Why Some People Live Past 100: The Role of the Immune System in Centenarians, Semi-Supercentenarians and Supercentenarians

Centenarians, semi-supercentenarians and supercentenarians (i.e., oldest centenarians) display complex and heterogeneous immune remodelling. In this setting, immune attrition, memory, cytotoxic defence, inflammatory regulation and tissue surveillance remain sufficiently balanced to support survival with relatively preserved health. This review examines these processes within an integrated framework encompassing sex and gender differences, genetic background, the exposome and immunobiography. We consider how haematopoietic stem cell ageing, age-related myeloid bias, thymic involution, immune ageing and inflammaging contribute to immune-system remodelling across the life course. Findings from conventional phenotyping and single-cell transcriptomic studies in centenarians, semi-supercentenarians and supercentenarians indicate selective immune remodelling rather than preservation of a youthful immune system. These changes include NK-cell expansion, differentiated B-cell states, enrichment of effector-memory CD8⁺ T cells, marked expansion of clonally selected cytotoxic CD4⁺ T cells and increased GZMK⁺GZMB^- CD8⁺ T cell populations. Exceptional longevity also appears to depend on limiting the detrimental consequences of chronic inflammation through delayed or better-controlled inflammaging, restrained NLRP3 inflammasome activation and preserved capacity to buffer oxidative stress. Thus, extreme survival appears to reflect successful accommodation of age-related immune change through sustained cytotoxic surveillance, immune memory, inflammatory control and favourable lifelong adaptation to antigenic exposures.