CALORIC RESTRICTION ATTENUATES PROTEIN OXIDATIVE DAMAGE IN AGING MICE

热量限制可减轻衰老小鼠的蛋白质氧化损伤

• 批准号: 6665857
• 负责人: CHRISTIAAN LEEUWENBURGH
• 金额: $ 15.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665857
• 关键词: animal tissue; biological products; biomedical resource; drug adverse effect; environmental toxicology; liver; neoplasm /cancer; spectrometry; urinary tract

Oxidative damage, particularly to proteins, has been widely postulated to be a major causitive factor in the loss of functional capacity during senescence. The nature of the various mechanisms that may contribute to protein oxidation is only partially understood. In this study, concentrations of two markers for oxidative damage, o,o'-dityrosine and o-tyrosine, were determined using stable isotope dilution gas chromatography-mass spectrometry in four tissues of the mouse, namely heart, skeletal muscle, brain and liver during youth (4 month old), adulthood (14 month old) and old (30 month old) age. A comparison was made between mice that had access to unlimited calories with those that were restricted to 60 % of the caloric intake of the ad libitum regimen. In vitro studies demonstrated that o,o'-dityrosine was generated selectively in proteins exposed to tyrosyl radical. o-Tyrosine increased in proteins oxidized with hydroxyl radical, which also resulted in a va riable inc rease in o,o'-dityrosine. In the ad-libitum fed mice, levels of o,o'-dityrosine increased with age in cardiac and skeletal muscle but not in liver or brain. In contrast, o-tyrosine levels did not rise with age in any of the tissues examined. These results suggest that tyrosyl radical-induced protein oxidation increases selectively with age in skeletal muscle and heart. Caloric restriction prevented the increase in o,o'-dityrosine levels in cardiac and skeletal muscle but did not influence o-tyrosine levels in any of the four tissues. This selective increase in o,o'-dityrosine levels and its prevention by life-prolonging caloric restriction regimen raises the possibility that oxidation of muscle proteins by tyrosyl radical contributes to the deterioration of cardiac and skeletal muscle function with advancing age.

氧化损伤，尤其是蛋白质的氧化损伤，已被广泛 被认为是导致功能丧失的主要因素 衰老过程中的能力。 各种机制的性质 可能有助于蛋白质氧化的情况仅被部分了解。 在 这项研究，两种氧化损伤标志物的浓度， o,o'-二酪氨酸和邻酪氨酸，使用稳定同位素测定 四种组织的稀释气相色谱-质谱分析 小鼠，即青年时期的心脏、骨骼肌、大脑和肝脏（4 月龄）、成年（14 个月）和老年（30 个月）年龄。 一个 对摄入无限卡路里的老鼠进行了比较 那些限制热量摄入60%的人 随意服用的方案。 体外研究表明 o,o'-二酪氨酸在暴露于 酪氨酰基。 氧化蛋白质中的邻酪氨酸增加 羟基自由基，这也导致了不同程度的增加 o,o'-二酪氨酸。 在随意喂养的小鼠中， 心肌和骨骼肌中的o,o'-二酪氨酸随着年龄的增长而增加，但 不在肝脏或大脑中。 相比之下，邻酪氨酸水平没有上升 随着任何检查组织的年龄。 这些结果表明 酪氨酰自由基诱导的蛋白质氧化选择性增加 骨骼肌和心脏的年龄。 热量限制阻止了 心肌和骨骼肌中o,o'-二酪氨酸水平增加，但 不影响四种组织中任何一种的邻酪氨酸水平。 这 选择性增加 O,O'-二酪氨酸水平及其预防 延长生命的热量限制方案增加了可能性 酪氨酰自由基对肌肉蛋白的氧化有助于 心脏和骨骼肌功能的恶化 年龄的增长。