Jianfei Mu, Qinlu Lin, Shuang Wang, Mingfeng Chen, Jian‐qiang Wang, Yajuan Chen, Yusheng Li, Ying Liang
Aging-related neuroinflammation drives cognitive decline; however, the mechanisms by which gut microbiota-modulating bioactive compounds, such as rice bran peptide KF-8, mitigate this process remain unclear. Here, KF-8 was shown to ameliorate age-related traits in aged mice by reshaping gut microbiota, notably by stabilizing Akkermansia muciniphila (AKK), to suppress systemic inflammation and cognitive deficits. Specifically, antibiotic-treated mice receiving KF-8 exhibited neuroinflammation and declined cognition. KF-8 and AKK synergistically attenuated pro-inflammatory pathways, particularly TNF-α, in the blood and in the hippocampus. While TNF-α antibodies mirrored KF-8's benefits, TNF-α recombinant protein negated KF-8's protective effects. Combined KF-8 and AKK interventions aligned with TNF-α antibody outcomes, underscoring TNF-α's pivotal role. Our findings reveal that KF-8 enhances healthy aging by modulating gut microbiota, sustaining AKK, and suppressing TNF-α-driven neuroinflammation, thereby rescuing cognitive function in aged mice.