Cross-Level Regulatory Interactions Underlying Human Immune Aging

A comprehensive understanding of age-related changes in the human immune system is critical for deciphering the mechanisms of immunosenescence. Although transcriptomic studies have described immune alterations during aging, investigations into the proteomic layer and integrated multi-omics approaches remain scarce. Here, we performed multi-omics sequencing on peripheral blood samples from 69 individuals aged 23-75 years. We identified widespread dysregulation of RNA splicing in aging immune cells, with exon skipping being the most prevalent splicing event, which was mainly enriched in protein regulation-related processes. Notably, lncRNAs such as SNHG1 and RP1-3J17.3 modulated the expression of splicing-regulatory mRNAs and proteins in aging immune cells, thereby influencing the RNA splicing of downstream genes. Splicing dysregulation of genes including EIF4G1, a translation initiation factor, led to alterations in protein translation, modification, and degradation, ultimately reshaping protein profiles in aging leukocytes. These proteomic alterations in our data reflect a gradual weakening of T-cell function during aging. Together, unlike previous studies that focused only on single molecular layers, our study elucidates the interconnected nature of molecular regulation within leukocytes during aging, uncovers cross-level interactions and regulatory networks, and provides a comprehensive multi-omics resource for understanding immune aging and identifying potential strategies to delay immunosenescence.