Loss of Natural IgM Recognition Capacity Links B-Cell Repertoire Aging to Defective Senescent-Cell Immunosurveillance

Abstract Background Senescent-cell accumulation contributes to inflammaging and age-related tissue dysfunction, but the mechanisms underlying deterioration of senescent-cell immunosurveillance remain incompletely understood. We investigated whether natural immunoglobulin M (IgM) contributes to early recognition and clearance of senescent cells and whether this function deteriorates with age independently of circulating IgM abundance. Methods Natural IgM from younger, middle-aged, and older donors was evaluated against independently generated senescent and matched non-senescent cellular states. Functional recognition was quantified using an IgM Senescence Recognition Index (IgM-SRI) and integrated with complement deposition, macrophage-mediated phagocytosis, residual senescent-cell burden, and senescence-associated secretory phenotype (SASP) activity. IgM depletion and autologous reconstitution assessed functional dependence, while B-cell receptor (BCR) profiling evaluated age-associated repertoire remodeling. Results In the modeled dataset, IgM-SRI declined from 2.82 ± 0.58 in younger donors to 2.21 ± 0.52 in middle-aged donors and 1.55 ± 0.44 in older donors (P