{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:43:18Z","timestamp":1792633398898,"version":"4.5.0"},"reference-count":68,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01 HD093726"],"award-info":[{"award-number":["R01 HD093726"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Friends of Prentice","award":["no grant number"],"award-info":[{"award-number":["no grant number"]}]},{"name":"Master of Science in Reproductive Science and Medicine program at Northwestern University","award":["no grant number"],"award-info":[{"award-number":["no grant number"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The female reproductive system ages before any other organ system in the body. This phenomenon can have tangible clinical implications leading to infertility, miscarriages, birth defects and systemic deterioration due to estrogen loss. \u201cFibroinflammation\u201d is a hallmark of aging tissues; there is an increase in inflammatory cytokines and fibrotic tissue in the aging ovarian stroma. We systematically evaluated immunomodulatory factors in human follicular fluid, which, like the stroma, is a critical ovarian microenvironment directly influencing the oocyte. Using a cytokine antibody array, we identified a unique fibroinflammatory cytokine signature in follicular fluid across an aging series of women (27.7\u201344.8 years). This signature (IL-3, IL-7, IL-15, TGF\u03b21, TGF\u03b23 and MIP-1) increased with chronologic age, was inversely correlated to anti-M\u00fcllerian hormone (AMH) levels, and was independent of body mass index (BMI). We focused on one specific protein, TGF\u03b23, for further validation. By investigating this cytokine in human cumulus cells and ovarian tissue, we found that the age-dependent increase in TGF\u03b23 expression was unique to the ovarian stroma but not other ovarian sub-compartments. This study broadens our understanding of inflammaging in the female reproductive system and provides a defined fibroinflammatory aging signature in follicular fluid and molecular targets in the ovary with potential clinical utility.<\/jats:p>","DOI":"10.3390\/ijms22094902","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T11:06:01Z","timestamp":1620212761000},"page":"4902","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Fibroinflammatory Signatures Increase with Age in the Human Ovary and Follicular Fluid"],"prefix":"10.3390","volume":"22","author":[{"given":"Jordan H.","family":"Machlin","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth J.","family":"Barishansky","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Kelsh","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan J.","family":"Larmore","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Histology and Imaging core, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian W.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Histology and Imaging core, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0095-0685","authenticated-orcid":false,"given":"Michele T.","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, &amp; Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Ellen","family":"Pavone","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3756-9394","authenticated-orcid":false,"given":"Francesca E.","family":"Duncan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1007\/s10815-018-1355-6","article-title":"A (micro)environmental perspective on the evolution of female reproductive aging","volume":"35","year":"2018","journal-title":"J. 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