Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice
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Summary: 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 (SAMP 8) and age‐matched senescence‐accelerated mouse resistant 1 (SAMR 1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR 1‐control mice, SAMP 8‐control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA 3 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 SAMR 1 and SAMP 8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age‐related cognitive dysfunction in SAMR 1 mice and aggravate the cerebral aging process of SAMP 8 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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In the brain, TMAO is detrimental to neuronal physiology as it induces neuronal senescence, oxidative stress, and alters synaptic plasticity.
“In the brain, TMAO is detrimental to neuronal physiology as it induces neuronal senescence, oxidative stress, and alters synaptic plasticity.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [668]
Mice treated with dietary TMAO show increased brain aging and cognitive impairment.
“mice treated with dietary TMAO show increased brain aging and cognitive impairment, likely due to increased oxidative stress, mitochondrial dysfunction, and inhibition of mammalian target of rapamycin (mTOR) signaling in the brain [11].”
From The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease (2018) · cites this paper as [11]
TMAO is implicated in oxidative stress enhancement, blood-brain barrier disruption, mitochondria dysfunction, brain aging and neurodegeneration.
“TMAO is an amine oxide product of the bacterial metabolism that has been implicated in oxidative stress enhancement, BBB disruption, mitochondria dysfunction, brain aging and neurodegeneration [105,106,107]”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [107]
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Choline Pathway Nutrients and Metabolites and Cognitive Impairment After Acute Ischemic Stroke
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- Authors
- Li, D., Ke, Y., Zhan, R., Liu, C., Zhao, M., Zeng, A., Shi, X., Ji, L., Cheng, S., Pan, B., Zheng, L., & Hong, H.
- Affiliations
- Union Hospital (CN)
- Peking University (CN)
- 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; Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Ministry of Health; Beijing Key Laboratory of Cardiovascular Receptors Research Beijing China
- Capital Medical University (CN)
- Corresponding author
- Zheng, Lemin
- Hong, Huashan
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2018-05-10
- Volume
- 17
- Issue
- 4
- Pages
- e12768-e12768
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC6052480
- OpenAlex
- W2800864806
- Cited by
- 304
- References
- 49
- Citations by year
- 2026: 32 · 2025: 46 · 2024: 52 · 2023: 50 · 2022: 60 · 2021: 33 · 2020: 19 · 2019: 11 · 2018: 1
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81570448, 91639108, 81370235, 81770272)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Antioxidants, Aging, Portulaca oleracea
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- trimethylamine N-oxide, brain aging, cognitive impairment, gut microbiota, cellular senescence, neuronal senescence, hippocampal CA3, mitochondrial dysfunction, superoxide, synaptic damage, synaptic plasticity, mTOR signaling, SAMP8 mice, SAMR1 mice
- MeSH terms
- Adolescent, Adult, Aged, Animals, Brain, Humans, Male, Methylamines, Middle Aged, Cellular Senescence, Mice, Young Adult, Cognitive Dysfunction
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