AUTHOR=Li Shuhan , Lv Haohao , Zhang Renxin , Li Jinjun , Chen Zhiyuan , Yang Naixue , Dai Shaoxing 

TITLE=Aging-related alternative splicing drive neoantigen emergence revealed by transcriptome analysis of 1,255 human blood samples

JOURNAL=Frontiers in Aging

VOLUME=Volume 6 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2025.1575862

DOI=10.3389/fragi.2025.1575862

ISSN=2673-6217

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.