Aging Drives Region-Specific Metabolic Changes in Gut Muscularis Macrophages

In the aging brain, altered metabolism in brain macrophages, known as microglia, results in a dysfunctional state characterized by lipid droplet (LD) accumulation linked to neurodegeneration. Akin to microglia, intestinal muscularis macrophages (MMs) function to support the enteric nervous system, which controls gut function.

Aging causes pro-inflammatory changes to MMs that drive neuronal loss and impair gut motility, however whether metabolic alterations are responsible is unclear. Using metabolomics, transcriptomics, flow cytometry, and microscopy, we show that aging induces metabolic reprogramming in small intestine MMs characterized by increased glycolysis, mitochondrial dysfunction, and LD accumulation. These changes correlate with reduced phagocytic activity and a pro-inflammatory phenotype, and selectively affect a ‘neuron-associated’ subset of MMs.