Extensive sex-dimorphism in age-related transcriptional remodeling in mouse peritoneal macrophages

Abstract

Abstract Chronic low-level inflammation is one of the hallmarks of aging. In addition, age-related diseases share common inflammatory mechanisms, a phenomenon named “inflamm-aging”. To date, the effect of age and sex on the genomic landscape of macrophages is largely unexplored, especially regarding sex-dimorphic trajectories in aging macrophages. Based on accumulating evidence indicating aging is highly sex-dimorphic, we hypothesize that aging will affect the phenotype of immune cells, such as macrophages, in a sex-dimorphic manner. To test our hypothesis, we used female and male C57BL/6N mice aged 4 and 20 months to investigate resident peritoneal macrophages. We generated RNA-seq data from purified peritoneal macrophages and identified genes modulated with aging as a function of sex. Complementing this ‘omic’ dataset, we performed an array of functional assays for these cells in several cohorts of aging mice, including immunophenotyping, metabolic profiling, lysosomal acidification tracking, phagocytic efficiency, etc. We observed sex-dependent functional decline, such as a male-specific decrease in macrophage ability to acidify lysosomes upon exposure to Zymosan. Interestingly, aspects of age-related functional changes may be mediated by age-related changes in circulating sex hormones. We are currently analyzing our single cell RNA-seq datasets from peritoneal lavages of naïve aging female and male mice, and generating complementary datasets that are profiling chromatin-level changes to identify putative drivers of age-related transcriptional and functional remodeling in macrophages. Ultimately, this project will help delineate sex dimorphic mechanisms modulating “inflamm-aging”.