Evolution and development of innate immune memory

Innate immune memory (trained immunity) is mediated by epigenetic and metabolic reprogramming of innate immune cells and hematopoietic progenitors, enabling altered responses to subsequent challenges. Mechanistically conserved across eukaryotes, trained immunity in mammals operates as a dynamically regulated, life-phase-specific system. The demands and constraints on innate immune memory shift across the life span: from tolerogenic programming and maternal immune transfer in fetal and neonatal life, through establishment of innate set points during early-life microbial colonization, to full integration of central and peripheral training with adaptive immunity in adulthood. Aging disrupts this integration, producing simultaneous immunosenescence and inflammaging, potentially through cumulative maladaptive training at the hematopoietic stem cell level. In this Review, we examine how the exposome continuously shapes innate immune trajectories across life and discuss implications for trained immunity-based strategies to limit maladaptive inflammation.