Abstract
This study aimed to determine whether trimethylamine N-oxide (TMAO) was involved in sympathetic activation in aging and the underline mechanisms. Our hypothesis is that TMAO reduces P2Y12 receptor and induces microglia-mediated inflammation in the paraventricular nucleus, then leading to sympathetic activation in aging. Eighteen young adults (20-40 years old) and sixteen old adults (65-90 years old) were involved in the study. Aging rats were established by injecting D-galactose (200 mg/kg/d) subcutaneously for 12 weeks. TMAO (120 mg/kg/d) or 1% 3, 3-dimethyl-l-butanol (DMB, a structural analog of choline, inhibiting TMA formation) was administrated in drinking water for 12 weeks to investigate their effects on neuroinflammation and sympathetic activation in aging rats. Heart rate variability was analyzed by 24 h ambulatory ECG multichannel recording system (CT-083S Holter ECG recorder, BENEWARE, Hangzhou) in young and old adults. The PowerLab 15T data acquisition system (AD Instruments, Australia) was used to record blood pressure and renal sympathetic nerve activity in the rats. Plasma levels of TMAO, noradrenaline, and IL-1β in old adults were higher than those in young group. In addition, standard deviation of all normal to normal intervals and standard deviation of the average of normal to normal intervals were lower in old adults and negative correlated with TMAO, which indicating sympathetic activation in old adults and related to the increased TMAO. Rats treatment with D-gal showed increased senescence-associated protein, microglia-mediated inflammation levels and decreased P2Y12 receptor in the paraventricular nucleus. Plasma levels of TMAO, noradrenaline, and IL-1β were increased, accompanied by enhanced renal sympathetic nerve activity. While TMAO supplementation aggravated the above phenomenons, and DMB abated them. These findings suggested that TMAO might contribute to the sympathetic hyperactivity of aging via downregulating P2Y12 receptor in microglia and increasing inflammation in the paraventricular nucleus. These results may provide a new target for the prevention and treatment of aging and aging-related diseases. This work was supported by the Program for the National Natural Science Foundationof China (32271155 and 31671185), the Science and Technology Project of the Hebei Education Department (ZD2021076), the Youth Top Talent Foundation of Hebei Province of China and the Program of Clinical Medicine Innovation Research Team of Hebei Medical University (2022LCTD-A1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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