植物化学物EGCG延长不同膳食模式下大鼠寿命的作用及机制研究

Diet is closely associated with lifespan. Some studies revealed that high carbohydrate and high fat diet can make the body produce inflammatory and oxidative stress, leading to a variety of many chronic diseases such as obesity, diabetes and cardiovascular disease, which are associated with shorting lifespan. Phytochemicals epigallocatechin gallate (EGCG) had many beneficial biological effects including anti-inflammation, anti-oxidative stress and lowering serum glucose and lipids. Furthermore, we found that EGCG can maintenance health and increase the lifespan in healthy rats by improving inflammatory and oxidative stress and effective dosage was also determined in our previous study. However, it is unclear whether long-term phytochemicals supplementation of EGCG can be against the damages of unhealthy dietary patterns on the body and play a role to extend the life of the body. Therefore, our study is to investigate the effects of dietary patterns (normal, high fat, high carbohydrate) on lifespan, and the effects of EGCG on the lifespan of rats in different dietary patterns. The levels of heart rate, blood pressure, inflammation, oxidative stress, serum glucose and lipids will be dynamically detected in the course of the experiment, which would help us to elucidate the molecular mechanisms of dietary patterns on lifespan and EGCG on lifespan in different dietary patterns. Further, cell experiments will be used to certify and clarify their mechanisms on increasing lifespan. All studies above will provide scientific guide for daily dietary habits and the development of founctional foods by EGCG.

膳食与寿命密切相关。研究表明，高脂高碳水化合物膳食能够使机体产生炎性和氧化应激，导致肥胖、糖尿病、心血管疾病等多种慢性病的发生，影响机体的寿命。植物化学物表没食子儿茶素酸酯（简称EGCG）具有抗炎、抗氧化、降血糖、降血脂等多种有益的生物学作用。另外，我们前期工作发现EGCG能够通过抗炎抗氧化来维持大鼠的健康、延长大鼠的寿命，并确定了EGCG的有效剂量。那么长期补充EGCG能否在一定程度上对抗不健康膳食模式对机体的损害，发挥延长机体寿命的作用？为此，本课题拟研究正常、高脂、高碳水化合物膳食对寿命的影响，以及在不同膳食模式下补充EGCG对大鼠寿命的影响；动态监测心率、血压、炎症、氧化应激水平、血脂、血糖以及反映肝脏、肾脏功能的指标，以期发现EGCG在不同膳食模式下延长寿命的机制；并利用体外实验进一步证实上述作用并探讨分子机制，为膳食干预或者利用EGCG开发保健食品提供理论依据和科学指导。

表没食子儿茶素没食子酸酯（EGCG）是茶叶中多酚的主要活性形式，具有抗炎、抗氧化、降血糖、降血脂、降血压等与寿命相关的有益的生物学作用。本项目研究了EGCG对普通饲料和高脂饲料喂养大鼠寿命的作用及机制，并利用体外实验对其发挥作用的机制进行了验证。结果分为四个部分：.1. EGCG对高碳水化合物膳食喂养的Wistar大鼠寿命的作用及机制研究。结果发现与对照组相比，EGCG的半数生命周期曲线显著增加，动物死亡率延迟大约8-12周。EGCG显著降低了血清中炎症和氧化应激水平，同时EGCG减低了肝脏、肾脏组织的炎症和氧化应激水平，保护年龄引起的肝脏、肾脏损害；EGCG能够显著降低大鼠肝脏和肾脏组织中转录因子NF-κB的mRNA水平和蛋白表达水平，增加寿命相关蛋白组织叉头框蛋白O-3a（FOXO3a）和沉默信息调节因子1（SIRT1）的表达。.2. .EGCG对高脂膳食饲养的Wistar大鼠寿命的作用及机制研究。随机将大鼠分为对照组、高脂组和表没食子儿茶素酸酯（EGCG）组，长期喂养110周，动态监测大鼠体重、摄食量、饮水量、血清生化学指标、炎症及氧化应激水平,结果发现EGCG在高脂膳食模式下降低大鼠血糖、血脂，改善炎症及氧化应激状态，延长大鼠寿命。.3.植物化学物EGCG改善油酸诱导的SW872脂肪细胞胰岛素抵抗的作用及机制：结果发现，与正常组比较，油酸模型组葡萄糖摄取和GLUT4蛋白表达明显降低，TNF–α、IL–6、CRP的mRNA和蛋白分泌水平明显升高；与模型组相比，给予EGCG组能够显著增加脂肪细胞对葡萄糖的摄取和GLUT4蛋白的表达，TNF–α、IL–6、CRP的mRNA和分泌蛋白水平显著下降。.4.EGCG对二倍体成纤维细胞寿命的作用及机制研究及对肝癌细胞HepG2细胞糖脂代谢的影响。动态监测<25代WI-38细胞衰老状况、炎症因子和氧化应激水平，给予不同剂量EGCG干预的25代WI-38细胞衰老状况、炎症和氧化应激水平，与对照组相比无统计学差异。EGCG显著降低25 mM的葡萄糖和0.25 mM的棕榈酸诱导的HepG2细胞炎症和氧化应激水平。