Crossing Gene Sets From GTEx, Metabolomics and RummaGEO Reveals Coenzyme A As a Potential Modulator of Cardiac Aging and Metabolic Regulation

Abstract

Biomedical omics resources are often examined as isolated datasets, which can obscure shared molecular mechanisms and limit translational insight. To address this limitation we crossed three complementary Common Fund geneset libraries: the GTEx TissueSpecific Aging signatures that capture genes downregulated in aging heart tissue, the Metabolomics MetaboliteEnzyme Associations that define enzymes linked to the coenzymeA metabolite, and the RummaGEO Drug Perturbation signatures that report genes upregulated by metformin exposure in mouse. By evaluating all possible threeway combinations we identified a single crossing that contained the maximal number of genes shared among the three libraries, yielding nine genes present in every set. These intersecting genes encode core mitochondrial enzymes and lipidremodeling proteins that sustain cellular energy production, redox balance, and membrane integrity, highlighting a coordinated metabolic hub that links agerelated cardiac expression changes, coenzymeAdependent pathways, and metforminresponsive transcriptional programs. Enrichment analysis reinforced this theme by revealing strong signals for acetylCoA biosynthesis, citratecycle activity, pyruvate metabolism, and branchedchain aminoacid catabolism, while transcriptionfactor profiling pointed to regulators such as PPARG and CREB1. The convergence of these findings suggests that metformin may beneficially target this metabolic hub, offering a mechanistic rationale for its potential utility in ameliorating ageassociated cardiac dysfunction and broader metabolic dysregulation.