衰老是有机体多种生理功能随时间推移逐渐衰退的过程,并且人类衰老往往伴随着多种与年龄相关高危疾病的发生,如糖尿病、心血管疾病和神经系统疾病等[1]。全球老龄化的加速将改变劳动力结构,提高医疗保健成本,增加社会经济负担。延缓老龄化的进程,消除老年疾病的潜在危险因素已迫在眉睫。大量流行病学研究表明,喝茶有利于人类的健康衰老[2]。茶叶中含有茶多酚、茶氨酸和咖啡碱等多种活性成分,在体内外试验中均表现出抗衰老作用[3-6],且茶叶能有效预防及改善心血管疾病、神经性退行疾病以及Ⅱ型糖尿病等与年龄相关的疾病[7-9]。本文对茶叶抗衰老作用及其调控能量感应网络延缓衰老的作用机制进行综述,并对今后茶叶抗衰老研究进行展望。
1 茶叶预防衰老及衰老相关疾病的研究现状
1.1 茶叶的抗衰老作用
流行病学研究表明,饮茶与个人遗传特征相互作用,可以有效干预膳食营养吸收,促进人类健康衰老[10]。在秀丽线虫、果蝇和老鼠等动物模型中均发现茶叶水提物在正常状况或不同应激条件下能延长其寿命[3-4,11-12]。在野生型秀丽线虫模型中,Fei等[12]人研究发现普洱茶、红茶和绿茶能显著延长秀丽线虫的寿命。在另一项研究中,红茶提取物在0.05、0.1、0.2 mg·mL -1 3种质量浓度下均不能增加正常状况下秀丽线虫的寿命,却能增加其在渗透压力、高温和紫外线照射处理等多种非生物胁迫状态下的抗性[6]。在果蝇模型中,3个浓度龙井绿茶水提物(1、5、10 mg·mL -1)均能提高野生型果蝇的平均寿命和最长寿命[3]。10 mg·mL -1绿茶提取物能延长雄性w1118果蝇的平均寿命19% [13]。同时,5 mg·mL -1和10 mg·mL -1红茶提取物能延长野生型雄性果蝇的平均寿命7.8%和9.8% [14]。在老鼠模型中,Strong等[5]用绿茶提取物对遗传异质小鼠进行终身干预发现雄性小鼠的死亡率没有显著影响,但能降低雌鼠中年时期的死亡率。
1.2 茶叶主要活性成分的抗衰老作用
茶叶主要的活性成分分别是多酚类化合物、嘌呤碱和游离氨基酸。其中,多酚类化合物主要包括儿茶素类、黄酮及其糖苷类和酚酸类;嘌呤碱主要有咖啡碱;茶叶中含量最高的游离氨基酸为茶氨酸。这些茶叶活性成分均表现出抗衰老作用。
1.2.1 儿茶素类化合物的抗衰老作用
儿茶素类化合物是茶叶中多酚类化合物的主体成分,其中儿茶素(Catechin,C)、表儿茶素(Epicatechin,EC)和表没食子儿茶素没食子酸脂(Epigallocatechin gallate,EGCG)在不同动物模型中具有抗衰老作用。在秀丽线虫模型中,用 110、200、300 μmol·L-1 儿茶素干预能使其中位寿命分别增加11.24% 、13.27%和 9.56%,平均寿命分别增加 8.39%、8.87%和 5.86% [15]。Saul 等[16]研究也表明200 μmol·L-1 儿茶素能使秀丽线虫平均寿命延长 10% 左 右 。 在 果蝇模型中 , 100~1 000μmol·L-1 EC 处理组与空白组相比平均寿命延长 37.5% [17]。在糖尿病小鼠模型中,持续 15周每日摄入 0.25% EC 可以提高存活率 41.6%,还可以改善血清低密度胆固醇含量、总超氧化物歧化酶活性、系统炎症标志物和肝脏抗氧化剂谷胱甘肽浓度等与衰老相关的指标[17]。
