Microbiome-Metabolomics Reveals the Bidirectional Associations Between Aging and Depression

Aging increases the susceptibility to depression, and depression accelerates the aging process of body. However, it is needed to be studied deeply that the connotations of the correlation between aging and depression. By integrally applying metabolome and microbiome techniques, the study aimed to explore underlying mechanisms of bidirectional associations between aging and depression. Aging rat model and depression rat model were carried out. Classical behaviors were measured to assess the impacts of aging and depression on rats. On top of this, potential changes in the organism are revealed to elucidate the bi-directional associations between aging and depression based on the 16S rRNA sequencing of gut flora and ¹H-NMR of gut metabolites, respectively. Depression weakened the ability of autonomous activities, spatial memory, and gastrointestinal functions of rats, which are also closely related to aging. Vice versa, aging also weakens the autonomous activities of rats, which frequently appears in depression. Secondly, valine, propionate, etc. are potential fecal metabolites that are commonly shared by aging and depression, and these metabolites are closely related to changes in gut microbiota composition. Lastly, both aging and depression decreased the ratio of Firmicutes to Bacteroidetes. Spearman's analysis found that a variety of metabolites, including proline, strongly correlated with Lactobacillus and Corynebacterium, suggesting that these bacterial species play a significant role in the metabolic changes observed in both aging and depression. Meanwhile, differential metabolites and gut microbiota were strongly associated with the number of rearings and gastrointestinal movement of rats, suggesting that potential associations between aging and depression remarkably occur at multiple levels. Exploring the bidirectional association of aging and depression from the perspectives of metabolome and microbiome will not only deepen our understanding of aging and depression, but also provide novel ideas for clinically treating the co-existence and co-occurrence of aging with depression.

The online version contains supplementary material available at 10.1007/s12088-025-01538-0.