Aging is a systemic physiological degenerative process, with alterations in gut microbiota and host metabolism. However, due to the interference of multiple confounding factors, aging-associated molecular characteristics have not been elucidated completely. Therefore, based on 16S ribosomal RNA (rRNA) gene sequencing and non-targeted metabolomic detection, our study systematically analyzed the composition and function of the gut microbiome, serum, and fecal metabolome of 36 male rhesus monkeys spanning from 3 to 26 years old, which completely covers juvenile, adult, and old stages. We observed significant correlations between 41 gut genera and age. Moreover, 86 fecal and 49 serum metabolites exhibited significant age-related correlations, primarily categorized into lipids and lipid-like molecules, organic oxygen compounds, organic acids and derivatives, and organoheterocyclic compounds. Further results suggested that aging is associated with significant downregulation of various amino acids constituting proteins, elevation of lipids, particularly saturated fatty acids, and steroids. Additionally, age-dependent changes were observed in multiple immune-regulatory molecules, antioxidant stress metabolites, and neurotransmitters. Notably, multiple age-dependent genera showed strong correlations in these changes. Together, our results provided new evidence for changing characteristics of gut microbes and host metabolism during aging. However, more research is needed in the future to verify our findings.

Stress is a risk factor for the development of various types of cancer. However, its impact and related underlying mechanisms in oral squamous cell carcinoma (OSCC) progression remain unclear. Therefore, the present study aimed to investigate how chronic stress affects OSCC progression. We assessed mitochondrial metabolism by investigating tumor growth and performing behavioral analysis and molecular assessment, including non-targeted metabolomics and U-13C5-glutamine isotope metabolic flow analysis. We knocked down glutamate dehydrogenase 1 (GLUD1) using lentiviral vectors and investigated it both in vitro (HSC3 and HN6 cells) and in vivo (xenograft models). Our results indicated that chronic stress enhanced glutamate oxidative deamination and tricarboxylic acid cycle metabolism in OSCC cells. It also increased α-ketoglutarate (α-KG) levels, adenosine triphosphate synthesis, and oxygen consumption. Notably, GLUD1-knockdown suppressed these metabolic pathways and significantly inhibited tumor growth both in vitro and in vivo. Furthermore, under chronic stress, GLUD1 regulated OSCC progression through histone H3 trimethylation at lysine 4. However, α-KG supplementation partially reversed GLUD1-knockdown-induced OSCC progression inhibition. Collectively, our results indicate that the glutamate-dependent metabolic phenotype regulated by the GLUD1—α-KG metabolic axis is involved in the progression of OSCC under chronic stress.

The potential association between short-chain fatty acids (SCFAs) and aging has gained increasing research attention. Although most studies have focused on fecal SCFAs, limited attention has been directed toward SCFAs in peripheral blood. Furthermore, this relationship remains insufficiently explored in non-human primate models. Serum samples were collected from eighty-five healthy Macaca mulatta. Serum SCFA concentrations were quantified using targeted gas chromatography-mass spectrometry. A subset of samples (19 males and 19 females) was further analyzed for reproductive and stress-related hormones using enzyme-linked immunosorbent assay kits. Significant age-related alterations in SCFA concentrations were identified. Isobutyric acid levels increased with age, whereas acetic acid, propionic acid, and valeric acid levels decreased. Moreover, the direction of SCFA alterations differed between males and females. Integrated analysis with hormone assays demonstrated that these sex-specific differences in SCFAs were closely associated with the activity of the hypothalamic-pituitary-gonadal axis. Serum SCFA profiles varied significantly with both age and sex. The secretion of reproductive and stress-related hormones was highly correlated with these differences. These findings provide new insights into how aging influences sex-dependent SCFA metabolism and may contribute to understanding the mechanisms underlying age- and sex-related physiological changes.

Depression is a complex disorder with multiple contributing factors, and chronic stress has previously been recognized as a major causative factor, while gut microbes have also been found to be involved in depression recently. However, gene expression in depression models with different etiologies is unclear. Here, we compared the transcriptomes of the striatum in chronic social defeat stress (CSDS) model of C57BL/6J male mice and fecal microbiota transplant (FMT) model of Kumming male mice. We found that the proportion of shared differentially expressed genes (DEGs) between the two models was only 24 %. The specific DEGs of FMT model were enriched in immune and inflammatory, and are associated with changes in vascular and ciliated ependymal cells. The specific DEGs of CSDS model were enriched in neuron and synapse. The results of network analysis suggested the expression patterns and biological function of depressive-like behaviors-related modules in the two models are different. Further, the alternative splicing events of CSDS are more than FMT. Our results suggested models of depression induced by different etiologies differ significantly in gene expression and biological function. Our study also suggested us to pay attention to the characteristics of models of depression of different etiologies and provided a more comprehensive understanding of the heterogeneity of depression.