Crossing Gene Sets From GTEx, MoTrPAC and RummaGEO Reveals Nicotinamide As a Potential Modulator of Aging and Exercise

Abstract

Biomedical omics resources are frequently treated as isolated datasets, which fragments insight and hampers discovery of shared mechanisms. By crossing gene sets from multiple Common Fund programs, it becomes possible to identify molecular programs that are reproducible across diverse biological contexts, to assess robustness of findings, and to connect molecular signatures to physiological outcomes. In this report we intersected three complementary gene set libraries: the GTEx Tissue-Specific Aging signatures that capture blood expression changes associated with advancing age, the MoTrPAC Rat Endurance Exercise Training transcriptomics that describe early-life female blood RNA alterations after short-term exercise, and the Rum- maGEO Drug Perturbation signatures that reflect the response of mouse liver to nicotinamide treatment. The workflow harmonized the libraries, evaluated all possible three-way combinations, and selected the crossing that contained the maximal set of genes shared by all three resources for detailed analysis. The resulting inter- secting gene set is enriched for secreted plasma proteins that participate in extracellular matrix organization, complement-mediated immunity, and the regulation of lipid and cholesterol metabolism, including factors such as angiopoietin-like protein 3, apolipoproteins C1 and C2, and coagulation components. Enrichment of hemostatic and lipid-handling pathways, together with transcription factor signatures linked to nuclear receptors, highlights a coherent biological theme. The presence of nicotinamide-responsive genes suggests that nicotinamide or related agents may modulate these pathways, offering a potential therapeutic avenue that aligns with the shared molecular signatures uncovered across the three datasets.