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Of these, the ones involving enhanced \u03b2\u2010sheet or \u2010strand interactions are of pathological relevance since they have been associated with neurodegeneration. Although there is much understanding of biopolymer phase behavior, an inclusive thermodynamic framework that unifies phase separation and \u03b2\u2010sheet\u2010based aging is lacking. We present a time\u2010dependent, multi\u2010component extension of associating polymer theory that describes phase separation and aging of an intrinsically disordered protein (IDP) capable of associating through local, reversible folding. The model shows how the Second Law of Thermodynamics applies throughout, whether phase separation precedes and encourages aging or, vice versa, whether the increase in \u201cstickiness\u201d during aging drives phase separation. Our calculations show how the time\u2010dependence of the average valency of associating sites determines the aging kinetics and the development of viscoelastic properties of a biocondensate. The agreement between our calculations and the change in dynamics of condensates of \u201cperfect repeat\u201d analogues of nucleoporin\u201098 not only validates the theory but also identifies these Nup98 variants as model systems for studying aging.<\/jats:p>","DOI":"10.1002\/advs.76691","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:39:26Z","timestamp":1784547566000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Unifying Thermodynamic Model for Phase Separation and Aging of Biopolymers"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1591-4449","authenticated-orcid":false,"given":"Jasper J.","family":"Michels","sequence":"first","affiliation":[{"name":"Max Planck Institute for Polymer Research  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8791-4766","authenticated-orcid":false,"given":"Joana","family":"Caria","sequence":"additional","affiliation":[{"name":"Biocentre II Johannes Gutenberg University  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0634-0503","authenticated-orcid":false,"given":"Edward A.","family":"Lemke","sequence":"additional","affiliation":[{"name":"Biocentre II Johannes Gutenberg University  Mainz Germany"},{"name":"Institute For Molecular Biology  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.4c00138"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202510115"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010025\u201000897\u20102"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201062055\u20108"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010genet\u2010112618\u2010043527"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101194"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2522993123"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010024\u201001423\u2010w"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/bfgp\/elac022"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2012.204"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010022\u201001035\u20107"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201048194\u20104"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201907157"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/ma970616h"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/ma970617"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010biophys\u2010121219\u2010081629"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.5c00224"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.4c00609"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.macromol.8b00661"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.macromol.3c00854"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.62403"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.1c01301"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.macromol.4c03065"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo7885"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12551-017-0346-7"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.012413"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.56159"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201008130\u20102"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2024.12.017"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1103\/PRXLife.2.023011"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.09.047"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.2c00814"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201024292\u20105"},{"key":"e_1_2_10_35_1","volume-title":"Principles of Polymer Chemistry","author":"Flory P. 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