秀丽线虫、果蝇、雄性魏-凯二氏大鼠、小鼠及蜜蜂等体内试验均表明,EGCG 有延缓衰老的作用[18-22]。在正常状态下,100 μmol·L-1EGCG 能使秀丽线虫的平均寿命和最大寿命分别提高 20%和 13% [23],10 mg·mL -1(约 21 815μmol·L-1)EGCG 能够使果蝇的平均寿命延长 3.3 d、中位寿命延长 4.3 d [22],每天喂食25 mg·kg-1 EGCG 能使健康大鼠的中位寿命延长 13.5%(约 12.5 周)[21]。300 μmol·L-1 EGCG喂食蜂蜜,与对照组相比其平均寿命延长7.7%。此外,在多种应激状态下,EGCG 在不同动物模型中也表现出抗衰老作用。Zhang等 [20]在秀丽线虫模型中发现 , 0.1 μg·mL-1(约 0.218 15 μmol·L-1)EGCG 在 35℃的热应激下能使平均寿命提高 13.1%;在氧化胁迫下,能使平均寿命提高 172.9%。Liu 等[24]在快速老化型老鼠模型中发现,每天 3.2 g·kg-1(3 200 mg·kg-1)EGCG 干预 12 周可以改善其胰岛素敏感性,缓解由衰老引起的代谢紊乱。
虽然秀丽线虫的寿命会受到温度及食物的影响,但是在 15、20、23℃ 3 种不同温度下,200 μmol·L-1 儿茶素干预后均能延长秀丽线虫寿命,而且喂食秀丽线虫死菌或活菌均不会影响试验结果[15]。本实验室研究发现,EGCG 对秀丽线虫的长寿效应也不受温度及抗菌性的影响。该研究还表明干预时间在成虫的早中期时,EGCG 长寿效应最为显著[25]。
1.2.2 黄酮类化合物的抗衰老作用
黄酮类化合物是植物普遍的次生代谢产物,茶叶主要含有槲皮素(Quercetin)、山柰酚(Kaempferol)、杨梅素(Myricetin)及其糖苷类。大多数研究表明补充黄酮类化合物能延长秀丽线虫寿命[26-28]。将 100 μmol·L -1 槲皮素加入秀丽线虫的食物大肠杆菌中,从成虫开始干预,与空白组相比槲皮素能延长秀丽线虫平均寿命 15% [29]。同样,100 μmol·L-1 山柰酚和杨梅素处理也能延长秀丽线虫的平均寿命5.6%和 18% [30-31]。黄酮类化合物还能使秀丽线虫抗热应激和抗氧化应激等抗逆性增强[27]。此外,Xu 等[32]研究发现槲皮素(20 μmol·L-1)与达沙替尼(1 μmol·L-1)联合使用能杀死老鼠体内的衰老细胞,减少炎症因子的分泌,每间隔 11 d后连续灌胃 3 d能使老年老鼠(24~27个月)寿命延长 36%左右。
有研究表明,黄酮类化合物抗衰老作用主要取决于其 C 环结构性质,同时与 B 环上羟基基团数量相关。Grunz 等[31]将 100 μmol·L-1的槲皮素、山柰酚和杨梅素分别干预秀丽线虫,发现抗衰老活性顺序为杨梅素>槲皮素>山柰酚。此外,Duenas 等[33]通过对比槲皮素-3-O-葡糖苷(Q3Glc)和槲皮素对秀丽线虫的影响发现,Q3Glc 在虫体内更容易被吸收,并且发现槲皮素在虫体中去糖基化和糖苷配基积累的代谢过程与其抗衰老作用相关。黄酮类化合物的抗菌特性、饮食限制及抗氧化作用不是黄酮类延长秀丽线虫寿命的主要原因,主要原因可能与其调节能量代谢相关[34]。
1.2.3 酚酸类化合物的抗衰老作用
茶叶中酚酸类总量占鲜叶干重的 5%左右。研究表明,茶叶中的没食子酸(Gallic acid)、绿原酸(Chlorogenic Acids)、咖啡酸(Caffeicacid)及鞣花酸(Ellagic acid)在抗衰老方面均表现出积极作用。在秀丽线虫模型中,没食子酸(300 μmol·L-1)、绿原酸(50 μmol·L-1)、咖啡酸(300 μmol·L-1)及鞣花酸(50 μmol·L-1)均能延长其平均寿命,其中没食子酸和鞣花酸对秀丽线虫的抗衰老作用依赖于抗菌作用,但绿原酸和咖啡酸的抗衰老作用与抗菌性无关[16,34-35]。鞣花酸对秀丽线虫的抗衰老作用还会受到干预时间和体内代谢作用的影响。鞣花酸从成虫开始干预平均寿命能延长 10%左右,但从幼虫开始干预则不能延长寿命[16,36]。而且鞣花酸在老鼠肠道代谢受到个体差异影响能产生尿石素 A、尿石素 B、尿石素 C 和尿石素 D等代谢物,其中尿石素 A(50 μmol·L-1)从幼虫开始干预平均寿命能延长 45.4%左右,其作用效果明显强于鞣花酸。此外,每天 25 mg·kg-1 喂食尿石素 A 能提高幼年老鼠(5.5 周)的运动能力,减缓老年老鼠(16~24 个月)肌肉功能的衰退[36]。
