Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs

Moss, Charlotte E. and Johnston, Simon A. and Kimble, Joshua V. and Clements, Martha and Codd, Veryan and Hamby, Stephen and Goodall, Alison H. and Deshmukh, Sumeet and Sudbery, Ian and Coca, Daniel and Wilson, Heather L. and Kiss-Tóth, Endre (2024) Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs. CELL REPORTS, 43 (4). ISSN 2639-1856

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Abstract

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 (>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.

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