comparative study in autoimmune and non-autoimmune diseases","volume":"143","author":"Nasu","year":"1984","journal-title":"J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/S0161-6420(95)30971-2","article-title":"Histopathologic study of human lacrimal gland. Statistical analysis with special reference to aging","volume":"102","author":"Obata","year":"1995","journal-title":"Ophthalmology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1542-0124(12)70177-5","article-title":"The aging lacrimal gland: Changes in structure and function","volume":"6","author":"Rocha","year":"2008","journal-title":"Ocul. Surf."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.ajpath.2013.11.019","article-title":"Ocular surface disease and dacryoadenitis in aging C57BL\/6 mice","volume":"184","author":"McClellan","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.exger.2014.11.005","article-title":"Aging disturbs the balance between effector and regulatory CD4+ T cells","volume":"60","author":"Abdulahad","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/j.exger.2013.09.003","article-title":"The Th17\/Treg balance is disturbed during aging","volume":"48","author":"Schmitt","year":"2013","journal-title":"Exp. Gerontol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/j.1755-3768.1991.tb02016.x","article-title":"Correlation of conjunctival impression cytology results with lacrimal function and age","volume":"69","author":"Paschides","year":"1991","journal-title":"Acta Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1097\/ICO.0b013e31820ca468","article-title":"Evaluation of age-related changes in human palpebral conjunctiva and meibomian glands by in vivo confocal microscopy","volume":"30","author":"Wei","year":"2011","journal-title":"Cornea"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"DES163","DOI":"10.1167\/iovs.17-23402","article-title":"Potential Role of Oxidative Stress in Ocular Surface Inflammation and Dry Eye Disease. The antiaging approach for the treatment of dry eye","volume":"59","author":"Dogru","year":"2018","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1016\/j.ajpath.2012.01.019","article-title":"Age-related dysfunction of the lacrimal gland and oxidative stress: Evidence from the Cu,Zn-superoxide dismutase-1 (Sod1) knockout mice","volume":"180","author":"Kojima","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1097\/ICO.0b013e318228167f","article-title":"Effect of calorie restriction on change in lacrimal gland with age","volume":"30","author":"Kawashima","year":"2011","journal-title":"Cornea"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s00441-011-1271-x","article-title":"Detection of BrdU-label retaining cells in the lacrimal gland: Implications for tissue repair","volume":"346","author":"You","year":"2011","journal-title":"Cell Tissue Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1097\/ICO.0000000000000092","article-title":"Comparison of meibomian gland loss and expressed meibum grade between the upper and lower eyelids in patients with obstructive meibomian gland dysfunction","volume":"33","author":"Eom","year":"2014","journal-title":"Cornea"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S318","DOI":"10.1097\/ICL.0000000000000467","article-title":"Relationships Between Meibomian Gland Loss and Age, Sex, and Dry Eye","volume":"44","author":"Pult","year":"2018","journal-title":"Eye Contact Lens"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E310","DOI":"10.1097\/OPX.0b013e318244e487","article-title":"Relation between upper and lower lids\u2019 meibomian gland morphology, tear film, and dry eye","volume":"89","author":"Pult","year":"2012","journal-title":"Optom. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1097\/OPX.0b013e318253de93","article-title":"Infrared imaging of meibomian gland structure using a novel keratograph","volume":"89","author":"Srinivasan","year":"2012","journal-title":"Optom. Vis. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ajo.2016.06.025","article-title":"Development of Definitive and Reliable Grading Scales for Meibomian Gland Dysfunction","volume":"169","author":"Arita","year":"2016","journal-title":"Am. J. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yeh, T.N., and Lin, M.C. (2017). Risk factors for severe Meibomian gland atrophy in a young adult population: A cross-sectional study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185603"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jtos.2012.09.005","article-title":"Morphological evaluation of meibomian glands using noncontact infrared meibography","volume":"11","author":"Ban","year":"2013","journal-title":"Ocul. Surf."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.exer.2009.08.013","article-title":"Age-related changes in the meibomian gland","volume":"89","author":"Nien","year":"2009","journal-title":"Exp. Eye Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"37731","DOI":"10.1074\/jbc.R100034200","article-title":"PPARgamma: A nuclear regulator of metabolism, differentiation, and cell growth","volume":"276","author":"Rosen","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S1097-2765(00)80211-7","article-title":"PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro","volume":"4","author":"Rosen","year":"1999","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.exer.2017.02.008","article-title":"Meibocyte differentiation and renewal: Insights into novel mechanisms of meibomian gland dysfunction (MGD)","volume":"163","author":"Hwang","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.jtos.2016.08.001","article-title":"PPARgamma Regulates Mouse Meibocyte Differentiation and Lipid Synthesis","volume":"14","author":"Jester","year":"2016","journal-title":"Ocul. Surf."