1.2.4 茶氨酸及咖啡碱的抗衰老作用
茶氨酸(L-theanine)和咖啡碱(Caffeine)也是茶叶中重要的活性成分。茶氨酸是茶叶中特有的游离氨基酸,在 0.1 μmol·L-1 下能使秀丽线虫的平均寿命和最大寿命分别延长 3.6%和 3.2%。在应激状态下也表现出抗衰老作用,例如:在 10 mmol·L-1 百草枯氧化应激下,0.1、1、10 μmol·L-1 的茶氨酸均能延长秀丽线虫的寿命,其中 0.1 μmol·L-1 作用最显著,平均寿命和最长寿命与空白组相比分别延长 3.6%和 4.42%[37]。在老年小鼠中茶氨酸能增强胞内谷胱甘肽的合成,改善免疫应答从而起到抗衰老作用[38]。在衰老老鼠模型的饮水中加入 20 μg·mL-1(约 114.81 μmol·L-1)茶氨酸能延缓衰老死亡[39]。
咖啡碱是茶叶中主要的嘌呤碱之一,能兴奋中枢神经系统并且预防年龄相关的神经退行性疾病[40]。同时,咖啡碱还能作为卵母细胞衰老抑制剂,能维持绵羊、猪、小鼠等动物卵母细胞的纺锤体形态,增加衰老卵母细胞的原核形成,减少卵母细胞的碎裂从而维持老化后卵母细胞的质量[40-42]。在动物模型中,咖啡碱也表现出抗衰老作用,例如:Bridi 等[43]研究表明咖啡碱能延缓幼虫的发育,15 000 μmol·L-1 咖啡碱从幼虫开始干预能延长秀丽线虫的平均寿命 51.61%。Matt 等[44]研究表明咖啡碱对成虫的干预效果会受到温度的影响,10 000 μmol·L-1 咖啡碱从成虫开始干预秀丽线虫的中位寿命在 15℃和 20℃时分别延长 36.7%和 16.9%。Strachecka 等[45]发现蜜蜂补充咖啡碱后寿命延长,且不易受鼻毛虫感染。
1.3 茶叶预防及改善衰老相关疾病
1.3.1 茶叶预防及改善心血管疾病
由心脏和血管功能异常引起心血管疾病的患病率和死亡率均居各类疾病之首。其中心血管疾病常见病症(中风、高血压和动脉粥样硬化等)的高发人群为中老年人[46]。茶叶提取物能增强微血管功能,有效降血压和血浆胆固醇[47]。大部分流行病学研究表明饮茶与心血管疾病死亡率呈负相关关系。Kokubo 等[48]对 82 369 名成年人(年龄均在 45~74 岁,无心血管疾病史)长达 13 年的随访发现,每日饮用绿茶 4 杯以上中风的发生率显著降低。在中国和美国分别进行的两项流行病学研究均表明定期饮茶能降低冠状动脉钙化程度,减少冠心病发生率和死亡率[49-50]。此外,Wang 等[51]对 6 组病例对照研究和 12 组定群研究进行meta 分析,表明绿茶对心血管疾病的保护作用强于红茶。但是也有研究指出,成人每日饮用绿茶大于 6 杯才能有效降低血管疾病的死亡率[52]。同时,由于茶饮中含有的咖啡碱具有兴奋作用,有人不建议患有严重心血管疾病的患者饮茶[53]。
1.3.2 茶叶预防及改善Ⅱ型糖尿病
