Single‐Cell Profiling Reveals Distinct Immune Communication Networks in Centenarians and Elderly Controls

Aberrant cell-cell communication (CCC) is a recognized hallmark of aging, yet comprehensive analyses of immune CCC-particularly in the context of healthy aging-remain limited. Using single-cell transcriptomics of PBMCs from centenarians (CEN), their offspring (CO), and elderly controls, we found that immune CCC in controls was characterized by myeloid-derived, self-amplifying SASP signals associated with immunosenescence and effector immune cell (EIC) exhaustion. In contrast, healthy-aging individuals (CEN/CO) exhibited reinforced positive regulatory factor (PRF)-mediated ligand-receptor (LR) interactions, such as IL-15 and IL-18, consistent with enhanced EIC cytotoxicity and immune surveillance. These findings were further supported in an independent longevity cohort. Our results suggest distinct immune CCC reprogramming with age and identify a characteristic immune remodeling pattern in centenarians, providing a framework for understanding healthy aging and exceptional longevity.