INTRODUCTION: Ageing is accompanied by coordinated molecular alterations across tissues, yet a key challenge in geroscience is the observed decoupling between epigenetic state and transcriptional output. The blood transcriptome provides a minimally invasive and systemically informative window into ageing mechanisms. We hypothesize that human ageing is reflected in distinct transcriptomic trajectories within blood, involving both structured longitudinal changes and a progressive increase in transcriptional entropy. The aims of this study are to (1) systematically characterise age-related transcriptional dynamics, (2) quantify transcriptional entropy as a marker of transcriptional disorder, and (3) construct age-stratified co-expression networks to identify coordinated pathway changes.
METHODS: A total of 63 publicly available human whole-blood RNA-seq datasets spanning the adult lifespan will be integrated. Differential Age Slopes will be calculated using linear regression models to identify progressive gene expression shifts. Transcriptional entropy will be quantified using Shannon-based indices. Weighted Gene Co-expression Network Analysis (WGCNA) will be used to build age-stratified co-expression modules. Permutation-based robustness testing and pathway enrichment analyses will support interpretability and biological validation, with integration of published biomarker datasets to facilitate clinical correlation analyses.
RESULTS (Expected Outcomes): We expect to define both linear and non-linear age-related expression trajectories, identify age-associated loss of network connectivity, and provide quantitative evidence linking increased transcriptional entropy with functional decline. The resulting resource will represent a comprehensive blood transcriptomic atlas of ageing.
DISCUSSION & CONCLUSION: These findings are expected to advance understanding of systemic ageing mechanisms and support the development of transcriptome-derived biomarkers of biological age, contributing to precision geroscience and targeted ageing interventions.