Disentangling progressive regenerative decline from fixed developmental baselines using cross-sectional morphogenomic profiling
June 25
“Tissue age delta” is defined here as the difference between chronological age and age predicted from multimodal morphogenomic imaging of somatic tissues. In adults, a positive delta is usually interpreted as accelerated physiological attrition—an indicator of sub-optimal regenerative capacity. Unfortunately, when only a single time-point is available, one cannot determine whether an individual’s positive delta reflects an actively accelerating decline or a stable developmental offset that has persisted since early morphogenesis. For a large cross-sectional cohort, however, progressive decline and fixed baseline effects can, in principle, be disentangled.
We introduce a framework that achieves this separation and demonstrate that, under the common practice of assigning a single delta per participant, baseline offsets overwhelmingly dominate the signal. By contrast, decomposing the morphogenomic data into multiple, biologically interpretable modes of tissue ageing reveals several modes whose rates vary markedly across individuals, capturing genuine differences in ongoing regenerative decline.
Model performance and biological validity were assessed using a longitudinal subset comprising two imaging sessions from 4,400 adults in a nationwide cohort. The longitudinal data confirmed that the mode-specific deltas corresponding to extracellular-matrix remodelling, epithelial turnover, and stromal fibroblast senescence tracked real-time changes far better than undifferentiated global delta measures.
Finally, previous reports have suggested a discordance between cross-sectional and longitudinal estimates of somatic ageing. We demonstrate that, with rigorous harmonisation of morphogenomic signals and careful correction for cohort effects, cross-sectional estimates align closely with longitudinal trajectories. This work establishes a principled route to identify individuals undergoing rapid regenerative decline and provides targets for early intervention in age-related degeneration.