Soluble fermentable dietary fiber attenuates age-related cognitive impairment via neuroimmune and antioxidant modulation: evidence from multilevel analyses in populations and aging mouse models.

Abstract

BACKGROUND: Age-related cognitive impairment (ARCI) is an urgent public health concern with limited therapeutic options. Soluble fermentable dietary fiber (SFDF) is a safe, accessible nutritional factor that may support cognition through microglial remodeling and antioxidant defense, but its dose-response effects and cellular mechanisms remain unclear. METHODS: We combined three levels of evidence (1). In 2,350 older adults from NHANES (2011-2014), weighted regression and spline modeling assessed the association between total dietary fiber intake and cognitive performance. (2) In a D-galactose-induced aging mouse model, inulin supplementation (as a representative SFDF) was tested for effects on behavior, cytokines, and oxidative stress. (3) We analyzed an independent single-nucleus RNA-seq dataset of naturally aged mice receiving a 5% SFDF intervention to characterize microglial state remodeling. RESULTS: Higher total dietary fiber intake was nonlinearly associated with better cognition, with ~15 g/day as the threshold for maximal benefit. In mice, SFDF improved memory and learning, alleviated anxiety-like behavior, reduced IL-6, TNF-α, and lipid peroxidation, and enhanced antioxidant defenses. Single-nucleus analyses indicated that the 5% SFDF intervention was associated with a shift toward a reparative Mic.7 microglial subtype enriched for immune regulation and oxidative defense programs. CONCLUSIONS: These convergent population, animal, and single-cell findings support a model in which higher total dietary fiber intake is associated with better late-life cognition, and SFDF interventions can attenuate aging-related neuroimmune activation and oxidative stress in experimental systems, highlighting dietary fiber as a scalable nutritional strategy to support healthy cognitive aging.