Interconnections between Inflammageing and Immunosenescence during Ageing

Abstract

Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from the continued presence of the initial trigger, or the dysfunction of signalling and/or effector pathways, is harmful to health. While successful ageing in older adults, including centenarians, is associated with low levels of inflammation, elevated inflammation increases the risk of poor health and death. Hence inflammation has been described as one of seven pillars of ageing. Age-associated sterile, chronic, and low-grade inflammation is commonly termed inflammageing—it is not simply a consequence of increasing chronological age, but is also a marker of biological ageing, multimorbidity, and mortality risk. While inflammageing was initially thought to be caused by “continuous antigenic load and stress”, reports from the last two decades describe a much more complex phenomenon also involving cellular senescence and the ageing of the immune system. In this review, we explore some of the main sources and consequences of inflammageing in the context of immunosenescence and highlight potential interventions. In particular, we assess the contribution of cellular senescence to age-associated inflammation, identify patterns of pro- and anti-inflammatory markers characteristic of inflammageing, describe alterations in the ageing immune system that lead to elevated inflammation, and finally assess the ways that diet, exercise, and pharmacological interventions can reduce inflammageing and thus, improve later life health.

How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells

“…However, aging appears to promote a dysfunctional chemotactic capacity in neutrophils, which alters both dissemination and achievement of the site of damage. This is demonstrated by phenotypic changes, such as: (i) decreased expression of CD11b, which is involved in the recruitment of neutrophils to the infected tissue; (ii) up-regulation of chemokine receptors and adhesion molecules CXCR4, CD49d, and ICAM, which facilitate neutrophil migration through the endothelium; (iii) down-regulation of chemokine receptor CXCR2 which determines the capacity to reverse-transmigrate in the vessels; (iv) decreased mobilisation of actin and calcium related to the migration capacity [ 21 , 22 , 23 ]. Defects in chemotaxis and, consequently, in the ability to reach the site of damage, lead to altered neutrophil distribution, which also impairs pathogen recognition and elimination.…”

“…This can be evidenced by the increased expression of both CD63 on the cell surface and the increased release of protease from granules. CD63 contributes not only to tissue damage but also to systemic inflammation related to the ability to disseminate through different organs in a trans-endothelial manner [ 23 , 24 ].…”

“…The latter event affects complement- and immunoglobulin-mediated opsonization of pathogens and impairs the ability of neutrophils to create the neutrophil extracellular trap (NET), a trap for microbes in the process called NET-osis [ 20 , 25 ]. The combination of these events contributes to an enhanced status of inflammaging and may be a possible explanation for the greater susceptibility of the older people to invasive bacterial infections [ 23 ]. The majority of these events can be detected following in vitro stimulation with formyl-methionine-leucine-phenylalanine, lipopolysaccharide (LPS), and granulocyte–macrophage colony-stimulating factor (GM-CSF) [ 26 ].…”

“…Several studies have reported an age-associated decline in cell number and function, especially in pDC, while other reports have shown a decline with age in the number of mDC, but not of pDC [ 43 , 64 , 65 , 66 , 67 , 68 ]. Impaired migration and phagocytosis, and a diminished or delayed migration potential toward lymphoid organs and peripheral tissues by the aged DCs have also been reported, leading to decreased antigen presentation [ 23 , 69 ].…”

“…Some authors have reported the possibility of reverting the dysfunction of aged neutrophils. The treatment of aged neutrophils with statins, which act on CDC42, a cell division control protein 42 homolog, involved in the signalling to actin, improves neutrophil chemotaxis and reduces NET-osis [ 23 ]. Other reports show that high doses of simvastatin can influence the GTPase activity, involved in polarity and migration capacity.…”