Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs
Charlotte E. Moss,
Simon A. Johnston,
Joshua V. Kimble,
Martha Clements,
Veryan Codd,
Stephen Hamby,
Alison H. Goodall,
Sumeet Deshmukh,
Ian Sudbery,
Daniel Coca,
Heather L. Wilson,
Endre Kiss-Toth
Affiliations
Charlotte E. Moss
Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Healthy Lifespan Institute, University of Sheffield, Sheffield, UK
Simon A. Johnston
Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
Joshua V. Kimble
Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Healthy Lifespan Institute, University of Sheffield, Sheffield, UK
Martha Clements
Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
Veryan Codd
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; National Institute for Healthcare Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
Stephen Hamby
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; National Institute for Healthcare Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
Alison H. Goodall
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; National Institute for Healthcare Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
Sumeet Deshmukh
School of Biosciences, University of Sheffield, Sheffield, UK
Ian Sudbery
School of Biosciences, University of Sheffield, Sheffield, UK
Daniel Coca
Healthy Lifespan Institute, University of Sheffield, Sheffield, UK; Department of Autonomic Control and Systems Engineering, University of Sheffield, Sheffield, UK
Heather L. Wilson
Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Healthy Lifespan Institute, University of Sheffield, Sheffield, UK; Corresponding author
Endre Kiss-Toth
Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Healthy Lifespan Institute, University of Sheffield, Sheffield, UK; Biological Research Centre, Szeged, Hungary; Corresponding author
Summary: 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.
