Outcomes of the lifestyle on microglial aging and neurodegenerative diseases along the aging trajectory: diet and the gut-brain axis

The microbiota-gut-brain axis (MGBA) has emerged as a key regulator of microglial development, homeostasis, and inflammatory function across ageing and in neurodegenerative diseases. Gut-derived signals, including microbial metabolites and neurotransmitters modulate microglia reactivity through neural and systemic pathways involving processes such as short chain fatty acid-mediated epigenetic regulation, tryptophan/aryl hydrocarbon receptor signalling, bile acid receptor activation, and innate immunity. Age-related gut dysbiosis and Western-style dietary patterns disrupt microbial diversity, impair metabolite production, and promote systemic inflammation, collectively priming microglia toward dysfunctional, pro-inflammatory phenotypes associated with cognitive decline and neurodegeneration. In contrast, dietary patterns rich in fibre, polyphenols, and omega-3 fatty acids, particularly the Mediterranean diet increase neuroprotective metabolites that support microglial homeostasis and reduce neuroinflammation. The use of MGBA-targeted interventions such as probiotics, prebiotics and synbiotics are currently under investigation and show promising effects for microglial homeostasis and neuronal health. While mechanistic insights from preclinical models highlight causal links between microbial products and microglial reactivity, human evidence remains largely correlational. Advances in single-cell omics, spatial transcriptomics, gnotobiotic approaches, and in vivo microglial imaging now enable high-resolution characterization of MGBA-driven microglial states and support the development of targeted interventions, including engineered probiotics. Future therapeutic strategies will require personalized integration of host genetics, microbiome composition, and dietary context to harness MGBA modulation for healthy brain ageing and mitigation of neurodegenerative disease.