Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice |
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Authors: | Dang Li Yilang Ke Rui Zhan Changjie Liu Mingming Zhao Aiping Zeng Xiaoyun Shi Liang Ji Si Cheng Bing Pan Lemin Zheng Huashan Hong |
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Affiliation: | 1. Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China;2. The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education;3. Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health;4. Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China;5. Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China;6. China National Clinical Research Center for Neurological Diseases, Tiantan Hospital, The Capital Medical University, Beijing, China;7. Fujian Medical University Union Hospital, Fuzhou, China |
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Abstract: | Gut microbiota can influence the aging process and may modulate aging‐related changes in cognitive function. Trimethylamine‐N‐oxide (TMAO), a metabolite of intestinal flora, has been shown to be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24‐week‐old senescence‐accelerated prone mouse strain 8 (SAMP8) and age‐matched senescence‐accelerated mouse resistant 1 (SAMR1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR1‐control mice, SAMP8‐control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA3 region and cognitive dysfunction. Surprisingly, TMAO treatment increased the number of senescent cells, which were primarily neurons, and enhanced the mitochondrial impairments and superoxide production. Moreover, we observed that TMAO treatment increased synaptic damage and reduced the expression levels of synaptic plasticity‐related proteins by inhibiting the mTOR signalling pathway, which induces and aggravates aging‐related cognitive dysfunction in SAMR1 and SAMP8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age‐related cognitive dysfunction in SAMR1 mice and aggravate the cerebral aging process of SAMP8 mice, which might provide new insight into the effects of intestinal microbiota on the brain aging process and help to delay senescence by regulating intestinal flora metabolites. |
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Keywords: | brain aging cognitive function mammalian target of rapamycin neuron senescence oxidative stress trimethylamine‐N‐oxide |
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