北大郑乐民课题组与福建协和医院洪华山课题组：血管衰老与肠道菌群代谢物氧化三甲胺有关

撰文 战锐

随着我国人口结构老龄化日趋严重，老年病给社会和家庭化都带来了沉重的负担。“血管有多老，人就有多老（A man is as old as his arteries）”，血管衰老，回伴随着全身各器官的衰老。已有多项研究发现，血管衰老与动脉粥样硬化、高血压等心血管疾病的发生、发展密切相关，严重影响老年人健康。多项研究发现：肠道菌群与衰老息息相关，但肠道菌群及代谢产物是否参了血管老化，仍待进一步研究。2016年郑乐民课题组建立了准确测定 TMAO 等肠道菌群代谢物的质谱学方法（相关研究成果发表在 J Chromatogr B Analyt Technol Biomed Life Sci），并进一步研究发现，TMAO 与 AS 斑块稳定性密切相关（研究成果发表在 American Journal of Cardiology）。已有多项研究发现肠道菌群明星代谢物“氧化三甲胺（TMAO）”，与多种心血管疾病相关，然而 TMAO 是否通过影响血管衰老参与心血管疾病的发生发展，目前国际上相关研究甚少。

2018年1月8日，国际学术期刊 Free Radical Biology and Medicine 杂志在线发表了北京大学医学部教授郑乐民研究组和福建医科大学附属协和医院洪华山教授研究组的最新研究成果（论文信息见文末）。研究发现：无论是人还是小鼠，老年组的血浆氧化三甲胺水平明显高于年轻组。同时，他们在快速老化小鼠模型中证实了氧化三甲胺可促进小鼠血管老化，使血管舒缩功能受损。进一步研究发现，氧化三甲胺加速血管衰老主要与其促进脐静脉内皮细胞衰老、下调长寿基因 SIRT1 表达、增加细胞氧化应激水平进而激活 p53/p21/Rb 信号通路有关。

该研究首次揭示了肠道菌群代谢物 TMAO 与血管衰老之间的关系及作用机制，为老年人心血管疾病防治提供了新思路。通过干预肠道菌群代谢物 TMAO，或许可以延缓老年人血管衰老，推迟各种心血管疾病的发生发展，延长人类寿命，提高老年人生活质量。研究生柯一郎和李珰为论文第一作者，郑乐民教授和洪华山教授为论文共同通讯作者。

相关论文信息

标题 Gut flora-dependentmetabolite Trimethylamine-N-oxide accelerates endothelial cell senescence andvascular aging through oxidative stress

期刊 Free Radical Biology andMedicine

作者 Yilang Ke, Dang Li,Mingming Zhao, Changjie Liu, Jia Liu, Aiping Zeng, Xiaoyun Shi, Si Cheng, BingPan, Lemin Zheng* , Huashan Hong*

发表日期  online 08 January 2018

摘要 Trimethylamine-N-oxide(TMAO), gut microbiota-dependent metabolites, has been shown to be associatedwith cardiovascular diseases. However, little is known about the relationshipbetween TMAO and vascular aging. Here, we observed a change in TMAO during theaging process and the effects of TMAO on vascular aging and endothelial cell(EC) senescence. We analyzed age-related plasma levels of TMAO in young adults(18–44 years old), older adults (≥ 65 years old), and1-month-old, 3-month-old, 6-month-old and 10-month-old senescence accelerated mouseprone 8 (SAMP8) and age-matched senescence-accelerated mouse resistance 1(SAMR1) models. We found that circulating TMAO increased with age both inhumans and mice. Next, we observed that a TMAO treatment for 16 weeks inducedvascular aging in SAMR1 mice and accelerated the process in SAMP8 mice, asmeasured by an upregulation of senescence markers includingsenescence-associated β-galactosidase(SA-β-gal), p53, and p21, vasculardysfunction and remodeling. In vitro, we demonstrated that prolonged TMAO treatmentinduced senescence in human umbilical vein endothelial cells (HUVECs),characterized by reduced cell proliferation, increased expressions ofsenescence markers, stagnate G0/G1, and impaired cell migration. Furthermore,TMAO suppressed sirtuin 1 (SIRT1) expression and increased oxidative stressboth in vivo and in vitro and then activated the p53/p21/Rb pathway resultingin increased p53, acetylation of p53, p21, and decreased CDK2, cyclinE1, andphosphorylation of Rb. In summary, these data suggest that elevated circulatingTMAO during the aging process may deteriorate EC senescence and vascular aging,which is probably associated with repression of SIRT1 expression and increasedoxidative stress, and, thus, the activation of the p53/p21/Rb pathway.

链接 https://www.sciencedirect.com/science/article/pii/S0891584918300170

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