Lu Ryan J, Chen Shiqi, Kim Minhoo, Sampathkumar Nirmal K, Lee Evelyn H, Christensen Amy, Wang Eric E, Lau Isabella Y, Parihar Shivay, Ravikumar Charan K, Jung Jane, Brown Shelby, Xu Alan, Alvarenga Julio L, Mehalko Kristen, Lee Changhan D, Goodridge Helen S, Benayoun Bérénice A
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Graduate Program in the Biology of Aging, University of Southern California, Los Angeles, CA 90089, USA.
bioRxiv. 2025 Jun 27:2025.06.11.659200. doi: 10.1101/2025.06.11.659200.
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 murine peritoneal macrophage transcriptomic and epigenomic landscapes. Consistently, peritoneal macrophages undergo sex-specific functional remodeling with aging (. 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.
衰老 是一个复杂的过程，其特征是在生物和环境因素的驱动下生理功能逐渐衰退，且存在明显的性别差异。免疫功能受生物性别影响很大，会影响先天性和适应性免疫反应，包括巨噬细胞的行为。在本研究中，我们调查了年龄和性别对腹腔微环境中免疫细胞组成的影响，并确定巨噬细胞是受影响最大的细胞类型。巨噬细胞作为先天性免疫系统的核心组成部分，在维持组织稳态和应对感染方面发挥着关键作用。在此，我们发现衰老会诱导小鼠腹腔巨噬细胞转录组和表观基因组景观的性别特异性重塑。一致地，随着衰老，腹腔巨噬细胞会发生性别特异性功能重塑（. 雌性特异性吞噬能力下降和代谢重编程）。性腺激素信号的调节表明，循环雌激素水平的变化可能是雌性特异性巨噬细胞与年龄相关变化的一个原因。重要的是，多组学分析确定了候选转录因子，其性别特异性年龄调节表达可能驱动随着衰老出现的性别特异性“组学”重塑。具体而言，雌性巨噬细胞中Irf2的下调概括了巨噬细胞雌性衰老表型的不同转录组和代谢特征。这些发现表明，雌性特异性与年龄相关的功能重塑是通过腹腔巨噬细胞中激素依赖性和非依赖性机制产生的。
