The effect of ageing on macrophage Toll-like receptor-mediated responses in the fight against pathogens

Abstract

SummaryThe cellular changes during ageing are incompletely understood yet immune system dysfunction is implicated in the age-related decline in health. The acquired immune system shows a functional decline in ability to respond to new pathogens whereas serum levels of cytokines are elevated with age. Despite these age-associated increases in circulating cytokines, the function of aged macrophages is decreased. Pathogen-associated molecular pattern receptors such as Toll-like receptors (TLRs) are vital in the response of macrophages to pathological stimuli. Here we review the evidence for defective TLR signalling in normal ageing. Gene transcription, protein expression and cell surface expression of members of the TLR family of receptors and co-effector molecules do not show a consistent age-dependent change across model systems. However, there is evidence for impaired downstream signalling events, including inhibition of positive and activation of negative modulators of TLR induced signalling events. In this paper we hypothesize that despite a poor inflammatory response via TLR activation, the ineffective clearance of pathogens by macrophages increases the duration of their activation and contributes to perpetuation of inflammatory responses and ageing.

HIV-1 Infection and the Aging of the Immune System: Facts, Similarities and Perspectives

“…81e85 In fact, as a person ages, the adaptive immune system shows a functional decline in ability to respond to new pathogens whereas serum levels of some cytokines (typically, those with proinflammatory activity) are elevated. 86 Despite age-associated increases in cytokines, the function of aged macrophages is decreased: toll-like receptor expression and function decline, wheras there are elevated levels of activated nuclear factor-kB (NFkB), 87 whose activation by means of toll-like receptor stimulation results in the production and the secretion of proinflammatory cytokines. 88 Furthermore, in elderly persons infected by HIV, who display a chronic inflammation because of their age, age-associated defects in innate immunity are exacerbated by the infection, and viral clearance is further compromised.…”

CD4+ T cell surface alpha enolase is lower in older adults

“…This QC was fixed in Optilyse C, stored frozen in aliquots and a new aliquot was labelled with antibodies freshly each analysis day. We analysed leukocytes in batches of 10 in the following order; first from an older in duplicate (1,2), followed by younger leukocytes in duplicate (3,4), then repeated this on other older and younger cells (5)(6)(7)(8) before analysing the pooled QC leukocytes (9)(10). If the variance between duplicates or QC batches was greater than 10%, samples were re-analysed.…”

“…Biomarkers represent an attractive measure of biological ageing and potentially may improve our understanding of underlying ageing processes and age-related disease (5). Recent studies suggest that cell surface receptors may also be modified post-translationally, undergo changes in trafficking or level of expression (6)(7)(8)(9). However, to date the cell surface proteome has not been investigated systematically for age-dependent biomarkers.…”

Aging and Cancer Vaccines

“…It has been reported that Toll-like receptor (TLR) signaling in macrophages is defective at older age. 25,26 Also, aging in mice has been associated with an increase in the number of bone marrow macrophages that have an impaired ability to respond to infections, while cytokines such as circulating IL-6 or IL-10 increases with age upon stimulation with LPS. 27,28 …”