DOI: 10.4103/agingadv.agingadv-d-25-00048 ISSN: 3050-6735
Effects of caloric restriction on cognitive function, inflammation, and the gut microbiota in aged mice fed a high-fat diet
Fei Zhang, Lanping Cao, Shiyu He, Jianping Su, Ying Li, Rui Liang, Zhengxing Li, Long Xiao, Yiyang Wu, Boyuan Sun, Qianyun Feng, Chao Ying JOURNAL/agad/04.03/02274129-202610000-00002/figure1/v/2026-10-29T020439Z/r/image-tiff
Objectives:
Aging and a high-fat diet have synergistic damaging effects, accelerating multi-system functional decline and gut microbiota dysbiosis. Time-restricted feeding, an emerging dietary intervention, has been shown to improve metabolism. However, its specific effects and underlying mechanisms in a composite aging and high-fat diet model remain unclear. This study aimed to investigate whether time-restricted feeding could mitigate the synergistic damage caused by aging and a high-fat diet, focusing on its potential role in modulating the gut microbiota.
Methods:
A composite aging model was established in C57BL/6J mice via intraperitoneal injection of D-galactose (Gal) combined with a high-fat diet feeding. Thirty-two mice were randomly assigned to four groups (
n
= 8/group): normal control (Normal), aging model (Gal), high-fat aging model (HF-Gal), and time-restricted feeding intervention (CR-Gal, “8 + 16” feeding regimen). In the CR-Gal group, the 8 + 16 intermittent diet method was used, with free access to food from 9:00 a.m. to 5:00 p.m. every day, and the remaining 16 hours served as a strict fasting period. During the experimental period, body weight, blood lipids (triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), cognitive function (Morris water maze test), serum inflammatory markers (interleukin-1β, interleukin-6, and tumor necrosis factor-α), oxidative stress indicators (superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and malondialdehyde), and gut microbiota composition (16S rRNA sequencing) were systematically evaluated.
Results:
Compared with the normal group, the HF-Gal group presented significant increases in body weight, as reflected by a higher final body weight (35 g
vs
. 27 g,
P
< 0.01), an elevated fat mass/body weight ratio, and increased serum lipid levels, including a 160% increase in triglycerides (
P
< 0.01). In addition, inflammatory cytokine levels were markedly increased, with interleukin-1β rising to approximately 12 pg/mL (
P
< 0.01). The HF-Gal group also showed impaired cognitive performance, as indicated by prolonged escape latency on day 4 of the Morris water maze test (
P
< 0.05), and reduced gut microbiota α-diversity, as evidenced by a significant decrease in the abundance-based coverage estimator index (
P
< 0.001). CR-Gal significantly ameliorated these abnormalities: it reduced body weight and lipid levels (triglyceride levels decreased by 60% compared with that in the HFGal group,
P
< 0.01), decreased the expression of inflammatory markers (e.g., interleukin-1β levels decreased by 70%,
P
< 0.01), improved cognitive function (e.g., escape latency shortened by 20 seconds
vs.
that in the HFGal group,
P
< 0.05; target quadrant time increased by 133%,
P
< 0.01), and partially restored microbiota richness and diversity (abundance based coverage estimator index increased from 570 to 720
vs
. that in the HFGal group,
P
< 0.001). Correlation analysis revealed significant associations between specific microbiota changes (e.g., increased Firmicutes/Bacteroidetes ratios) and adverse host health indicators.
Conclusion:
Time-restricted feeding may mitigate the synergistic damage caused by aging and a high-fat diet, and this beneficial effect is associated with the modulation of the gut microbiota.