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.
摘要：
巨噬细胞是中枢先天免疫细胞，其功能随年龄增长而下降。与年龄相关的变化背后的分子机制仍然知之甚少，特别是在人类巨噬细胞中。我们报告了吞噬作用的大幅减少，迁移,与年轻（18-30岁）供体相比，来自年龄较大（>50岁）的人类单核细胞衍生巨噬细胞（MDMs）的趋化性，同时下调转录因子MYC和USF1。在年轻捐赠者的MDM中，MYC或USF1的敲除降低吞噬作用和趋化性，并改变相关基因的表达，伴随着粘附和细胞外基质重塑。MYC和USF1靶基因的一致失调也在来自老年供体的MDM中观察到。此外，年龄较大和MYC或USF1在MDM中的丢失导致细胞大小增加，形态学改变，和减少肌动蛋白含量。一起,这些结果将MYC和USF1定义为MDM年龄相关功能衰退的关键驱动因素,并确定了在衰老过程中改善巨噬细胞功能的下游靶标.
