Y. Yang, P. R. Hess, X. E. Chen, S. Huang, M. G. Teneche, H. Wang, K. N. Miller, A. E. Davis, C. Miciano, K. Y. Li, S. Mamde, K. Yip, B. Ren, Q. Yang, E. Smoot, A. Wang, B. Johnson, A. C. Huang, P. Wilson, P. D. Adams, N. R. Zhang
Aging reshapes tissues through changes in cellular composition, coordinated transcriptional reprogramming, and loss of transcriptional coordination. Whereas the first two have been characterized across aging tissues, the third remains difficult to quantify. We introduce an unsupervised, first-principles framework for measuring transcriptional dyscoordination in single cells as deviation from a learned, predictable structure accounting for technical noise. Orthogonal validation links transcriptional dyscoordination to classical intrinsic noise and distinguishes it from coordinated change. In controlled perturbations, dyscoordination rises after genotoxic injury and senescence induction, then falls following senolytic depletion. Across mouse, rat, and human tissues, dyscoordination increases with chronological age, especially in regenerative compartments. In human T cells, dyscoordination increases with clonal expansion and effector function yet declines within persisting clones after checkpoint blockade. Cross-modal analyses further link dyscoordination to chromatin-based mitotic age and genome instability. These results identify loss of transcriptional coordination as a distinct and dynamic feature of cellular aging.