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

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 < 0.001), while total serum IgM remained comparatively preserved (126 ± 31, 121 ± 29, and 116 ± 32 mg/dL; P = 0.34). Recognition breadth decreased from 81 ± 12% to 44 ± 16%, accompanied by reductions in C3 deposition (67 ± 13% vs 38 ± 13%) and macrophage-mediated clearance (64 ± 12% vs 36 ± 12%; both P < 0.001). IgM-SRI correlated strongly with clearance (r = 0.72, P < 0.001), whereas total IgM did not (r = 0.18, P = 0.22). IgM depletion reduced clearance by approximately 45%, while autologous reconstitution restored approximately 85% of the lost activity. Conclusions These findings identify deterioration of natural-IgM recognition as a potential mechanism linking immunosenescence to impaired senescent-cell clearance and inflammaging. Preservation or restoration of functional immune-recognition capacity may therefore represent a previously underexplored biological pathway toward maintaining tissue homeostasis and promoting healthy longevity.