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bioRxiv · 10.64898/2026.05.19.726397

Multi-layer transcriptomic characterization of age-related immune dynamics

Zhao, Z.·Zhao, S.·Jin, J.·Ni, T.
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Abstract

Despite the pivotal role of mRNA isoform diversity in governing immune cell function, current investigations into peripheral immune aging predominantly focused on gene-level expression, obscuring deeper regulatory layers of transcriptome complexity. Here, we leveraged a 5' scRNA-seq atlas comprising approximately 2.5 million PBMCs from 378 healthy donors. We demonstrate that immune aging is characterized by profound, non-linear transcriptional reprogramming that extends beyond gene-level shifts to include fine-tuned regulation of alternative transcription initiation and splice site selection. By quantifying the transcriptional activity of cis-regulatory elements, we resolved their contributions to age-related expression dynamics. Notably, we identified a subset of endogenous retroviruses that are reactivated in older individuals, some of which served as alternative promoters driving the production of chimeric transcripts. Furthermore, our analysis revealed EDA as a top-ranked gene consistently upregulated with age across multiple independent cohorts. Increasing EDA expression in in vitro-stimulated naive CD4+ T cells from young individuals recapitulated aged phenotypes. This comprehensive resource elucidates the multi-layered transcriptomic landscape of the aging immune system and facilitates the identification of novel drivers of immune aging.

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Zhao, Z., Zhao, S., Jin, J., Ni, T.. 2026-05-21. Multi-layer transcriptomic characterization of age-related immune dynamics. https://doi.org/10.64898/2026.05.19.726397

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