Transcriptional Entropy as a Cross-Tissue Marker of Aging: A Multi-Cohort, Confounder-Controlled Analysis

This pre-registered protocol specifies a fully defined, falsifiable analysis testing whether transcriptional entropy — measured via Shannon entropy across gene expression distributions — increases with chronological age across human tissues. Using GTEx v8 as the discovery cohort and independent public datasets for replication, the study controls for sex, RNA integrity, ischaemic time, batch effects, and cell-type composition. Four hypotheses are pre-specified: that entropy increases with age within tissues, that the rate differs by tissue, that the effect persists after composition adjustment, and that entropy correlates with established ageing proxies. Negative controls, technical sensitivity analyses, and explicit falsification conditions are defined. This study is linked to the companion framework Disease as Information Disorder (OSF) and represents a specific empirical test of whether the progressive loss of regulatory coherence is a measurable, quantifiable feature of human ageing. All analyses are exploratory and hypothesis-generating. We invite domain experts to critique, refine, and execute this protocol.