Trained immunity enhances host resistance to infection in aged mice

Abstract Aging significantly increases the incidence and severity of infections, with individuals aged 65 and above accounting for 65% of sepsis cases. Innate immune training, known as “trained immunity” or “innate immune memory,” has emerged as a potential strategy to enhance infection resistance by modulating the aging immune system. We investigated the impact of -glucan-induced trained immunity on aged mice (18 to 20 mo old) compared with young adult mice (10 to 12 wk old). Our findings showed that β-glucan equally augmented the host resistance to infection in both young and aged mice. This enhancement was characterized by augmented bacterial clearance, enhanced leukocyte β, and decreased cytokine production in response to Pseudomonas aeruginosa infection. Furthermore, young and aged trained macrophages displayed heightened metabolic capacity and improved antimicrobial functions, including enhanced phagocytosis and respiratory burst. RNA-seq analysis showed a distinctive gene expression pattern induced by trained immunity in macrophages characterized by activation of pathways regulating inflammation and the host response to infection and suppression of pathways regulating cell division, which was consistently observed in both young and aged groups. As compared with macrophages from young mice, aged macrophages showed increased activation of gene ontology pathways regulating angiogenesis, connective tissue deposition, and wound healing. Our results indicate that immune training can be effectively induced in aging mice, providing valuable insights into potential strategies for enhancing infection resistance in the elderly.