Age-Related Remodeling of Cross-Tissue Transcriptional Coordination in the Human Motor System

How aging is coordinated across the anatomically distinct tissues that collectively constitute the human motor system remains unclear. Here, we integrated data from the Genotype-Tissue Expression (GTEx) project and Gene Expression Omnibus (GEO), comprising 7,145 samples from 15 human tissues spanning three functional levels of motor control, signal transmission, and peripheral execution, and reconstructed age-related transcriptional trajectories using generalized additive models. Most age-related genes were shared across multiple tissues, yet their direction of regulation, effect magnitude, and temporal trajectories showed marked tissue specificity. Despite the clear central-to-peripheral functional organization of the motor system, transcriptional aging did not follow a stable temporal sequence or spatial gradient along this functional chain. Instead, cross-tissue transcriptional synchrony progressively increased from early to mid-adulthood, reached a relatively high level around midlife, and subsequently declined in later life, a pattern supported at both the gene and pathway levels. This late-life loss of coordination was selective, prominently involving the peripheral nerve-skeletal muscle axis and multiple tissue connections involving the striatum. Our analyses indicate that transcriptional aging of the human motor system is characterized by tissue-specific responses built upon a broadly shared molecular basis of aging, together with age-dependent reorganization of cross-tissue coordination and selective late-life decoupling.