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

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.