Frailty-Associated Immune Aging Signatures characterized by SASP and T Cell Effector Function Profiling 2258858

Abstract Introduction Immunosenescence contributes to infection risk, poor vaccine response, and chronic inflammation in older adults. Because chronological age does not reflect biological variability, clinical frailty offers a functional measure of physiological aging. Using the Korean Frailty Index (K-Frail), this study investigated frailty-associated immune signatures through integrated analyses of systemic inflammation and T cell profiles. Methods Peripheral blood was collected from young, healthy-, and frail-aged donors classified by K-Frail. PBMCs and plasma were analyzed for cellular and soluble immune factors. Multicolor flow cytometry assessed T cell subsets, senescence markers, and cytokine production. Plasma senescence-associated secretory phenotype (SASP) factors were quantified using a Luminex assay. Results Aging was characterized by reduced naïve and increased memory T cells with higher senescence marker expression. These phenotypic changes were comparable between healthy-aged and frail-aged groups, indicating limited additional T cell remodeling with frailty. However, functional assays revealed elevated frequencies of TNF-producing, polyfunctional CD8+ T cells (IFN-γ+MIP-1β+TNF+) in frail individuals. Systemic profiling identified a TNF-centered SASP network involving TNFR1, TNF-α, and IL-6, which was upregulated in frailty. TNFR1 levels and frequencies of polyfunctional CD8+ T cells correlated positively with K-Frail scores, linking TNF-associated inflammatory activity to frailty severity. Conclusion Frailty does not substantially augment peripheral T cell senescence beyond chronological aging but is characterized by a distinct immune signature featuring enhanced TNF-producing CD8+ effector responses and elevated TNF-related SASP factors. The parallel increases in TNFR1, TNF-producing CD8+ T cells, and frailty scores suggest a TNF-driven mechanism contributing to immune frailty, offering a potential target for inflammation-modulating interventions in aging. Funding Source Ministry of Science and ICT (MSIT), Republic of Korea Topic Categories Translational and Interventional Immunology (TI)