D-半乳糖衰老模型及其氧化损伤机理与α-硫辛酸的干预作用研究
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摘要
随着世界人口老龄化进程的不断加速，衰老及老年病已成为当今日益严重的社会和医疗问题，因此，研究衰老机理，寻找延缓衰老药物对人类延年益寿、减轻家庭和社会负担都具有十分重要的意义。衰老模型是研究衰老机理、表现和筛选延缓衰老药物的必要手段。目前国际上多采用自然衰老动物，但老年动物极难获得，且价格昂贵、死亡率高，易患肿瘤、高血压、糖尿病等复杂疾患，给实验带来很多困难，影响结果的可靠性。D-半乳糖衰老模型是80年代中期由我国学者首次提出的，通过大量研究，使其从机理到应用都得到了极大丰富和拓展。但是，该模型仍存在不足，有些领域还未探讨过，尚属空白。
本文围绕D-半乳糖衰老模型进行了两部分研究工作，第一部分从寿命、中枢胆碱能和谷氨酸能系统的功能改变、神经元凋亡、神经干细胞(NSCs)的增殖与分化等方面对D-半乳糖衰老模型及其氧化损伤机理进行了研究；第二部分基于线粒体氧化损伤在衰老及其相关疾病中所起的重要作用，用线粒体抗氧化剂α-LA对D-半乳糖衰老模型进行干预以验证其氧化损伤机制，同时，应用该模型对α-LA的抗氧化、抗衰老作用进行评价，为D-半乳糖衰老模型的机理和应用研究提供参考资料，并为α-LA延缓衰老作用提供依据。
第一部分 D-半乳糖衰老模型及其氧化损伤机理研究
1．D-gal分别从培养基和饮水中给予果蝇(6.5％)和家蝇(2％)，观察它对寿命和存活率的影响，并检测组织中氧化和抗氧化水平。结果显示，D-gal使果蝇和家蝇的平均寿命和最高寿命均显著缩短，存活率下降，果蝇和家蝇头MDA水平升高，SOD活力降低，此外，家蝇头中脂褐素含量也显著升高，提示D-gal引起的寿命缩短与氧化损伤有关。
2．C57BL／6J小鼠，随机分成对照组(生理盐水，颈背部s.c.持续6w)、模型组(D-gal100mg／kg.d，颈背部s.c.持续6w)和HupA阳性对照组(D-gal 100mg／kg.d，颈背部s.c.
Aging and age-related diseases have become more and more important social and medical problems with the acceleration of population senescence in the world. Many hypotheses have been proposed to explore the process of aging, however, the underlying mechanisms are yet not well-known. The investigation of the mechanisms of aging and the search for effective agents that can delay the aging process will be beneficial for the human longevity and releasing family and social burdens.
Natural old animals are usually used in aging study, however, they are expensive and not easy to obtain. In addition, old animals have high mortality rate and high incidence of tumor, hypertension, diabetes and other diseases. Therefore, developing good aging model is essential and important for studying aging mechanisms and anti-aging agents. D-galactose (D-gal)-induced aging model was first reported in China 20 years ago. This aging model has been continually studied and widely used. However, the underlying mechanism remains largely unknown.
The present thesis reports two studies on the D-gal induced aging in different animals. The first study investigated D-gal induced the lifespan shortening in fruit fly and housefly, and the impairment of behavior, changes in central cholinergic and glutamate system function, neuronal apoptosis and the inhibition of proliferation and differentiation of neural stem cells (NSCs) in mice. The second study, based on the mitochondrial free radical theory of aging, mainly investigated the antagonistic effect of R-α-lipoic acid (a-LA), a mitochondrial antioxidant, on D-gal-induced aging in fruit flies, mice, and primary cultured cells of rat cerebral cortex and hippocampus.
本文围绕D-半乳糖衰老模型进行了两部分研究工作，第一部分从寿命、中枢胆碱能和谷氨酸能系统的功能改变、神经元凋亡、神经干细胞(NSCs)的增殖与分化等方面对D-半乳糖衰老模型及其氧化损伤机理进行了研究；第二部分基于线粒体氧化损伤在衰老及其相关疾病中所起的重要作用，用线粒体抗氧化剂α-LA对D-半乳糖衰老模型进行干预以验证其氧化损伤机制，同时，应用该模型对α-LA的抗氧化、抗衰老作用进行评价，为D-半乳糖衰老模型的机理和应用研究提供参考资料，并为α-LA延缓衰老作用提供依据。
第一部分 D-半乳糖衰老模型及其氧化损伤机理研究
1．D-gal分别从培养基和饮水中给予果蝇(6.5％)和家蝇(2％)，观察它对寿命和存活率的影响，并检测组织中氧化和抗氧化水平。结果显示，D-gal使果蝇和家蝇的平均寿命和最高寿命均显著缩短，存活率下降，果蝇和家蝇头MDA水平升高，SOD活力降低，此外，家蝇头中脂褐素含量也显著升高，提示D-gal引起的寿命缩短与氧化损伤有关。
2．C57BL／6J小鼠，随机分成对照组(生理盐水，颈背部s.c.持续6w)、模型组(D-gal100mg／kg.d，颈背部s.c.持续6w)和HupA阳性对照组(D-gal 100mg／kg.d，颈背部s.c.
Aging and age-related diseases have become more and more important social and medical problems with the acceleration of population senescence in the world. Many hypotheses have been proposed to explore the process of aging, however, the underlying mechanisms are yet not well-known. The investigation of the mechanisms of aging and the search for effective agents that can delay the aging process will be beneficial for the human longevity and releasing family and social burdens.
Natural old animals are usually used in aging study, however, they are expensive and not easy to obtain. In addition, old animals have high mortality rate and high incidence of tumor, hypertension, diabetes and other diseases. Therefore, developing good aging model is essential and important for studying aging mechanisms and anti-aging agents. D-galactose (D-gal)-induced aging model was first reported in China 20 years ago. This aging model has been continually studied and widely used. However, the underlying mechanism remains largely unknown.
The present thesis reports two studies on the D-gal induced aging in different animals. The first study investigated D-gal induced the lifespan shortening in fruit fly and housefly, and the impairment of behavior, changes in central cholinergic and glutamate system function, neuronal apoptosis and the inhibition of proliferation and differentiation of neural stem cells (NSCs) in mice. The second study, based on the mitochondrial free radical theory of aging, mainly investigated the antagonistic effect of R-α-lipoic acid (a-LA), a mitochondrial antioxidant, on D-gal-induced aging in fruit flies, mice, and primary cultured cells of rat cerebral cortex and hippocampus.
引文
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