Persistent ER stress in macrophages fuels age-related inflammation and vulnerability to infection

Aging is accompanied by a state of chronic, low-grade inflammation known as inflammaging that underlies increased susceptibility to infection and many age-related pathologies. Although macrophages are central to immune regulation and inflammation, the molecular mechanisms driving their age-associated dysfunction remain incompletely defined. Here, we performed bulk RNA-sequencing on FACS-sorted peritoneal macrophages from young and aged mice. Analysis of differentially expressed genes revealed that genes upregulated in aged macrophages were significantly enriched for pathways related to "response to interferon-beta" and "response to interferon-gamma". Further investigation of our RNA-seq data for upstream mediators of these genes showed that Stat1 was markedly upregulated in aged macrophages. These transcriptomic findings suggest that the chronic activation of ER UPR in aged macrophages drives an enhanced ISG program, representing a potential mechanism for inflammaging.