Ⅱ型糖尿病是以高血糖为特征的胰岛素分泌障碍及能量代谢紊乱相关的慢性代谢疾病。动物试验研究表明,茶多酚类物质能影响肠道微生物群,抑制糖异生和脂肪生成,增强脂质分解和协调能量代谢[54]。茶多糖尤其是粗多糖能促进 MIN-6 细胞胰岛素分泌量,还能降低糖尿病小鼠的血糖[55]。多数流行病学研究指出定期饮茶能缓解代谢综合症,降低糖尿病的患病率并且能改善糖尿病患者的骨质疏松症[56-57]。2013 至 2015 年期间,Nguyen等[58]对 599 例新诊断的糖尿病患者和 599 名健康人(年龄均在 40~65 岁)进行横断面研究显示,相较于每日平均饮茶量少于 1 杯的人群,平均每日饮茶两杯的人患糖尿病概率为 0.66。但是 Grosso 等[59]对 8 821 名成年人(51.4%女性)进行横断面研究发现饮茶能有效改善女性的代谢综合症,对男性却无效。此外,连续12 周每天摄入 300 mg EGCG 不会影响绝经女性的代谢指标[60]。近期有研究指出饮茶温度对能量代谢影响不同,低温饮茶比高温饮茶更有利于脂肪的氧化[61]。
1.3.3 茶叶预防及改善神经性退行疾病
神经性退行疾病是由氧化应激、炎症和蛋白质异常聚集物累积等引起神经元死亡的疾病 , 主 要 包 括 阿 尔 茨 海 默 病 ( Alzheimer’s disease,AD)和帕金森病(Parkinson disease,PD)等老年疾病。大量动物试验研究表明,茶叶中儿茶素类、咖啡碱、茶氨酸及茶黄素等多种活性成分能穿过血脑屏障(Blood-brian barrier,BBB)并充分发挥神经保护作用,有效预防及治疗神经性退行疾病[62-64]。许多流行病学研究表明,饮茶量与 AD 和 PD 的发生率成反比[65]。Beking 等[66]对来自 23 个不同国家的人群调查显示,在不同的遗传背景下,黄酮类化合物的摄入量与 AD 的患病率呈负相关关系。Qi 等[67]对 8 项研究(包括 344 895名参与者)和 7 项研究(包括 492 724 名参与者)进行 meta 分析表明,饮茶量与 PD 的发病率呈负线性关系。Mineharuy 等[52]对 26 项调研进行观察性研究认为饮用绿茶、乌龙茶和红茶均能降低认知能力下降的风险,但是饮茶量与 AD 之间的关联有待进一步研究。
2 茶叶调节能量感应网络延缓衰老的研究现状
在生物活动过程中,能量感应网络能响应营养摄入总量、氧化还原状态和蛋白稳态等有机体代谢状况,包含多条高度保守的抗衰老途径。近年来研究发现,茶叶多种活性成分能调节能量感应网络,包括调控胰岛素/胰岛素样生长因子信号(Insulin/insulin-likegrowth factor signaling,IIS)通路,激活腺苷酸 活 化 蛋 白 激 酶 ( AMP-activated proteinkinase,AMPK)和脱乙酰酶(Sirtuins),抑制雷帕霉素(Mammalian target of rapamycin,mTOR),协调能量稳态,直接或间接延缓机体衰老[68]。
2.1 茶叶对 IIS 途径的调控
IIS 途径是能量稳态和代谢过程中关键的能量调节通路,具有高度保守性[69],能被与能量密切相关的两种多肽:胰岛素(Insulin)和胰岛素样生长因子 ( Insulin-like growthfactor,IGF)激活[69]。IIS 途径主要经过胰岛素和 IGF 与跨膜酪氨酸激酶受体结合激活下游信号通路 PI3K/Akt,能最终作用于 FoxO 叉头转录因子的磷酸化,降低 FoxO 核转移的水平并激活多个下游元件,包括:超氧化物歧化酶(Superoxide dismutase,SOD)、谷胱甘肽硫转移酶(Glutathione s-transferases,GSTs)、过氧化氢酶(Catalase,CAT)和热休克蛋白(Heat shock proteins,HSPs)从而影响衰老[70-73]。IIS 途径或其上下游元件的下调均能影响机体的基因表达水平,蛋白质稳态和氧化还原状态等,从而延长机体寿命[74]。
