Chronic inflammation and aging: DNA damage tips the balance

Abstract

The aged immune system, typically hyporesponsive to infection and vaccination, can be hyperresponsive in the context of inflammatory pathology. Here we review current work examining the mechanisms behind the amplified inflammatory profile of aged adaptive immunity, and the reciprocal relationship between chronic inflammation and immune aging. Aged hematopoietic stem cells are driven to differentiate following accumulated DNA damage, thus depleting the stem cell pool and increasing the number of damaged effector cells in the circulation. Chronic DNA damage responses in lymphocytes as well as senescent cells of other lineages initiate the production of inflammatory mediators. In addition, aged lymphocytes become less reliant on specific antigen for stimulation and more prone to activation through innate receptors. When these lymphocytes are exposed to inflammatory signals produced by senescent tissues, the bias toward inflammation exacerbates destruction without necessarily improving immunity.

Figure 1. DNA damage responses (DDR) are induced by many different age-associated DNA damage events and promotes inflammation through different mechanisms

A) Accumulated DNA damage in lymphoid hematopoietic stem cells (HSCs) induces differentiation into mature lymphocytes and leads to an imbalance in the stem cell pool, which becomes dominated by myeloid precursors. The reduction in lymphoid HSCs, combined with thymic involution and reduced bone marrow output, leads to a reliance on innate immunity favouring broad inflammatory responses. B) The lymphocytes differentiating from damaged HSCs may harbor unfavorable mutations that then integrate into the adaptive repertoire. In addition, DDR induced by age-associated nontelomeric DNA damage or telomeric erosions can contribute to the activation of T effector cell populations and production of inflammatory mediators. C) Cellular senescence induced by DNA damage has also been shown to induce the production of inflammatory cytokines by a variety of cell lineages not directly related to the immune system, a process coined as senescence-associated secretory pattern (SASP). In addition to directly causing pathology, this inflammatory tissue environment can attract and activate lymphocytes in a bystander fashion, even in the absence of specific antigen stimulation.

Figure 2. Age-associated changes to B and T lymphocytes

Aging of the immune system is associated with changes to B and T lymphocytes. These changes have different underlying mechanisms but related downstream consequences. T and B cells experience reduced selection pressure, owing to changes in primary lymphoid tissues and changes in survival requirements. Both cell types become less reliant on exposure to specific antigen through the BCR and TCR for activation, and more responsive to innate/antigen-independent signals, such as TLR ligands and cytokines. Additionally, there is cross talk between populations. Aged B cells are effective antigen presenters, and preferentially induce Th1 and Th17 responses in T cells. In parallel, aged regulatory T cells fail to suppress Th17 responses, with the effect that proinflammatory responses are promoted.