The long-lived immune system of centenarians.

Abstract

Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in semi-supercentenarians (105-109 years) and supercentenarians (≥110 years), whose immune profiles often resemble those of much younger individuals. In this Review, we explore how centenarians modulate key hallmarks of immune ageing across innate and adaptive immune compartments. We discuss evidence that they limit the pathological effects of inflammageing, potentially through reduced NLRP3 inflammasome activation, enhanced autophagy and a tempered senescence-associated secretory phenotype. Omics studies further reveal transcriptomic, epigenetic and microbial signatures consistent with preserved immune function, including youth-like gene expression patterns in circulating immune cells and beneficial shifts in gut microbiome composition. Together, these findings suggest that centenarians achieve longevity through coordinated adaptations that maintain immune homeostasis and disease resistance and may inform strategies to enhance healthspan in ageing societies.