Antibiotic treatment that eliminates gut bacteria reversed key hallmarks of brain aging in old mice, improving hippocampal memory performance while restoring vascular density, promoting myelination, enhancing neurogenesis, and reducing microglial reactivity. Single-nucleus RNA sequencing revealed widespread transcriptional changes across brain cell types, with decreased pro-inflammatory cytokines including the chemokine eotaxin-1, which alone could reverse several aging markers when inhibited. This counterintuitive finding challenges the prevailing view that beneficial gut bacteria are universally protective throughout life. The results suggest that aged microbiomes may shift toward inflammatory profiles that accelerate brain decline—a stark contrast to the microbiome's beneficial role in younger organisms. While promising for identifying therapeutic targets like eotaxin-1, this mouse study raises complex questions about microbiome interventions in humans, where complete depletion would eliminate beneficial functions like pathogen resistance and nutrient synthesis. The work represents a paradigm-shifting discovery that age-related microbial inflammation directly contributes to cognitive decline, potentially opening new therapeutic avenues through selective microbiome modulation rather than broad elimination.