{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:36:17Z","timestamp":1790710577636,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG089455"],"award-info":[{"award-number":["R01AG089455"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG090356"],"award-info":[{"award-number":["R01AG090356"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Understanding how secreted factors from aged tissue, often referred to as the senescence\u2010associated secretome, reshape cellular phenotypes remains a major challenge due to the complexity of downstream molecular cascades. Here, we present a computational framework for\n                    <jats:italic>in silico<\/jats:italic>\n                    perturbation modeling designed to predict distinct transcriptional responses to age\u2010specific extracellular environmental cues. We exemplify applications of this framework using articular chondrocytes exposed to secretomes derived from infrapatellar fat pads\u2014an integral component of the cartilage microenvironment\u2014excised from the knee joints of young and aged animals. First, we accessed public transcriptomic data of cartilage from healthy and osteoarthritic knee joints and constructed a cartilage\u2010specific co\u2010expression network using topological overlap matrices, which measure network interconnectedness. We then implemented a Random Walk with Restart to simulate the downstream signal propagation of differentially expressed ligands secreted from young and aged infrapatellar fat pads. We benchmarked predicted perturbation signatures against RNA\u2010seq data from aged chondrocytes treated in\u00a0vitro with either young or aged infrapatellar fat pad\u2010conditioned medium. Our evaluation pipeline included functional enrichment comparison and receiver operating characteristic analysis. These analyses confirmed that simulated perturbations recapitulated chondrocyte signaling pathways modulated by young and aged infrapatellar fat pad secretomes, including primary effects on mitochondrial respiration, a central hallmark of aging. The network paradigm introduced here provides a data\u2010driven strategy to disentangle how complex, age\u2010dependent extracellular environments influence cellular fate. Ultimately, we anticipate that this pipeline can be extended to diverse tissues and age\u2010related diseases to guide the development of interventions that restore youthful cellular phenotypes.\n                  <\/jats:p>","DOI":"10.1111\/acel.70683","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T13:59:35Z","timestamp":1787407175000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Network Model to Predict Age\u2010Related Transcriptional Reprogramming"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2921-1496","authenticated-orcid":false,"given":"Tyler J.","family":"McNeill","sequence":"first","affiliation":[{"name":"Discovery Center for Musculoskeletal Recovery Schoen Adams Research Institute at Spaulding  Charlestown Massachusetts USA"},{"name":"Department of Physical Medicine and Rehabilitation Spaulding Rehabilitation Hospital  Charlestown Massachusetts USA"},{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5497-5968","authenticated-orcid":false,"given":"Fabrisia","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Discovery Center for Musculoskeletal Recovery Schoen Adams Research Institute at Spaulding  Charlestown Massachusetts USA"},{"name":"Department of Physical Medicine and Rehabilitation Spaulding Rehabilitation Hospital  Charlestown Massachusetts USA"},{"name":"Department of Physical Medicine and Rehabilitation Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5504-1502","authenticated-orcid":false,"given":"Hirotaka","family":"Iijima","sequence":"additional","affiliation":[{"name":"Discovery Center for Musculoskeletal Recovery Schoen Adams Research Institute at Spaulding  Charlestown Massachusetts USA"},{"name":"Department of Physical Medicine and Rehabilitation Spaulding Rehabilitation Hospital  Charlestown Massachusetts USA"},{"name":"Department of Physical Medicine and Rehabilitation Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00353\u201021"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1017802"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02714"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3356"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000599"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010019\u20100667\u20105"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101224"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202407110"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glaf072"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2023.11.018"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2018.07.012"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045517"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.95"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010022\u201001251\u20100"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2021.12.015"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf1356"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2024.09.006"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201035359\u20102"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14043"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.2174\/156652412803833607"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/19476035211063858"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102105\u20109\u2010559"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859\u2010018\u20102199\u2010x"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq108"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075\u2010025\u201003563\u20102"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.65"},{"key":"e_1_2_10_28_1","first-page":"1","volume-title":"Combinatorics, 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