Aging-related alternative splicing drive neoantigen emergence revealed by transcriptome analysis of 1,255 human blood samples
Shuhan Li, Haohao Lv, Renxin Zhang, Jinjun Li, Zhiyuan Chen, Naixue Yang, Shao‐Xing Dai
Abstract
This study aimed to identify age-related genes and alternative splicing (AS) events by comprehensive transcriptome analysis of 1,255 healthy blood samples from individuals aged 8-87 years. We identified 1,029 up-regulated and 1,186 down-regulated genes in older individuals, including 17 genes overlapped with known aging-associated genes, such as TFAP2A and Klotho. Gene set enrichment analysis revealed significant alterations in immunoregulatory and metabolic pathways during aging. However, many senescence-associated secretory phenotypes (SASP) involved genes did not exhibit changes in gene expression, suggesting that AS events may reveal additional age-related mechanisms. Aging also altered 6,320 AS events in 4,566 genes, impacting immune-related protein domains. The RNA-binding protein RBMS3 emerged as a key regulator of aging-specific AS events. In addition, neoantigen prediction analyses further identified potential neoantigens generated by aging-related AS events, with the HLA-C14:02 allele presenting the most neoantigenic peptides. Notably, 60 neoantigenic peptides were confirmed using proteomic data from elderly individuals, suggesting their potential as novel targets for anti-aging immunotherapy. Our study provides new insights into the role of alternative splicing in aging, highlights promising avenues for anti-aging immunotherapy.