Li Shuhan, Lv Haohao, Zhang Renxin, Li Jinjun, Chen Zhiyuan, Yang Naixue, Dai Shaoxing
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China.
Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan, China.
Front Aging. 2025 May 9;6:1575862. doi: 10.3389/fragi.2025.1575862. eCollection 2025.
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.
本研究旨在通过对1255份年龄在8至87岁的健康个体血液样本进行全面的转录组分析，来鉴定与年龄相关的基因和可变剪接（AS）事件。我们在老年个体中鉴定出1029个上调基因和1186个下调基因，其中包括17个与已知衰老相关基因重叠的基因，如TFAP2A和Klotho。基因集富集分析显示，衰老过程中免疫调节和代谢途径发生了显著变化。然而，许多涉及衰老相关分泌表型（SASP）的基因在基因表达上并未表现出变化，这表明可变剪接事件可能揭示了其他与年龄相关的机制。衰老还改变了4566个基因中的6320个可变剪接事件，影响了与免疫相关的蛋白质结构域。RNA结合蛋白RBMS3成为衰老特异性可变剪接事件的关键调节因子。此外，新抗原预测分析进一步鉴定了由衰老相关可变剪接事件产生的潜在新抗原，其中HLA-C14:02等位基因呈现出最多的新抗原肽段。值得注意的是，利用老年个体的蛋白质组学数据证实了60种新抗原肽段，表明它们有望成为抗衰老免疫治疗的新靶点。我们的研究为可变剪接在衰老中的作用提供了新的见解，突出了抗衰老免疫治疗的有前景的途径。
