Selman Colin, McLaren Jane S, Meyer Claus, Duncan Jackie S, Redman Paula, Collins Andrew R, Duthie Garry G, Speakman John R
Aberdeen Centre for Energy Regulation and Obesity (ACERO), School of Biological Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK.
Mech Ageing Dev. 2006 Dec;127(12):897-904. doi: 10.1016/j.mad.2006.09.008. Epub 2006 Nov 7.
Oxidative stress is suggested to be central to the ageing process, with endogenous antioxidant defence and repair mechanisms in place to minimize damage. Theoretically, supplementation with exogenous antioxidants might support the endogenous antioxidant system, thereby reducing oxidative damage, ageing-related functional decline and prolonging life- and health-span. Yet supplementation trials with antioxidants in animal models have had minimal success. Human epidemiological data are similarly unimpressive, leading some to question whether vitamin C, for example, might have pro-oxidant properties in vivo. We supplemented cold exposed (7+/-2 degrees C) female C57BL/6 mice over their lifespan with vitamin C (ascorbyl-2-polyphosphate), widely advocated and self administered to reduce oxidative stress, retard ageing and increase healthy lifespan. No effect on mean or maximum lifespan following vitamin C treatment or any significant impact on body mass, or on parameters of energy metabolism was observed. Moreover, no differences in hepatocyte and lymphocyte DNA oxidative damage or hepatic lipid peroxidation was seen between supplemented and control mice. Using a DNA macroarray specific for oxidative stress-related genes, we found that after 18 months of supplementation, mice exhibited a significantly reduced expression of several genes in the liver linked to free-radical scavenging, including Mn-superoxide dismutase. We confirmed these effects by Northern blotting and found additional down-regulation of glutathione peroxidase (not present on macroarray) in the vitamin C treated group. We suggest that high dietary doses of vitamin C are ineffective at prolonging lifespan in mice because any positive benefits derived as an antioxidant are offset by compensatory reductions in endogenous protection mechanisms, leading to no net reduction in accumulated oxidative damage.
氧化应激被认为是衰老过程的核心，机体存在内源性抗氧化防御和修复机制以将损伤降至最低。从理论上讲，补充外源性抗氧化剂可能会支持内源性抗氧化系统，从而减少氧化损伤、与衰老相关的功能衰退并延长寿命和健康期。然而，在动物模型中进行的抗氧化剂补充试验收效甚微。人类流行病学数据同样不尽人意，这使得一些人质疑例如维生素C在体内是否可能具有促氧化特性。我们在雌性C57BL/6小鼠的整个生命周期中对其进行冷暴露（7±2摄氏度）并补充维生素C（抗坏血酸-2-多聚磷酸酯），维生素C被广泛提倡且可自行服用，旨在减轻氧化应激、延缓衰老并延长健康寿命。未观察到维生素C处理对平均寿命或最大寿命有影响，对体重或能量代谢参数也无任何显著影响。此外，在补充维生素C的小鼠和对照小鼠之间，未发现肝细胞和淋巴细胞DNA氧化损伤或肝脏脂质过氧化存在差异。使用针对氧化应激相关基因的DNA微阵列，我们发现补充18个月后，小鼠肝脏中与自由基清除相关的几个基因的表达显著降低，包括锰超氧化物歧化酶。我们通过Northern印迹法证实了这些效应，并发现维生素C处理组中谷胱甘肽过氧化物酶（微阵列上未显示）的表达进一步下调。我们认为，高剂量饮食补充维生素C对延长小鼠寿命无效，因为作为抗氧化剂获得的任何积极益处都会被内源性保护机制的代偿性降低所抵消，导致累积氧化损伤没有净减少。
