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Updated: Jun 29, 2025
Reprograming Model of Human Monocyte-derived Macrophages for In-vitro Assays
Published on: April 18, 2025
Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs
Charlotte E Moss1, Simon A Johnston2, Joshua V Kimble1
1Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Healthy Lifespan Institute, University of Sheffield, Sheffield, UK.
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.
Insights
Aging impairs macrophage function, reducing phagocytosis and migration. This decline is linked to lower levels of transcription factors MYC and USF1, crucial for immune cell activity.
Area of Science:
- Immunology
- Cell Biology
- Aging Research
Background:
- Macrophages are vital innate immune cells.
- Their function deteriorates with advanced age.
- Mechanisms of age-related decline in human macrophages are not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms behind age-related functional decline in human macrophages.
- To identify key molecular players involved in these changes.
Main Methods:
- Comparison of human monocyte-derived macrophages (MDMs) from young (18-30 years) and older (>50 years) donors.
- Assessment of phagocytosis, migration, and chemotaxis.
- Gene expression analysis, including transcription factors MYC and USF1.
- Knockdown experiments for MYC and USF1 in young MDMs.
Main Results:
- Older MDMs showed reduced phagocytosis, migration, and chemotaxis compared to younger MDMs.
- Downregulation of transcription factors MYC and USF1 was observed in older MDMs.
- Knockdown of MYC or USF1 in young MDMs mimicked age-related functional deficits.
- Dysregulation of MYC and USF1 target genes was evident in older MDMs.
- Older age and loss of MYC/USF1 led to increased cell size, altered morphology, and reduced actin.
Conclusions:
- MYC and USF1 are key regulators of age-related functional decline in human macrophages.
- These transcription factors and their downstream targets are potential therapeutic targets for improving macrophage function in aging individuals.
