An Aging Clock Based on Immune Repertoire Features: COVID ‐19 Accelerates Aging

ABSTRACT

Aging induces immunosenescence, a progressive decline in immune function underpinning age‐related pathogen vulnerability, yet T/B cell receptor (TCR/BCR) repertoire remodeling during aging remains incompletely characterized, especially in non‐European populations. Additionally, SARS‐CoV‐2 may perturb immune homeostasis and accelerate aging, but its impact on immune repertoire aging is unclear. Here, we analyzed leukocyte DNA from 195 healthy Chinese individuals (25–93 years) and 94 post‐COVID‐19 cases via CDR3 high‐throughput sequencing. Aging correlated with shorter CDR3 sequences, reduced VDJ gene/V‐J combination diversity, declining TCR/BCR clonotype counts (179.7/507 per 3 years), expanded hyperexpanded TCR/large BCR clones, and reduced diversity (critical turning point ~60 years). These changes were intensified post‐COVID‐19, with altered amino acid usage, diminished diversity, and expanded SARS‐CoV‐2/ Mycobacterium tuberculosis ‐related clones. We developed a LightGBM‐based immune repertoire aging clock, validating accelerated biological aging (increased cAgeDiff) and reduced intrinsic capacity in post‐COVID‐19 individuals. Our findings reveal age‐dependent immune repertoire remodeling exacerbated by COVID‐19, deepening understanding of immunosenescence and post‐viral dysfunction, with potential clinical applications for age‐related immune decline and post‐COVID‐19 syndromes.