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 at-trition, 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 invo-lution, immune ageing and inflammaging contribute to immune-system remodelling across the life course. We then review evidence on immunity in centenarians and in semi- and supercentenarians, including NK cell expansion, T and B cell remodelling and the persistence of long-term immunological memory, as characterised by conventional flow cytometry and, more recently, single-cell transcriptomic analyses. Available data suggest that exceptional longevity does not reflect the maintenance of a youthful immune system, but rather the capacity to accommodate and compensate for age-related immune re-modelling through preserved cytotoxic surveillance, controlled inflammation, main-tained immune memory and favourable lifelong adaptation to antigenic exposures. Understanding these mechanisms may help identify immune trajectories associated with healthspan, delayed morbidity and resistance to age-related diseases.