Abstract

Aging is associated with cognitive decline and increased vulnerability to neurodegeneration driven by an array of molecular and cellular changes like impaired vascular integrity, demyelination, reduced neurogenesis, and chronic inflammation. Recent studies implicate the gut microbiome as a modulator of brain aging, but the underlying mechanisms remain elusive. Here, we show that depleting the gut microbiome by administering antibiotics to aged mice induces widespread molecular and structural rejuvenation in the brain. Our transcriptomic analyses by single-nucleus RNA sequencing revealed pronounced transcriptional shifts across multiple brain cell types. We confirmed that antibiotic treatment improves vascular density, promotes myelination, enhances neurogenesis, and reduces microglial reactivity. Functionally, microbiome-depleted mice showed improved hippocampal memory performance. Analyses of brain and plasma cytokine levels showed a decrease in several pro-inflammatory factors post-treatment and identified candidate factors, including the chemokine eotaxin-1. Inhibiting eotaxin-1 alone can reverse several aspects of brain aging. Our findings demonstrate that age-associated microbial inflammation contributes to brain aging and that its attenuation can restore youthful features at the molecular, cellular, and functional levels. Targeting the gut microbiome or its circulating mediators may therefore represent a non-invasive approach to promote brain health and cognitive resilience in aging.