Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, restructures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.

Methionine restriction (MR) extends lifespan and delays the onset of aging-associated pathologies. However, the effect of MR on age-related cognitive decline remains unclear. Here, we find that a 3-month MR ameliorates working memory, short-term memory, and spatial memory in 15-month-old and 18-month-old mice by preserving synaptic ultrastructure, increasing mitochondrial biogenesis, and reducing the brain MDA level in aged mice hippocampi. Transcriptome data suggest that the receptor of fibroblast growth factor 21 (FGF21)-related gene expressions were altered in the hippocampi of MR-treated aged mice. MR increased FGF21 expression in serum, liver, and brain. Integrative modelling reveals strong correlations among behavioral performance, MR altered nervous structure-related genes, and circulating FGF21 levels. Recombinant FGF21 treatment balanced the cellular redox status, prevented mitochondrial structure damages, and upregulated antioxidant enzymes HO-1 and NQO1 expression by transcriptional activation of Nrf2 in SH-SY5Y cells. Moreover, knockdown of Fgf21 by i.v. injection of adeno-associated virus abolished the neuroprotective effects of MR in aged mice. In conclusion, the MR exhibited the protective effects against age-related behavioral disorders, which could be partly explained by activating circulating FGF21 and promoting mitochondrial biogenesis, and consequently suppressing the neuroinflammation and oxidative damages. These results demonstrate that FGF21 can be used as a potential nutritional factor in dietary restriction-based strategies for improving cognition associated with neurodegeneration disorders.

Scope Methionine restriction (MR) is known to potently alleviate inflammation and improve gut microbiome in obese mice. The gut microbiome exhibits diurnal rhythmicity in composition and function, and this, in turn, drives oscillations in host metabolism. High‐fat diet (HFD) strongly altered microbiome diurnal rhythmicity, however, the role of microbiome diurnal rhythmicity in mediating the improvement effects of MR on obesity‐related metabolic disorders remains unclear. Methods and results 10‐week‐old male C57BL/6J mice are fed a low‐fat diet or HFD for 4 weeks, followed with a full diet (0.86% methionine, w/w) or a methionine‐restricted diet (0.17% methionine, w/w) for 8 weeks. Analyzing microbiome diurnal rhythmicity at six time points, the results show that HFD disrupts the cyclical fluctuations of the gut microbiome in mice. MR partially restores these cyclical fluctuations, which lead to time‐specifically enhance the abundance of short‐chain fatty acids producing bacteria, increases the acetate and butyric, and dampens the oscillation of inflammation‐related Desulfovibrionales and Staphylococcaceae over the course of 1 day. Notably, MR, which protects against systemic inflammation, influences brain function and synaptic plasticity. Conclusion MR could serve as a potential nutritional intervention for attenuating obesity‐induced cognitive impairments by balancing the circadian rhythm in microbiome‐gut‐brain homeostasis.

Sesamol, a lignan in sesame, possesses several bioactivities, such as antioxidation, anti-inflammation, and neuroprotective capability. In this study, the effects of sesamol on aging-caused cognitive defects are investigated. Twelve-monthold mice were treated with sesamol (0.1%, w/w) as dietary supplementation for 12 weeks. Behavioral tests revealed that sesamol improved aging-associated cognitive impairments. Sesamol decreased aging-induced oxidative stress via suppression of malondialdehyde production and increased antioxidant enzymes. Histological staining showed that sesamol treatment improved aging-induced neuronal damage and synaptic dysfunction in the hippocampus. Furthermore, sesamol significantly reduced aginginduced neuroinflammation by inhibiting the microglial overactivation and inflammatory cytokine expressions. Meanwhile, the accumulation of Aβ 1−42 was reduced by sesamol treatment. Moreover, sesamol protected the gut barrier integrity and reduced LPS release, which was highly associated with its beneficial effects on behavioral and inflammatory changes. In conclusion, our findings indicated that the use of sesamol is feasible in the treatment of aging-related diseases.

The circadian clock is an intrinsic mechanism of biological adaptation to the cyclical changes of the environment. The circadian rhythm disorders affect the life activities of organisms. A variety of phytochemicals (e.g., polyphenols, flavonoids, alkaloids, and melatonin) reportedly can regulate the expression and rhythm of circadian clock genes and stabilize the internal environment. This perspective focuses on the relationship of circadian clock genes with oxidative stress, inflammatory response, and metabolic disorders and emphasizes the regulation of phytochemicals on the circadian clock. Potential mechanisms and applications of supplemental phytochemicals to improve metabolic disorders and circadian rhythm disorders are also discussed.