Aging murine peritoneal macrophages undergo female-specific remodeling driven by hormone-dependent and independent mechanisms

Aging is a complex process characterized by a progressive decline in physiological functions driven by both biological and environmental factors, with notable differences between sexes. Immune function is strongly influenced by biological sex, affecting both innate and adaptive immune responses, including macrophage behavior. In this study, we investigated the effects of age and sex on the immune cell composition within the peritoneal cavity niche and identified macrophages as the most affected cell type. Macrophages, as central components of the innate immune system, play critical roles in maintaining tissue homeostasis and responding to infections. Here, we find that aging induces sex-specific remodeling of peritoneal macrophage transcriptomic and epigenomic landscapes. Consistently, peritoneal macrophages undergo sex-specific functional remodeling with aging (i.e. female-specific phagocytic decline and metabolic rewiring). Modulation of gonadal hormone signaling showed that changes in circulating estrogen levels likely contribute to aspects of female-specific macrophage age-related changes. Importantly, multi-omic analysis identified candidate transcription factors whose sex-specific age-regulated expression may drive aspects of sex-specific 'omic' remodeling with aging. Specifically, Irf2 downregulation in female macrophages recapitulates distinct transcriptomic and metabolic aspects of macrophage female aging phenotypes. These findings suggest that female-specific age-related functional remodeling arises through hormone-dependent and -independent mechanisms in peritoneal macrophages.