ABSTRACT
CONTEXT: Aging is a major risk factor for various neurodegenerative diseases, and ferroptosis has been identified as an important mode of cell death during accelerated aging. As the main component of the edible plant YuZhu in China, Polygonatum polysaccharide (POP) is an important natural compound with anti-aging properties. OBJECTIVE: To evaluate the anti-aging effects of POP and the underlying molecular mechanisms involved and to evaluate the overall anti-aging effects of POP on cognitive impairment due to accelerated aging. MATERIALS AND METHODS: A D-galactose (D-gal)-induced accelerated aging rat model was established to evaluate the anti-aging effects of POP and the underlying molecular mechanisms involved. In turn, Morris water maze and open field experiments were used to evaluate the anti-aging effects of POP on cognitive impairment due to accelerated aging. RESULTS: The mechanism by which POP affects nuclear factor E2-related factor 2 (Nrf2), an essential transcription factor, was confirmed. POP significantly improved d-gal-induced cognitive dysfunction in treated model rats, which exhibited reduced pathological changes in the hippocampus, reduced latency of the water maze platform, and increased exploration time in the central area in the open field experiment compared to those of untreated model rats. Furthermore, POP intervention downregulated ferroptosis-related proteins and upregulated Nrf2 expression, and selective inhibition of Nrf2 eliminated the ability of POP to reduce ferroptosis. CONCLUSIONS: POP is a natural ingredient with therapeutic potential due to its ability to alleviate aging by activating Nrf2, inhibiting ferroptosis, and alleviating cognitive dysfunction.
ABSTRACT
The gut microbiota plays an important role in central nervous system (CNS) disorders. Apolipoprotein E (ApoE) can affect the composition of the gut microbiota and is closely related to the CNS. However, the mechanism by which ApoE affects cognitive dysfunction through the gut microbiota-brain axis has thus far not been investigated. In this study, we used wild-type mice and ApoE knockout (ApoE-/-) mice to replicate the aging model and examined the effects of ApoE deletion on cognitive function, hippocampal ultrastructure, synaptophysin (SYP) and postsynaptic density 95 (PSD-95) in aging mice. We also explored whether ApoE deletion affects the gut microbiota and the metabolite profile of the hippocampus in aging mice and finally examined the effect of ApoE deletion on lipids and oxidative stress in aging mice. The results showed that the deletion of ApoE aggravated cognitive dysfunction, hippocampal synaptic ultrastructural damage and dysregulation of SYP and PSD-95 expression in aging mice. Furthermore, ApoE deletion reduced gut microbial makeup in aging mice. Further studies showed that ApoE deletion altered the hippocampal metabolic profile and aggravated dyslipidemia and oxidative stress in aging mice. In brief, our findings suggest that loss of ApoE alters the composition of the gut microbiota, which in turn may affect cognitive function in aging mice through the gut microbiota-brain axis.
ABSTRACT
Background: Aging is an important cause of cognitive dysfunction. Liuwei Dihuang decoction (LW), a commonly applied Chinese medicine formula, is widely used for the treatment of aging-related diseases in China. Previously, LW was confirmed to be effective in prolonging life span and reducing oxidative stress in aged mice. Unfortunately, the underlying mechanism of LW remains unclear. The aim of this study was to interpret the mechanism by which LW alleviates cognitive dysfunction related to aging from the perspective of the microbiota-gut-brain axis. Method: All C57BL/6 mice (n = 60) were randomly divided into five groups: the control, model, vitamin E (positive control group), low-dose LW and high-dose LW groups (n = 12 in each group). Except for those in the control group, D-galactose was subcutaneously injected into mice in the other groups to induce the aging model. The antiaging effect of LW was evaluated by the water maze test, electron microscopy, 16S rRNA sequencing, combined LC-MS and GC-MS metabolomics, and ELISA. Results: Liuwei Dihuang decoction ameliorated cognitive dysfunction and hippocampal synaptic ultrastructure damage in aging mice. Moreover, LW decreased Proteobacteria abundance and increased gut microbiota diversity in aging mice. Metabolomic analysis showed that LW treatment was associated with the significantly differential abundance of 14 metabolites, which were mainly enriched in apelin signaling, sphingolipid metabolism, glycerophospholipid and other metabolic pathways. Additionally, LW affected lipid metabolism and oxidative stress in aging mice. Finally, we also found that LW-regulated microbial species such as Proteobacteria and Fibrobacterota had potential relationships with lipid metabolism, oxidative stress and hippocampal metabolites. Conclusion: In brief, LW improved cognitive function in aging mice by regulating lipid metabolism and oxidative stress through restoration of the homeostasis of the microbiota-gut-brain axis.
