Aging alters murine peritoneal macrophages in a sex-dimorphic fashion

Abstract

Abstract Aging is accompanied by general immune dysfunction, which is hypothesized to underlie the pathogenesis of many age-related diseases. In addition, there is accumulating evidence that aging is highly sex-dimorphic. However, the interactions of age and sex on the genomic and functional landscape of immune cells remain largely unexplored. To address this question, we have interrogated cells of the peritoneal cavity, an easily accessible immune niche, during aging in both sexes of C57BL/6 mice using single cell RNA-seq and flow cytometry. Interestingly, we found that macrophages were the most affected by age and sex among peritoneal immune cells, and that their frequency significantly dropped with aging. Macrophages are important for the initiating and resolving of inflammation, and dysfunction can contribute to inflammaging. Thus, we decided to further investigate the potentially sex-dimorphic impact of aging on the genomic landscape and function of peritoneal macrophages. We generated bulk 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 using purified peritoneal macrophages. We observed sex-dependent functional alterations, such as female-specific decrease in phagocytic ability. From our RNA-seq analysis, we identified potential regulators of phagocytosis that are significantly downregulated with age only in females. We are currently validating whether the potential regulators may indeed drive the observed female-specific decrease in phagocytic capabilities. Ultimately, this project will help delineate sex dimorphic mechanisms modulating immune aging. This work was supported by a Diana Jacobs Kalman/AFAR Scholarships for Research in the Biology of Aging and NIA T32 AG052374 (to R.J.L.), GCRLE-2020 post-doctoral fellowship from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, (to M.K.), and NIA R00 AG049934, Pew Biomedical Scholar award #00034120, an innovator grant from the Rose Hills foundation, and the Kathleen Gilmore Biology of Aging research award (to B.A.B). This work was also partially supported by NCI Cancer Center Support Grant P30 CA014089 through the use of shared resources.