Crossing Gene Sets from GTEx, MoTrPAC and RummaGEO Reveals Nicotinamide as a Potential Modulator of Aging and Endurance Exercise Training

Abstract

Biomedical omics resources are often analyzed as separate collections, which fragments insight and limits discovery of shared mechanisms. Combining gene sets from multiple Common Fund programs can reveal robust molecular programs that span distinct biological contexts and improve confidence in overlapping signals. In this study we crossed three curated libraries: the GTEx TissueSpecific Aging Signatures that capture blood gene expression changes with age, the MoTrPAC Rat Endurance Exercise Training Transcriptomics that represent sexspecific exerciseresponsive genes, and the RummaGEO Drug Perturbation Signatures that provide a nicotinamidetreated mouse expression profile. By harmonizing the GMT files from each source and evaluating all possible threeway combinations we identified a single crossing whose intersecting genes appear in every set, representing the maximal shared inclusion among the examined overlaps. The 27 intersecting genes are dominated by secreted glycoproteins and lipidhandling proteins such as ANGPTL3, several apolipoproteins, APOH, FGL1, HRG, TTR and complement component C8A, linking extracellular matrix remodeling, immune modulation and coagulation pathways that shift with aging. Enrichment analysis highlighted fibrinolysis, cholesterol metabolism, bile acid biosynthesis and nuclear receptor transcription factors, while GWAS links connected the set to cholesterol efflux and blood pressure traits. The presence of the nicotinamideresponsive signature suggests that the drug may modulate this core vascularmetabolic program, offering a potential avenue for therapeutic exploration of agerelated metabolic and vascular alterations.