Highlights • Spatial multi-omics atlas maps senescence across 51 human lymph nodes from ages 18–86 • Senescent-like cells shift from interfollicular zones to germinal centers with aging • p16/p21-expressing germinal-center B cells show impaired antibody and metabolic programs • Chromatin accessibility increases at CDKN1A, CDKN2A, and SASP loci in aged lymph nodes Summary Immunosenescence is a hallmark of human aging and contributes to age-related immune decline, yet the development of senescence-associated phenotypes in the human lymphoid organs remains poorly understood. Here, we integrate single-cell and spatial multi-omics to systematically characterize age-related senescence in human lymph nodes (LNs) across the lifespan. Spatial proteomic profiling of 99 LN sections from 51 donors (18–86 years) using high-plex immunofluorescence (∼20 million cells) mapped senescence markers (p16, p21, HMGB1, and γ-H2AX) at single-cell resolution, revealing diverse senescent-like cell types (“senotypes”) and a stepwise shift from extrafollicular to germinal-center localization with age. In aged LNs, germinal-center B cells exhibit focal accumulation of senescence-associated programs, accompanied by impaired functional signatures, metabolic remodeling, and altered regulatory networks. These findings define a spatially organized landscape of immunosenescence in human lymphoid tissue and highlight germinal-center B cells as a key locus of age-associated immune dysfunction.