Overcoming immune dysfunction in the elderly: trained immunity as a novel approach

Abstract

People with advanced age have a higher susceptibility to infections and exhibit increased mortality and morbidity as the ability of the immune system to combat infections decreases with age. While innate immune cells display functional defects such as decreased phagocytosis, chemotaxis and cytokine production, adaptive immune cells exhibit reduced receptor diversity, defective antibody production and a sharp decline in naive cell populations. Successful responses to vaccination in the elderly are critical to prevent common infections such as influenza and pneumonia, but vaccine efficacy decreases in older individuals compared with young adults. Trained immunity is a newly emerging concept that showed that innate immune cells possess non-specific immunological memory established through epigenetic and metabolic reprogramming upon encountering certain pathogenic stimuli. Clinical studies suggest that trained immunity can be utilized to enhance immune responses against infections and improve the efficiency of vaccinations in adults; however, how trained immunity responses are shaped with advanced age is still an open question. In this review, we provide an overview of the age-related changes in the immune system with a focus on innate immunity, discuss current vaccination strategies for the elderly, present the concept of trained immunity and propose it as a novel approach to enhance responses against infections and vaccinations in the elderly population.

Keywords: aging; immunosenescence; inflammaging; innate immune memory; vaccination.

Fig. 1.

Age-associated functional changes in the immune system. Both innate and adaptive immune systems undergo age-related alterations in terms of cell numbers and functions toward the later decades of human life. Multiple human and murine studies revealed that the cells of innate immunity such as neutrophils, monocytes, macrophages, dendritic cells and NK cells display impaired receptor expression, chemotaxis, phagocytosis, antigen presentation, cytotoxicity, ROS and cytokine production. Adaptive immune cells (B cells and T cells) experience shifts in sub-populations such as the depletion of naive cell pools and accumulation of late-differentiated effector and memory cells. Apart from those, both display reduced receptor diversity. Functionally, expression of the co-stimulatory molecule CD28 is critically diminished in T cells while B cells become weaker in class-switching and affinity maturation. Numbers of plasma cells and production of antibodies also decrease. Despite these functional down-regulations at the cellular level, levels of pro-inflammatory cytokines and chemokines are elevated in circulation with advancing age.

Fig. 2.

Overview of fundamental mechanisms in trained immunity. Certain infections and vaccinations alter metabolic pathways, leading to histone modifications that enable chromatin regions to be more open for transcription. Increased gene expression results in improved responses against pathogens during secondary infection.