在胰腺 β 细胞中,儿茶素类物质可以通过影响细胞膜上 Ca2+和 K +通道抑制葡萄糖诱导的胰岛素分泌,直接减少了胰岛素的分泌,下调 IIS 途径[75]。茶叶多酚类物质含有的多元酚基团能提供氢键供体与酪氨酸激酶受体结合调控 PI3K 水平[71]。在 T24 和 5637 细胞中,EGCG 能降低 PI3K/AKT 的磷酸化[76]。咖啡碱、绿原酸与儿茶素类化合物在有效剂量下不能延长线虫同源基因(daf-2 和 akt-1)突变体的寿命[15,35,43],表明茶叶在动物模型中的抗衰老作用与 PI3K/AKT 信号通路相关。此外,EGCG 和槲皮素还能上调 FoxO 的核转移水平,增加 FoxO 下游靶基因(sod、cat 及 hsp等)的表达,调节机体寿命[77-78]。
2.2 茶叶对 AMPK 的激活作用
AMP(Adenosine-5'-monophosphate)激活的蛋白激酶(AMPK)属于丝氨酸苏氨酸激酶,是一种高度保守的能量状态关键传感器[79]。在果蝇和秀丽线虫等动物模型中 AMPK 直接影响寿命,在哺乳动物中 AMPK 的活性会随着年龄的增加而逐渐下降[80]。绿茶、红茶、乌龙茶及黑茶均能直接激活 AMPK 调节葡萄糖摄取和脂质代谢[81-83]。Yang 等[54]提出茶通过影响 AMP/ADP/ATP 的比例激活 AMPK。本实验室研究表明,EGCG 诱导产生的 ROS能直接激活 AMPK 延长秀丽线虫寿命[25]。
2.3 茶叶对 mTOR 的抑制作用
哺乳动物雷帕霉素靶蛋白由负责细胞生长和代谢的 mTOR 复合物 1(mTORC1)和负责调节细胞骨架的组织 mTOR 复合物 2(mTORC2)组成,是经典的饮食和能量感应网络[84]。上游元件 PI3K/AKT 的下调及 AMPK的 激活能抑制 mTORC1 的活性 [1] 。 抑 制mTORC1 能调控自噬,激活翻译,由此协调能量稳态,延长寿命[85-86]。茶叶中咖啡碱在裂殖酵母细胞中能抑制 mTORC1 活性[87]。茶叶EGCG 通过降低 AKT 磷酸化,抑制 mTORC1活性,还能通过上调 AMPK 活性竞争性抑制mTOR 活性[88-89]。
2.4 茶叶对 Sirtuins 的激活作用
Sirtuins 是烟酰胺腺嘌呤二核苷酸依赖性蛋白脱乙酰基酶,首先在酵母细胞中被发现,能调节线粒体功能和细胞氧化还原状态,延长酵母细胞的寿命[90]。在多种动物模型中均发现 Sirtuins 有抗衰老作用[91]。Sirtuins 的激活依赖于烟酰胺腺嘌呤二核苷酸(NAD+),能响应细胞的能量状态,也受 AMPK 的调控[92]。活化后的 Sirtuins 抑制下游元件 NF-κB、P53、Bax 及 PPARy,同时促进线粒体的生物合成和能量代谢,从而延缓衰老[93]。茶多酚类物质能有效激活 Sirtuins[94]。在秀丽线虫模型中,EGCG 能通过 AMPK 激活 Sirtuins,从而延长寿命[25]。在小鼠模型中,EGCG 能激活Sirtuins,下调抗炎相关的信号通路 NF-κB,改善氧化损伤,起到抗衰老作用[21]。
3 展望
综上所述,流行病学研究及体内外试验均表明茶叶多种活性成分均具有抗衰老作用,作用机制与能量感应网络相关。茶叶主要活性物质通过调节 AMP/ADP/ATP 比例和诱导 ROS产生等方式调控 IIS 途径、激活 AMPK 和Sirtuins 并且抑制 mTOR 活性,从而调节机体的能量代谢,促进健康衰老,但是茶叶抗衰老作用及其机理还需要从多方面研究探索。
首先,茶叶各活性成分抗衰老作用的机理错综复杂,茶叶活性成分抗衰老作用之间是否存在相互作用仍然未知。一方面,茶叶中不同活性物质抗衰老的作用机理和调控的抗衰老途径不完全相同,其中茶叶多酚类化合物能够调控能量感应网络,而目前研究表明茶叶咖啡碱主要抑制 mTOR 途径[25,39,87-88]。另一方面,茶叶中不同活性物质之间可能存在相互作用,例如:EGCG 和茶氨酸对羟基自由基的清除和细胞氧化损伤的减少具有协同作用[95],咖啡碱能影响 EGCG 在人体内的吸收和代谢[96]。
