Life sciences · 2026
Trimethylamine N-oxide drives cardiac aging by activating NLRP3-mediated pyroptosis.
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Qiu Zhaoxu, Zhang Huaxing, Tan Bo, Chen Qian, Gao Huizi, Yao Yuhan, Peng Yangxuan, Xue Hongmei, Guo Qi, Tian Danyang, Xiao Lin, Teng Xu, Ma Yanzhuo, Wu Yuming, Jin Sheng
Аннотация
AIMS: The present study was aimed to investigate whether trimethylamine N-oxide (TMAO) contributed to cardiac aging and to explore the underlying mechanism.
MATERIALS AND METHODS: Male C57BL/6 J mice were randomly divided into four age groups (3, 12, 18, and 24 months) to assess the cardiac function. Markers of senescence, oxidative stress, and the protein expression of pyroptosis were also measured. To test the hypothesis that TMAO promoted cardiac aging, 8-week-old mice were intraperitoneally injected with TMAO for 1-3 months and 3,3-dimethyl-1-butanol was administered in drinking water starting from 15 months of age for three months to inhibit TMAO production. Gasdermin D (GSDMD) knockout mice were also used.
KEY FINDINGS: Plasma TMAO levels increased with age and correlated with upregulation of cardiac senescence markers, diastolic dysfunction, cardiac fibrosis, and elevated plasma brain natriuretic peptide levels. Starting from 2 months of TMAO treatment, impairment of cardiac diastolic function and progression of cardiac fibrosis were observed alongside the upregulation of senescence marker proteins expression. Mechanistically, TMAO promoted cardiac oxidative stress and activated the NLRP3-mediated pyroptosis pathway. Genetic ablation of GSDMD abolished TMAO-associated cardiac aging. Furthermore, pharmacological inhibition of TMAO production in aged mice attenuated oxidative stress, suppressed NLRP3-mediated pyroptosis activation, and alleviated cardiac aging.
SIGNIFICANCE: This study revealed that plasma TMAO levels progressively increase with age in mice and TMAO contributed to cardiac aging in a time-dependent manner through NLRP3-mediated pyroptosis driven by oxidative stress. Moreover, the inhibition of TMAO generation might offer a basis for future therapeutic strategies.
MATERIALS AND METHODS: Male C57BL/6 J mice were randomly divided into four age groups (3, 12, 18, and 24 months) to assess the cardiac function. Markers of senescence, oxidative stress, and the protein expression of pyroptosis were also measured. To test the hypothesis that TMAO promoted cardiac aging, 8-week-old mice were intraperitoneally injected with TMAO for 1-3 months and 3,3-dimethyl-1-butanol was administered in drinking water starting from 15 months of age for three months to inhibit TMAO production. Gasdermin D (GSDMD) knockout mice were also used.
KEY FINDINGS: Plasma TMAO levels increased with age and correlated with upregulation of cardiac senescence markers, diastolic dysfunction, cardiac fibrosis, and elevated plasma brain natriuretic peptide levels. Starting from 2 months of TMAO treatment, impairment of cardiac diastolic function and progression of cardiac fibrosis were observed alongside the upregulation of senescence marker proteins expression. Mechanistically, TMAO promoted cardiac oxidative stress and activated the NLRP3-mediated pyroptosis pathway. Genetic ablation of GSDMD abolished TMAO-associated cardiac aging. Furthermore, pharmacological inhibition of TMAO production in aged mice attenuated oxidative stress, suppressed NLRP3-mediated pyroptosis activation, and alleviated cardiac aging.
SIGNIFICANCE: This study revealed that plasma TMAO levels progressively increase with age in mice and TMAO contributed to cardiac aging in a time-dependent manner through NLRP3-mediated pyroptosis driven by oxidative stress. Moreover, the inhibition of TMAO generation might offer a basis for future therapeutic strategies.