Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N-6-carboxymethyllysine

Due to a microbiota-dependent increase in intestinal permeability with age, the gut metabolite N-6-carboxymethyllysine accumulates in the microglia of mouse and human brains. As a result, microglia display increased oxidative stress and mitochondrial dysfunction. Microglial function declines during aging. The interaction of microglia with the gut microbiota has been well characterized during development and adulthood but not in aging. Here, we compared microglial transcriptomes from young-adult and aged mice housed under germ-free and specific pathogen-free conditions and found that the microbiota influenced aging associated-changes in microglial gene expression. The absence of gut microbiota diminished oxidative stress and ameliorated mitochondrial dysfunction in microglia from the brains of aged mice. Unbiased metabolomic analyses of serum and brain tissue revealed the accumulation of N-6-carboxymethyllysine (CML) in the microglia of the aging brain. CML mediated a burst of reactive oxygen species and impeded mitochondrial activity and ATP reservoirs in microglia. We validated the age-dependent rise in CML levels in the sera and brains of humans. Finally, a microbiota-dependent increase in intestinal permeability in aged mice mediated the elevated levels of CML. This study adds insight into how specific features of microglia from aged mice are regulated by the gut microbiota.

Automated summary

This study reveals that the gut microbiota plays a role in age-related changes in microglial gene expression and function. The absence of gut microbiota improves oxidative stress and mitochondrial dysfunction in microglia from aging brains. Additionally, the accumulation of N-6-carboxymethyllysine (CML) in microglia leads to increased reactive oxygen species and impaired mitochondrial activity and ATP reservoirs. These findings provide insights into the regulation of microglial features by the gut microbiota in aged mice and humans.