Cai Weijing, He John Cijiang, Zhu Li, Chen Xue, Wallenstein Sylvan, Striker Gary E, Vlassara Helen
Mount Sinai School of Medicine, Box 1640, One Gustave Levy Place, New York, NY 10029, USA.
Am J Pathol. 2007 Jun;170(6):1893-902. doi: 10.2353/ajpath.2007.061281.
Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (Reg(AGE)) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (Low(AGE)), would decrease these abnormalities. C57BL6 male mice with a life-long exposure to a Low(AGE) diet had higher than baseline levels of tissue AGER1 and glutathione/oxidized glutathione and reduced plasma 8-isoprostanes and tissue RAGE and p66(shc) levels compared with mice pair-fed the regular (Reg(AGE)) diet. This was associated with a reduction in systemic AGE accumulation and amelioration of insulin resistance, albuminuria, and glomerulosclerosis. Moreover, lifespan was extended in Low(AGE) mice, compared with Reg(AGE) mice. Thus, OS-dependent metabolic and end organ dysfunction of aging may result from life-long exposure to high levels of glycoxidants that exceed AGER1 and anti-oxidant reserve capacity. A reduced AGE diet preserved these innate defenses, resulting in decreased tissue damage and a longer lifespan in mice.
衰老伴随着氧化应激（OS）增加和晚期糖基化终产物（AGEs）的积累。食物中AGE的形成受温度调节，摄入经过度加热制备的营养素会促进小鼠体内AGE的形成、OS以及心血管疾病。我们推测，正常饮食中持续暴露于高水平的促氧化AGEs（Reg(AGE)）会通过增加AGE负荷导致衰老，AGE负荷增加会引起AGER1失调和抗氧化能力耗竭，而等热量但AGE限制（减少50%）的饮食（Low(AGE)）会减少这些异常情况。与喂食常规（Reg(AGE)）饮食的配对小鼠相比，终生暴露于Low(AGE)饮食的C57BL6雄性小鼠的组织AGER1和谷胱甘肽/氧化型谷胱甘肽水平高于基线水平，血浆8-异前列腺素以及组织RAGE和p66(shc)水平降低。这与全身AGE积累减少以及胰岛素抵抗、蛋白尿和肾小球硬化的改善有关。此外，与Reg(AGE)小鼠相比，Low(AGE)小鼠的寿命延长。因此，衰老过程中依赖OS的代谢和终末器官功能障碍可能是由于终生暴露于超过AGER1和抗氧化储备能力的高水平糖氧化物所致。减少AGE的饮食保留了这些固有防御机制，从而减少了小鼠的组织损伤并延长了其寿命。
