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The role of aging in the decreased T\u2010cell repertoire, primarily because of thymic involution, has been extensively studied. However, increasing evidence indicates that aging also modulates the mechanical properties of cells and the internal ordering of diverse cell components. Cellular functions are generally dictated by the biophysical phenotype of cells, which itself is also tightly regulated at the molecular level. Based on previous evidence suggesting that the relative nuclear size contributes to variations of T\u2010cell stiffness, here we examined whether age\u2010associated changes in T\u2010cell migration are dictated by biophysical parameters, in part through nuclear cytoskeleton organization and cell deformability. In this study, we first performed longitudinal analyses of a repertoire of 111 functional, biophysical and biomolecular features of the nucleus and cytoskeleton of mice CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, in both naive and memory state. Focusing on the pairwise correlations, we found that age\u2010related changes in nuclear architecture and internal ordering were correlated with T\u2010cell stiffening and declined interstitial migration. A similarity analysis confirmed that cell\u2010to\u2010cell variation was a direct result of the aging process and we applied regression models to identify biomarkers that can accurately estimate individuals' age. Finally, we propose a biophysical model for a comprehensive understanding of the results: aging involves an evolution of the relative nuclear size, in part through DNA\u2010hypomethylation and nuclear lamin B1, which implies an increased cell stiffness, thus inducing a decline in cell migration.\n                  <\/jats:p>","DOI":"10.1111\/imm.13559","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T01:59:45Z","timestamp":1659664785000},"page":"622-639","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Aging is accompanied by T\u2010cell stiffening and reduced interstitial migration through dysfunctional nuclear organization"],"prefix":"10.1111","volume":"167","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1266-0917","authenticated-orcid":false,"given":"Blanca","family":"Gonz\u00e1lez\u2010Berm\u00fadez","sequence":"first","affiliation":[{"name":"Center for Biomedical 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Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"C\u00f3rcoles\u2010Lucas","sequence":"additional","affiliation":[{"name":"Center for Biomedical Technology Universidad Polit\u00e9cnica de Madrid  Madrid Spain"},{"name":"Department of Materials Science, E.T.S.I. de Caminos, Canales y Puertos Universidad Polit\u00e9cnica de Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Gonz\u00e1lez\u2010S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Genetics, Physiology and Microbiology, Facultad de Ciencias Biol\u00f3gicas Universidad Complutense de Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"De la Fuente","sequence":"additional","affiliation":[{"name":"Department of Genetics, Physiology and Microbiology, Facultad de Ciencias Biol\u00f3gicas Universidad Complutense de Madrid  Madrid 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