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Life sciences · Journal article
International Journal of Molecular Sciences · September 30, 2026
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Midlife obesity is an established independent risk factor for age-related cognitive decline, yet direct causal experimental evidence and underlying gut microbial mechanisms remain poorly defined. Using a mouse model of high-fat diet (HFD)-induced obesity restricted to the midlife period (6–12 months of age) in male wild-type C57BL/6J mice, we characterized the temporal and causal relationship between midlife weight gain and cognitive deterioration, and investigated the mediating function of Akkermansia muciniphila (Akk). Longitudinal body weight tracking across the lifespan revealed a stage-specific dynamic pattern, with sustained adipose tissue accumulation occurring during the midlife period (6–12 months of age). Midlife HFD exposure triggered multi-dimensional cognitive deficits accompanied by significant depletion of intestinal Akk, while oral supplementation of Akk effectively attenuated HFD-induced weight gain and ameliorated spatial, recognition and contextual memory impairments. Mechanistically, Akk suppressed hippocampal glial hyperactivation and proinflammatory factor upregulation, attenuated neuronal loss, and preserved hippocampal synaptic integrity. Serum metabolomics further identified midlife-specific metabolic remodeling characterized by dysregulated lipid metabolism and depleted microbiota-derived indole metabolites. Our findings establish a causal link between midlife obesity and accelerated cognitive aging, and identify Akk as a promising early intervention target for age-related cognitive decline.