The Immune Cell Atlas of “Longevity Molecular Tag”: Identification of Principal Immune Cell Subsets and Their Underlying Molecular Regulatory Mechanisms

TL;DR

This study identifies immune cell subsets and molecular mechanisms linked to longevity in centenarians, offering insights into healthy aging.

Contribution

The study introduces an immune cell atlas of 'Longevity Molecular Tags' using the Scissor algorithm to uncover novel immune mechanisms in centenarians.

Findings

Scissor+ cells include NK cells, CD8+ T cells, and γδ T cells with enhanced cytotoxic functions.

Scissor− cells involve CD4+ T cells, B cells, and DCs linked to inflammatory pathways.

Five eQTL-colocalized events were identified, suggesting genetic links to longevity.

Abstract

Immunosenescence represents a critical aspect of the aging process. Centenarians, serving as a nature model of “healthy aging,” demonstrate a distinctive immune “compensatory adaptation” mechanism that contributes to the maintenance of immune homeostasis. However, the specific immune cell subsets involved and the molecular mechanisms underlying these phenotypic traits remain incompletely understood. In this study, we integrated single‐cell RNA sequencing data spanning the entire lifespan of East Asian populations with bulk transcriptomic data from a centenarian cohort in Guangxi. Utilizing the Scissor algorithm, we identified immune cell subpopulations positively (Scissor+) and negatively (Scissor−) associated with longevity phenotypes, thereby constructing an immune cell atlas of “Longevity Molecular Tag.” Our findings indicate that Scissor+ cells predominantly comprise natural killer (NK) cells, CD8+ T cells, and γδ T cells, characterized by enhanced cytotoxic and immunomodulatory functions. Conversely, Scissor− cells mainly include CD4+ T cells, B cells, and dendritic cells (DCs), which are linked to inflammatory signaling pathways and Th17/Th1 differentiation. Trajectory analysis elucidated the differentiation pathways of NK, CD8+ T cells, CD4+ T cells, and B cells. Differentially expressed genes were enriched in pathways such as NF‐κB signaling, T cell receptor signaling, and NK cell cytotoxicity. Furthermore, co‐localization analysis revealed five eQTL‐colocalized events (rs3793537–GLIPR2/CD72/TLN1 and rs8019902–TRDV2/TRDC) associated with longevity. Collectively, these results suggest that centenarians achieve immune equilibrium by remodeling cytotoxic immune lineages and finely tuning inflammatory responses, thereby promoting health span and longevity. This study offers novel insights into potential strategies for modulating immunosenescence.

This study aims to develop an immune cell atlas of the “Longevity Molecular Tags” by employing the Scissor algorithm to identify key immune cell subsets associated with longevity phenotypes. Subsequently, the underlying immune molecular mechanisms contributing to the longevity‐associated immune cell subsets were investigated through differential gene expression analysis, pseudotime analysis, and co‐localization analysis.

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