Single‐Cell Transcriptome‐Wide Mendelian Randomization and Colocalization Analyses Uncover Cell‐Specific Mechanisms in Epigenetic Age Acceleration

ABSTRACT Epigenetic age acceleration (EAA) reflects biological aging processes beyond chronological age and is associated with morbidity and mortality. However, the causal gene regulatory mechanisms underlying epigenetic age remain unclear. Here, we integrated single‐cell expression quantitative trait loci (sc‐eQTL) data across 14 immune cell types with Mendelian randomization (MR) and Bayesian colocalization to identify eGenes whose cell‐type‐specific expression causally influences four major epigenetic clocks: IEAA, HannumAge, GrimAge, and PhenoAge. We identified 58 unique eGenes with strong evidence of causality, including ATM , ENO1 , DDX5 , and PSMB9 , with effects often confined to specific immune lineages such as CD8 T and NK cells. Functional enrichment analysis revealed that these eGenes are involved in immune regulation, NF‐κB signaling, and mitochondrial metabolism. Phenome‐wide association studies (PheWAS) further linked top eGenes, particularly ATM and DDX5 , to a spectrum of aging‐related traits, including metabolic and immune disorders. Our findings highlight the importance of immune‐cell‐specific gene regulation in shaping biological aging and provide candidate targets for future aging interventions.