Inflammaging decreases adaptive and innate immune responses in mice and humans

Abstract

Both the innate and adaptive immune systems decline with age, causing greater susceptibility to infectious diseases and reduced responses to vaccination. Diseases are more severe in elderly than in young individuals and have a greater impact on health outcomes such as morbidity, disability and mortality. Aging is characterized by increased low-grade chronic inflammation, called "inflammaging", measured by circulating levels of TNF-α, IL-6 and CRP, as well as by latent infections with viruses such as cytomegalovirus. Inflammaging has received considerable attention because it proposes a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we aim at summarizing the current knowledge on pathways contributing to inflammaging, on immune responses down-regulated by inflammation and mechanisms proposed. The defects in the immune response of elderly individuals presented in this review should help to discover avenues for effective intervention to promote healthy aging.

Keywords: Aging; Immunity; Inflammaging; Vaccine responses.

Figure 1. Molecular pathways for reduced B cell responses in aging

The production of high-affinity, class-switched antibodies (IgG/E/A) is decreased both in vivo and in vitro as a consequence of reduced class switch recombination (CSR) with aging. CSR is a DNA recombination event regulated by activation-induced cytidine deaminase (AID), the enzyme responsible for opening the double stands of DNA in the S (switch) regions of Immunoglobulin genes. AID also regulates somatic hypermutation and therefore is crucial for the production of protective antibodies. AID is decreased in stimulated B cells from aged mice and humans and is transcriptionally regulated by E47, the Helix-Loop-Helix transcription factor, which is decreased in aged B cells by mRNA stability. E47 mRNA stability is down-regulated by tristetraprolin (TTP), a negative regulator of the stability of transcription factor and cytokine mRNAs. TTP is higher in unstimulated B cells from aged mice and humans, and is positively regulated by B cell intrinsic TNF-α and particular inflamma-micro-RNAs (miRs), such as miR-155 and miR-16. Levels of TTP, TNF-α and miRs in unstimulated B cells are positively regulated by serum levels of pro-inflammatory cytokines and adipokines, microbial translocation and persistent infections with viruses such as CMV. We have shown that the age-related increase in these markers is associated with TNF-α production by unstimulated B cells and that this “pre-activated” phenotype of the B cells renders them incapable of being optimally stimulated by exogenous antigens, mitogens or vaccines.