Immunosenescence and human healthspan. Lessons from centenarians.

Abstract

Immunosenescence is a multidimensional remodeling of immunity, characterized by inflammaging, cellular senescence, T-cell exhaustion, and thymic involution, that raises infection and disease risk with age. Emerging evidence, notably from centenarians, shows immune aging follows divergent trajectories: rather than a uniform decline, extreme longevity often reflects adaptive remodeling and a maintained immune equilibrium. Centenarian immune profiles are characterized by selective retention of naïve T cells, expansion of cytotoxic CD4+ and CD8+ subsets, tightly regulated inflammatory signaling, and systemic protective mechanisms such as enhanced oxidative-stress resistance, preserved epigenetic regulation, and extracellular vesicle-mediated T-cell modulation. Progress is constrained by cohort heterogeneity and limited longitudinal, harmonized multi-omic data; addressing these gaps could produce biological-age biomarkers and inform immunometabolic or senotherapeutic strategies to extend healthspan. In this narrative review, we describe that immunosenescence should be viewed as a trajectory-dependent process in which balanced immune function, not mere preservation of youthful markers, determines resilience and healthy aging.