MYC and USF1 are Downregulated in Aged Human Macrophages
Researchers here explore age-related changes that take place in the innate immune cells known as macrophages, as well as the precursor circulating cell type known as monocytes. Macrophages undertake a wide range of tasks, not just responsible for chasing down infectious pathogens, but also clearing molecular waste and cell debris, destroying problematic cells, and helping to coordinate regenerative processes following injury. Altered macrophage behavior is implicated in a range of age-related diseases, and this is also the case for changes that take place in the analogous cell population of microglia resident in the central nervous system. A better understanding of these alterations may lead to ways to restore a more youthful pattern of behavior in these cells.
Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related 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 (more than 50 years old) compared with younger (18-30 years old) donors, alongside downregulation of transcription factors MYC and USF1.
In MDMs from young donors, knockdown of MYC or USF1 decreases phagocytosis and chemotaxis and alters the expression of associated genes, alongside adhesion and extracellular matrix remodeling. A concordant dysregulation of MYC and USF1 target genes is also seen in MDMs from older donors. Furthermore, older age and loss of either MYC or USF1 in MDMs leads to an increased cell size, altered morphology, and reduced actin content. Together, these results define MYC and USF1 as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in aging.