Ageing-related defects in macrophage function are driven byMYCandUSF1transcriptional programmes

Abstract

SummaryMacrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related immunity changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration and chemotaxis in human monocyte-derived macrophages (MDMs) from older (>50 years) compared with younger (18-30 years) donors, alongside downregulation of transcription factorsMYCandUSF1with age. In MDMs from young donors, knockdown ofMYCorUSF1decreased phagocytosis and chemotaxis and altered expression of genes associated with these functions, as well as adhesion and extracellular matrix remodelling. A concordant dysregulation ofMYCandUSF1target genes was also seen in MDMs from older donors. Furthermore, older age and loss of eitherMYCorUSF1in MDMs led to an increased cell size, altered morphology and reduced actin content. Together, these results defineMYCandUSF1as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in ageing.