Aging drives region specific metabolic changes in gut muscularis macrophages

Muscularis macrophages (MMs) are tissue-resident macrophages embedded in the gut muscle layer that regulate neuromuscular function. We show that aging causes metabolic remodeling of select small intestine (SI) MM subpopulations that share homeostatic features with microglia. These MMs, which are characterized by lipid droplet accumulation, show increased glycolytic and lipid-handling features, mitochondrial stress, increased lysosomal content, elevated inflammatory gene expression, and reduced phagocytic activity. Unlike SI, colon MMs are relatively resistant to this lipid-accumulating phenotype. Together, these findings show that MM metabolic aging in the gut is specific to region and subset and suggest that local intestinal environments and MM heterogeneity shape macrophage vulnerability during aging.