Reversible oxidation of methionine in aging

老化过程中蛋氨酸的可逆氧化

• 批准号: 6880064
• 负责人: TOSHINORI HOSHI
• 金额: $ 26.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880064
• 关键词: Drosophilidae; age difference; aging; alpha synuclein; aminoacid analog; aminoacid metabolism; cysteine; dietary supplements; enzyme activity; gene expression profiling; invertebrate locomotion; isozymes; longevity; methionine; neural degeneration; nutrition of aging; nutrition related tag; oxidation; oxidative stress; oxidoreductase; sulfoxide; transfection

DESCRIPTION (provided by applicant): Oxidation of amino acids by reactive oxygen species is considered to accelerate aging. The amino acid methionine is readily oxidized to form two epimers of methionine sulfoxide, methionine-R-sulfoxide (met-R-O) and methionine-S-sulfoxide (met-S-O). The enzyme methionine sulfoxide reductase A (MSRA) reduces met-S-O while the enzyme methionine sulfoxide reductase B (MSRB) reduces met-R-O. Multiple forms of MSRA and MSRB that differ in tissue and subcellular distributions are now known. Increasing evidence suggests that methionine oxidation may be an important determinant of the time course of normal aging. However, there is no systematic information available how the met-R/S-contents and MSRA/B activities change with age. Furthermore, it is not known whether different MSR forms play similar roles in aging. Using the model organism Drosophila, the study proposed here will provide a comprehensive view of the roles of methionine oxidation and MSRs in normal biology of aging. Age-dependent changes in the oxidized methionine contents and MSR activities in different tissues and subcellular fractions are systematically measured. Different forms of MSRs are overexressed in different tissues and subcellular regions to compare their efficacies in lifespan extension and delaying the onset of decline in the physical activity level and reproductive vigor. Furthermore, gene expression profiles in the long-living MSRA flies are systematically compared with those of control flies. The study will also test whether a food supplement, S-methyI-L-cysteine, could act to extend the animal lifespan by participating in the reversible methionine oxidation cycle involving the MSR system. The results expected should prove valuable in designing interventions to extend lifespan.

描述（由申请人提供）：活性氧对氨基酸的氧化被认为会加速衰老。氨基酸蛋氨酸很容易被氧化形成蛋氨酸亚砜的两种差向异构体，即蛋氨酸-R-亚砜(met-R-O)和蛋氨酸-S-亚砜(met-S-O)。蛋氨酸亚砜还原酶 A (MSRA) 还原met-S-O，而蛋氨酸亚砜还原酶 B (MSRB) 还原met-R-O。目前已知多种形式的 MSRA 和 MSRB 在组织和亚细胞分布上有所不同。越来越多的证据表明，蛋氨酸氧化可能是正常衰老时间进程的重要决定因素。然而，没有系统的信息可用，met-R/S-含量和 MSRA/B 活性如何随年龄变化。此外，尚不清楚不同的 MSR 形式是否在衰老过程中发挥相似的作用。使用模型生物果蝇，本文提出的研究将全面了解蛋氨酸氧化和 MSR 在正常衰老生物学中的作用。系统地测量了不同组织和亚细胞部分中氧化蛋氨酸含量和 MSR 活性随年龄的变化。不同形式的MSR在不同组织和亚细胞区域过度表达，以比较它们在延长寿命和延缓体力活动水平和生殖活力下降方面的功效。此外，系统地将长寿 MSRA 果蝇的基因表达谱与对照果蝇的基因表达谱进行比较。该研究还将测试食品补充剂 S-甲基-L-半胱氨酸是否可以通过参与涉及 MSR 系统的可逆蛋氨酸氧化循环来延长动物寿命。预期的结果对于设计延长寿命的干预措施应该是有价值的。