Mouse macrophages from diverse niches show generally divergent age-related transcriptional remodeling signatures

Abstract

Background: Aging is accompanied by widespread transcriptional remodeling across tissues, yet how aging impacts different categories of tissue-resident macrophages is not well understood. Macrophages are highly specialized innate immune cells shaped by their local microenvironments, suggesting that aging may elicit both shared and niche-specific transcriptional responses. Here, we performed a meta-analysis of publicly available bulk and single cell RNA-sequencing datasets to characterize age-associated transcriptional changes in murine macrophages across tissues and sexes. We curated and uniformly processed 33 macrophage transcriptomic datasets, derived from 10 distinct tissue niches, in male and female C57BL/6 mice using age as the covariate of interest. Results: The similarity of differentially expressed aging genes was compared across niches and pathway-level analyses uncovered conserved age-associated functional annotation signatures across macrophage populations, including increased antigen presentation, extracellular matrix remodeling, antioxidant responses, and negative regulation of ferroptosis, alongside decreased Wnt, GTPase, and cell-cycle-related signaling. Transcription factor activity inference analysis identified consistent age-associated activation of stress- and inflammation-related regulators such as AP-1 (Jun), Sp1, and Egr1 across niches. Meta-analysis further defined a core set of 35 genes consistently altered with age across mouse macrophage populations, highlighting coordinated dysregulation of small GTPase signaling as a shared feature of murine macrophage aging. Conclusions: These findings demonstrate that macrophage aging is shaped by both tissue niche and sex and provides a framework for understanding the transcriptomic signatures of macrophage aging across tissues.