其次,茶叶活性成分的抗衰老作用在干预的时间和剂量上仍然存在争议。茶叶活性物质能够延长健康寿命,预防老年疾病。其中,EGCG 诱导秀丽线虫延长寿命的有效作用时期在成虫早期至中期,鞣花酸从成虫时期干预才能诱导秀丽线虫长寿,咖啡碱能推迟秀丽线虫幼虫的发育延长寿命,茶叶其他活性成分抗衰老作用的干预时间缺乏具体研究[16,25-36,43]。此外,EGCG 在 2~20 μmol·L-1 时能提高人类精子的存活率,60 μmol·L-1 时反而会降低精子的存活率;在 50~300μmol·L-1 时能延长秀丽线虫的寿命,大于 800 μmol·L-1 时会缩短秀丽线虫寿命;在 300 μmol·L-1 和 500 μmol·L-1 时能延长果蝇的寿命,2200 μmol·L-1 时会加速果蝇衰老[18,25,97]。槲皮素在 100~200 μmol·L-1 能延长秀丽线虫的寿命,大于 250 μmol·L-1 时会缩短秀丽线虫的寿命[34]。鞣花酸在 50 μmol·L-1 时能延长秀丽线虫寿命,大于 250 μmol·L-1 时会缩短秀丽线虫寿命[16]。咖啡碱在 5 000~20 000 μmol·L-1 能延长秀丽线虫的寿命,大于 30 000 μmol·L-1时会缩短秀丽线虫的寿命[43-44]。由此,茶叶抗衰老作用与线粒体毒理兴奋效应相关,即干预剂量在适当低浓度刺激时有利于健康长寿,而相对高浓度应激下会加速衰老[98],目前尚未在高级哺乳动物(包括人类)中得到验证。儿茶素、表儿茶素和没食子酸等抗衰老作用的干预剂量缺乏系统研究。
再次,茶叶主要活性成分是自身还是体内代谢作用产生的代谢物发挥抗衰老作用仍然值得研究。多酚类化合物在机体内的直接生物利用度低,通常在有机体的肠道内经过特定的微生物群协助进行代谢吸收。多酚类物质能调节肠道微生物群,能促进益生菌生长,抑制致病菌。肠道微生物群对多酚类化合物的代谢吸收和最终的代谢产物可能会影响茶叶活性成分的抗衰老作用功效[99]。其中,没食子酸和鞣花酸对秀丽线虫的抗衰老作用依赖于抗菌作用[16]。在秀丽线虫模型中,相同浓度的鞣花酸代谢物尿石素 A 的抗衰老作用强于鞣花酸本身[36]。
最后,衰老是一个非常复杂的过程,受物种类别、基因遗传和生活环境的多重影响。衰老过程中的多重因素会影响流行病学调研结果,使茶叶预防衰老及衰老相关疾病在人类受试者中观察性研究结果不完全一致。同一物质也会因个体肠道微生物群的多样性而产生不同代谢物产物,导致抗衰老效果差异较大,如:鞣花酸的体内代谢会因个体差异产生 4 种代谢产物,其中尿石素 A 比鞣花酸产生的其它代谢产物的抗衰老效果更为显著[31,33,36]。
纵观已有研究,寿命是常用的抗衰老研究指标,茶叶主要活性物质能延长秀丽线虫、果蝇和老鼠等动物模型的寿命。而健康衰老区别于有机体寿命的延长,是指老年疾病的发生率降低而且有机体生理机能处于健康状态的寿命延长[100]。通过体内外试验和流行病学研究表明,茶叶主要活性成分能有效预防衰老相关的疾病,促进有机体健康衰老。然而目前茶叶各活性成分抗衰老的相互作用需要进一步的试验研究证实,茶叶中不同活性成分对不同有机体抗衰老的有效剂量和作用机制以及多酚类化合物的体内代谢过程和代谢产物的抗衰老功效有待系统研究,同时流行病学方面还缺乏前瞻性研究。
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This article is excerpted from the Journal of Tea Science by Wound World.