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrrheum.2018.1","article-title":"B cells in the pathogenesis of primary Sjogren syndrome","volume":"14","author":"Nocturne","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1167\/iovs.16-20843","article-title":"Therapeutic Efficacy of Nanocomplex of Poly(Ethylene Glycol) and Catechin for Dry Eye Disease in a Mouse Model","volume":"58","author":"Lee","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/j.1600-0420.1996.tb00594.x","article-title":"Influence of androgens and pituitary hormones on the structural profile and secretory activity of the lacrimal gland","volume":"74","author":"Sullivan","year":"1996","journal-title":"Acta Ophthalmol."},{"key":"ref_36","first-page":"2632","article-title":"Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sjogren\u2019s syndrome","volume":"35","author":"Sato","year":"1994","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"300","DOI":"10.3109\/02713683.2011.631720","article-title":"The role of dyslipidemia on ocular surface, lacrimal and meibomian gland structure and function","volume":"37","author":"Modulo","year":"2012","journal-title":"Curr. Eye Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kojima, T., Nagata, T., Kudo, H., Muller-Lierheim, W.G.K., van Setten, G.B., Dogru, M., and Tsubota, K. (2020). The Effects of High Molecular Weight Hyaluronic Acid Eye Drop Application in Environmental Dry Eye Stress Model Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103516"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kim, J., Choi, S.H., Kim, Y.J., Jeong, H.J., Ryu, J.S., Lee, H.J., Kim, T.W., Im, S.H., Oh, J.Y., and Kim, M.K. (2017). Clinical Effect of IRT-5 Probiotics on Immune Modulation of Autoimmunity or Alloimmunity in the Eye. Nutrients, 9.","DOI":"10.3390\/nu9111166"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1167\/iovs.16-20880","article-title":"Identification of Circulating Fibrocytes and Dendritic Derivatives in Corneal Endothelium of Patients With Fuchs\u2019 Dystrophy","volume":"58","author":"Wouters","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kim, Y.H., Kim, D.H., Shin, E.J., Lee, H.J., Wee, W.R., Jeon, S., and Kim, M.K. (2016). Comparative Analysis of Substrate-Free Cultured Oral Mucosal Epithelial Cell Sheets from Cells of Subjects with and without Stevens-Johnson Syndrome for Use in Ocular Surface Reconstruction. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0147548"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1002\/jcp.26061","article-title":"Troxerutin with copper generates oxidative stress in cancer cells: Its possible chemotherapeutic mechanism against hepatocellular carcinoma","volume":"233","author":"Subastri","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"eaas9164","DOI":"10.1126\/scitranslmed.aas9164","article-title":"Neutrophils cause obstruction of eyelid sebaceous glands in inflammatory eye disease in mice","volume":"10","author":"Reyes","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_44","first-page":"G1","article-title":"Cell Cycle Analysis Using the BD BrdU FITC Assay on the BD FACSVerse\u2122 System","volume":"2","author":"Biosciences","year":"2011","journal-title":"Growth"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.biopha.2016.10.048","article-title":"Gallic acid reduces cell growth by induction of apoptosis and reduction of IL-8 in HepG2 cells","volume":"84","author":"Lima","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Paral, P., Bajecny, M., Savvulidi, F., and Necas, E. (2019). Cell Cycle Analysis Using In Vivo Staining of DNA-Synthesizing Cells. Methods Mol. Biol.","DOI":"10.1007\/7651_2019_228"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nature11824","article-title":"T-helper-1-cell cytokines drive cancer into senescence","volume":"494","author":"Braumuller","year":"2013","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1167\/iovs.18-26051","article-title":"Bilateral Effect of the Unilateral Corneal Nerve Cut on Both Ocular Surface and Lacrimal Gland","volume":"60","author":"Lee","year":"2019","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1530\/REP-12-0404","article-title":"Development of a specific method to evaluate 8-hydroxy, 2-deoxyguanosine in sperm nuclei: Relationship with semen quality in a cohort of 94 subjects","volume":"145","author":"Cambi","year":"2013","journal-title":"Reproduction"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/4169\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:37:46Z","timestamp":1760175466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/4169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,11]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21114169"],"URL":"https:\/\/doi.org\/10.3390\/ijms21114169","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,11]]}}}