白藜芦醇通过SIRT1抑制肿瘤发生延缓贡氏假鳃鳉衰老的机理研究

Aging is the degenerative changes for the function of tissues and organs with age, and it is associated with an increase in numerous diseases such as cancer in humans. Aging process is reinforced by high incidence of age-dependent neoplasias. A prerequisite for intervention or even prevention of certain age-related diseases is a better understanding of the molecular mechanisms of ageing. SIRT1 is a critical regulator at the crossroads between cancer and aging. Resveratrol, a natural plant-derived polyphenol, prolongs lifespan in many animals and was found to act as an antioxidant and a potential cancer chemopreventive agent.. Our previous results showed that the pharmaceutical treatment of resveratrol prolonged the lifespan of N. guentheri by improving cognitive ability and locomotor activity in three behavioral assays and by retarding the aging-related histological markers in lipofuscin formation, the expression of senescence-associated beta-galactosidase activity and protection from neurodegeneration. We found that there is a high incidence of spontaneous neoplasias in livers of old N. guentheri and resveratrol has decreased the incidence of the tumorgenesis recently. Resveratrol has biological effects both to inhibit tumorgenesis and postpone population aging. However，aging research was hindered because of the long lifespan of available vertebrates. Annual fishes of Nothobranchius have become a new model organism for aging studies. It is first time to explore the mechanism on resveratrol to prolong lifespan by oxidative damage and aging-related genes SIRT1-dependent in the same fish of N. Guentheri. The proposal will provide a novel vertebrate model and data for resveratrol, a common constituent of the human diet, as a potential anti-aging agents in humans.

衰老是机体各组织、器官功能随年龄增长而发生的退行性变化，也与癌症等诸多疾病的发生有关，癌症的发生加速了衰老进程。SIRT1在癌症发生和衰老的交叉路口起了关键的调节作用。天然多酚白藜芦醇可以抑制肿瘤、延缓衰老，但由于缺乏合适的动物模型，白藜芦醇是否通过激活SIRT1抑制肿瘤发生和延缓衰老的机理还不清楚。我们的前期结果显示白藜芦醇通过改变行为学和组织学指标延长了一年生贡氏假鳃鳉的寿命，后续又发现白藜芦醇抑制了老年贡氏假鳃鳉肝脏内自发形成的肿瘤，但其作用机理尚不明确。本项目研究白藜芦醇是否通过SIRT1降低氧化损伤及调节衰老相关基因的表达而延缓了贡氏假鳃鳉的衰老进程。这将为白藜芦醇作为抗衰老药物的筛选提供新的脊椎动物模型和可靠实验依据。

衰老是机体各组织、器官功能随年龄增长而发生的退行性变化，由于现有脊椎动物模型的寿命较长，衰老的研究受到阻止。一年生的贡氏假鳃鳉正在成为研究衰老和抗衰老的脊椎动物模型。天然多酚白藜芦醇能够延缓无脊椎动物的衰老进程，也延长了一些鱼类的寿命，但白藜芦醇延缓衰老的过程尚不清楚，尤其是对氧化应激的影响。本项目从性成熟开始，用白藜芦醇长期饲喂一年生的硬骨鱼贡氏假鳃鳉，检测了生存曲线和在6，9，12月龄不同发育时期体内的氧化应激指标。总的223条鱼中，112条鱼饲喂每克食物含200μg白藜芦醇作为处理组，111条鱼作为正常对照。研究结果表明：白藜芦醇延长了贡氏假鳃鳉17.34%的平均寿命和17.66%的最大寿命。氧化应激指标的检测发现，随着衰老的进行，贡氏假鳃鳉体内活性氧和氧化损伤呈增加趋势，而抗氧化酶活性呈降低趋势。白藜芦醇处理显著上调了贡氏假鳃鳉不同发育时期过氧化氢酶（CAT）、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GPx）三种抗氧化酶的活性，降低了体内的活性氧水平，进而降低了蛋白氧化和脂质过氧化的程度，最终降低了体内脂褐素的积累。同时，白藜芦醇提高了寿命相关基因SIRT1在贡氏假鳃鳉体内的表达。这些结果证明，白藜芦醇能够延长一年生贡氏假鳃鳉的寿命，降低体内的活性氧水平和氧化损伤程度，一年生的贡氏假鳃鳉可以作为研究衰老和抗衰老的脊椎动物模型。.该项目通过对氧化应激指标的检测，研究了添加到食物中的白藜芦醇在生化水平和细胞水平上延缓贡氏假鳃鳉衰老的机理，相关实验结果整理成的文章发表在SCI源期刊 Rejuvenation Research 上(doi: 10.1089/rej.2014.1618，IF=3.931, 2区， 2015 Jan 8.)，另有两篇中文文章发表在中国科技论文在线上。