Mechanistic insights and biomarker discovery in immune cell aging and age-associated diseases
Prabhat Kumar Upadhyay, Aamir Suhail, Pukar Khanal, Sudhir Kumar
Abstract
Immunosenescence is the progressive deterioration of immune function with aging and is driven by dynamic molecular and cellular interactions, most notably the chronic low-grade inflammation (inflammaging). This inflammatory state arises from lifelong antigen exposure, environmental stress, and hormonal shifts, culminating in paradoxical immune dysfunction: innate immune cells exhibit numerical expansion but functional decline, including impaired macrophage phagocytosis and diminished dendritic cell-mediated T cell priming. Advances in single-cell RNA sequencing have uncovered biomarkers of immune aging, such as upregulation of cyclin-dependent kinase inhibitors (CDKN1A/p21 and CDKN2A/p16INK4a) and senescence-associated secretory phenotype (SASP) components like IL-6, IL-8, and TNF-α. Concurrent epigenetic dysregulation, such as EZH2-dependent H3K27me3 alterations and global DNA methylation shifts, further orchestrates immune decline. The adaptive immune system undergoes profound remodeling, marked by thymic involution, skewed T cell receptor diversity, and B cell repertoire contraction, which collectively impair responses to novel antigens and vaccination efficacy. Elucidating these mechanisms provides a roadmap for targeting strategies to restore immune resilience in aging populations.