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Age‐associated changes in T‐cell function play a central role in immunosenescence. The role of aging in the decreased T‐cell 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‐cell stiffness, here we examined whether age‐associated changes in T‐cell 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+ and CD8+ T cells, in both naive and memory state. Focusing on the pairwise correlations, we found that age‐related changes in nuclear architecture and internal ordering were correlated with T‐cell stiffening and declined interstitial migration. A similarity analysis confirmed that cell‐to‐cell 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‐hypomethylation and nuclear lamin B1, which implies an increased cell stiffness, thus inducing a decline in cell migration. [ABSTRACT FROM AUTHOR]