Aging reshapes the adaptive immune system from healer to saboteur

The classical role of adaptive immunity as a protector against external threats has expanded to include its functions in cancer surveillance, tissue repair and regeneration, and, more recently, it has emerged as a regulator of the aging process. In this Perspective, we discuss the mechanisms by which the deterioration of adaptive immunity contributes to inflammaging, cellular senescence and age-associated pathologies. We propose that age-related changes in lymphocytes contribute to aging through two distinct mechanisms. First, adaptive immune function worsens with age, impairing immunosurveillance of damaged or senescent cells and diminishing tissue regenerative potential, thereby indirectly disrupting tissue homeostasis. This disruption is particularly important in the gut, where maintaining tissue and microbiota homeostasis is crucial for overall health during aging. Second, adaptive immune cells often acquire pro-inflammatory and autoaggressive phenotypes with age, directly driving tissue damage, promoting senescence and exacerbating inflammaging. Finally, we explore the therapeutic potential of strategies aimed at enhancing the protective functions of lymphocytes or modulating their pathogenic phenotypes to promote healthy aging. Delgado-Pulido, Yousefzadeh and Mittelbrunn explore the molecular mechanisms by which adaptive immunity regulates the processes of aging, discussing age-related declines in protective functions and age-related gains of autoaggressive features in turn.