Markers of the ageing macrophage: a systematic review and meta-analysis

Abstract

IntroductionAgeing research is establishing macrophages as key immune system regulators that undergo functional decline. Due to heterogeneity between species and tissue populations, a plethora of data exist and the power of scientific conclusions can vary substantially. This meta-analysis by information content (MAIC) and systematic literature review (SLR) aims to determine overall changes in macrophage gene and protein expression, as well as function, with age. MethodsPubMed was utilized to collate peer-reviewed literature relating to macrophage ageing. Primary studies comparing macrophages in at least two age groups were included. Data pertaining to gene or protein expression alongside method used were extracted for MAIC analysis. For SLR analysis, data included all macrophage-specific changes with age, as well as species, ontogeny and age of groups assessed. ResultsA total of 240 studies were included; 122 of which qualified for MAIC. The majority of papers focussed on changes in macrophage count/infiltration as a function of age, followed by gene and protein expression. The MAIC found iNOS and TNF to be the most commonly investigated entities, with 328 genes and 175 proteins showing consistent dysregulation with age across the literature. Overall findings indicate that cytokine secretion and phagocytosis are reduced and reactive oxygen species production is increased in the ageing macrophage.DiscussionCollectively, our analysis identifies critical regulators in macrophage ageing that are consistently dysregulated, highlighting a plethora of targets for further investigation. Consistent functional changes with age found here can be used to confirm an ageing macrophage phenotype in specific studies and experimental models.

Impaired ATP hydrolysis in blood plasma contributes to age-related neutrophil dysfunction

“…Like PMNs, macrophages depend on autocrine signaling via P2Y2, A2, and other purinergic receptors to regulate chemotaxis, NLRP3 inflammasome activation, and other cell functions [ 53 – 55 ]. Systemic ATP accumulation could interfere with these purinergic signaling mechanisms and thereby disrupt macrophage functions such as phagocytosis, cytokine secretion, and ROS production that were reported to deteriorate in response to aging [ 56 ]. Further studies are needed to examine the exact mechanisms by which ATP accumulation and aging impact PMNs, macrophages, and other immune cell subsets.…”

Ageing-related defects in macrophage function are driven byMYCandUSF1transcriptional programmes

“…It is worth noting that monocyte counts between the young and older cohorts were comparable and not likely influencing these changes (10.27 ± 3.13 million vs 9.36 ± 2.9 million, respectively). While research has set out by others to assess changes in macrophage numbers with age, no real consensus has been drawn, with large tissue- and stimulus-specific variation, although it has been suggested that pro-inflammatory populations increase with age (6).…”

“…However, how the molecular changes that determine the chronic inflammatory phenotype translate to a decline in function is unclear, a critical gap limiting the development of new immunotherapeutics for ageing. A further barrier to new therapeutics is our current reliance on mouse models, with a lack of studies in humans (6). Here, we sought to measure ageing-related changes in macrophage migration and phagocytosis in a human cohort as a phenotypic marker to identify the molecular changes underlying macrophage ageing.…”