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

TL;DR

Eating more soluble fermentable dietary fiber may help prevent age-related cognitive decline by reducing brain inflammation and boosting antioxidants, according to studies in people and mice.

Contribution

This study provides multi-level evidence showing how soluble fermentable dietary fiber improves cognition through microglial and antioxidant mechanisms.

Findings

Higher dietary fiber intake (~15 g/day) was linked to better cognition in older adults.

In mice, SFDF reduced inflammation and oxidative stress while improving memory and learning.

Single-cell analysis showed SFDF promotes a brain-protective microglial subtype.

Abstract

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.

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.

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.

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.

This study adopted a multi-level design to investigate the role of soluble fermentable dietary fiber (SFDF) in age-related cognitive impairment. (I) Population analysis: Using NHANES 2011–2014 data (n=2,350; age ≥60), survey-weighted regression and restricted cubic spline models were applied to examine associations between total dietary fiber intake and multiple cognitive domains, with prespecified stratified analyses by sex, education, and smoking status. (II) A D-galactose–induced accelerated aging mouse model was established to evaluate the effects of SFDF supplementation (5% inulin as a representative SFDF) on behavior, neuroinflammation, and oxidative stress. (III) Mechanistic exploration: Single-nucleus transcriptomic sequencing combined with trajectory inference and network analyses was used to characterize microglial subtypes, lineage transitions, and functional remodeling under SFDF intervention. Created in BioRender. He, Y. (2026) https://BioRender.com/lt3y2t9.Infographic detailing SFDF's cognitive protection through microglial remodeling and anti-inflammatory modulation. Left: NHANES fiber intake and cognition analysis. Center: D-galactose mouse model shows improved cognition, reduced inflammation, oxidative stress after SFDF and inulin intervention. Right: Single-nucleus transcriptomics reveals microglial subtype trajectories and remodeling.

This study adopted a multi-level design to investigate the role of soluble fermentable dietary fiber (SFDF) in age-related cognitive impairment. (I) Population analysis: Using NHANES 2011–2014 data (n=2,350; age ≥60), survey-weighted regression and restricted cubic spline models were applied to examine associations between total dietary fiber intake and multiple cognitive domains, with prespecified stratified analyses by sex, education, and smoking status. (II) A D-galactose–induced accelerated aging mouse model was established to evaluate the effects of SFDF supplementation (5% inulin as a representative SFDF) on behavior, neuroinflammation, and oxidative stress. (III) Mechanistic exploration: Single-nucleus transcriptomic sequencing combined with trajectory inference and network analyses was used to characterize microglial subtypes, lineage transitions, and functional remodeling under SFDF intervention. Created in BioRender. He, Y. (2026) https://BioRender.com/lt3y2t9.

Figures