Abstract：
This study aimed to determine whether trimethylamine N-oxide (TMAO) was involved in sympathetic activation in aging and the underlying mechanisms. Our hypothesis is TMAO reduces P2Y12 receptor (P2Y12R) and induces microglia-mediated inflammation in the paraventricular nucleus (PVN), then leading to sympathetic activation in aging. This study involved 18 young adults and 16 old adults. Aging rats were established by injecting D-galactose (D-gal, 200 mg/kg/d) subcutaneously for 12 weeks. TMAO (120 mg/kg/d) or 1% 3, 3-dimethyl-l-butanol (DMB) was administrated via drinking water for 12 weeks to investigate their effects on neuroinflammation and sympathetic activation in aging rats. Plasma TMAO, NE and IL-1β levels were higher in old adults than in young adults. In addition, standard deviation of all normal to normal intervals (SDNN) and standard deviation of the average of normal to normal intervals (SDANN) were lower in old adults and negatively correlated with TMAO, indicating sympathetic activation in old adults, which is associated with an increase in TMAO levels. Treatment of rats with D-gal showed increased senescence-associated protein levels and microglia-mediated inflammation, as well as decreased P2Y12R protein levels in PVN. Plasma TMAO, NE and IL-1β levels were increased, accompanied by enhanced renal sympathetic nerve activity (RSNA). While TMAO treatment exacerbated the above phenomenon, DMB mitigated it. These findings suggest that TMAO contributes to sympathetic hyperactivity in aging by downregulating P2Y12R in microglia and increasing inflammation in the PVN. These results may provide promising new target for the prevention and treatment of aging and aging-related diseases.
摘要：
这项研究旨在确定三甲胺N-氧化物（TMAO）是否参与衰老的交感神经激活及其潜在机制。我们的假设是TMAO减少P2Y12受体（P2Y12R）并在室旁核（PVN）中诱导小胶质细胞介导的炎症，然后导致衰老的交感神经激活。这项研究涉及18名年轻人和16名老年人。通过注射D-半乳糖（D-gal，200mg/kg/d)皮下连续12周。通过饮用水给药TMAO（120mg/kg/d）或1％3，3-二甲基-1-丁醇（DMB）12周，以研究它们对衰老大鼠神经炎症和交感神经激活的影响。等离子TMAO,老年人的NE和IL-1β水平高于年轻人。此外,所有正常到正常间隔的标准偏差（SDNN）和正常到正常间隔的平均值的标准偏差（SDANN）在老年人中较低，并且与TMAO呈负相关，表明老年人的交感神经激活，这与TMAO水平的增加有关。用D-gal治疗大鼠显示衰老相关蛋白水平和小胶质细胞介导的炎症增加，以及PVN中P2Y12R蛋白水平降低。等离子TMAO,NE和IL-1β水平升高,伴有增强的肾交感神经活动（RSNA）。而TMAO治疗加剧了上述现象，DMB缓解了它。这些发现表明，TMAO通过下调小胶质细胞中的P2Y12R和增加PVN中的炎症而有助于衰老中的交感神经过度活跃。这些结果可能为防治衰老和衰老相关疾病提供有前景的新靶点。
