Personalized transcriptional network analysis links age-related loss of gene coordination to individual biological aging.

Background: Aging is characterized by the decline in biological functions, accompanied by changes in gene-to-gene transcriptional coordination, which can be estimated by expression coordination in gene transcriptional network. Notably, gene networks and coordinated expression relationships (CERs) showed inter-individual variability, while personalized aging-related gene expression coordination dynamics in human cohorts have yet to be investigated.

Methods: In this study, we constructed 15,933 personalized transcriptional networks across 26 tissues from 967 donors aged 20 to 80 years old, using the sample-specific network (SSN) framework based on data from the Gene-Tissue Expression (GTEx) project.

Results: We identified gene-gene CERs and characterized their age-dependent dynamic trends across tissues, observing a universal trend of increased gene-to-gene coordination loss during aging across tissues. The count of lost CERs is also positively correlated with individual-level aging and senescence-related molecular phenotypes. Notably, we revealed that the lost CERs have potential as biomarkers for individual aging and health status. In addition, we identified gene coordination loss events exhibiting significant positive correlation with age, defined as aging-related lost relationships (ARLRs), which may be functionally associated with pathways related to proteolytic processes. Finally, we showed that ARLRs may contribute to deleterious effects and increased pathogenicity through gene dosage imbalances.

Conclusions: This study establishes, for the first time, a connection between the loss of gene-to-gene expression coordination and individual-level aging progress. It provides proof-of-principle evidence for using lost gene coordinated expression relationships as biomarkers of healthy aging and highlights the potential risks associated with coordination loss in specific biological pathways during aging.