Reversible oxidation of methionine in aging

老化过程中蛋氨酸的可逆氧化

• 批准号: 7216174
• 负责人: TOSHINORI HOSHI
• 金额: $ 25.18万
• 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/7216174
• 关键词: Abdomen; Aconitate Hydratase; Age; Aging; Aging-Related Process; Amino Acids; Animal Model; Animals; Back; Behavior; Biology of Aging; Classification; Cysteine; Cytoplasm; Defect; Disease; Disease model; Drosophila genus; Ectopic Expression; Enzymes; Food Supplements; Free Radicals; Gene Expression; Gene Proteins; Head; Human; Laboratories; Life; Longevity; Measures; Methionine; Mitochondria; Modeling; Molecular Profiling; Motor Activity; Nervous system structure; Neurodegenerative Disorders; Nitrogen; Oxygen; Parkinson Disease; Phenotype; Physical activity; Physiology; Play; Protein Isoforms; Protein Overexpression; Proteins; Reactive Oxygen Species; Reproduction; Role; Subcellular Fractions; Sulfoxide; System; Testing; Time; Tissues; Work; age related; fly; harman; methionine sulfoxide; methionine sulfoxide reductase; normal aging; oxidation; prevent; protein expression; repaired; reproductive; senescence; synuclein; theories; therapy design

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）：氨基酸被活性氧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个外显体，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）能还原甲基硫代o，而蛋氨酸亚砜还原酶B （MSRB）能还原甲基硫代o。目前已知多种形式的MSRA和MSRB在组织和亚细胞分布上存在差异。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，met-R/ s含量和MSRA/B活性如何随年龄变化尚无系统的资料。此外，不同的MSR形式在衰老过程中是否起着相似的作用尚不清楚。本研究以果蝇为模型生物，对蛋氨酸氧化和MSRs在正常衰老生物学中的作用进行了全面的研究。系统地测量了不同组织和亚细胞组分中氧化蛋氨酸含量和MSR活性的年龄依赖性变化。不同形式的MSRs在不同的组织和亚细胞区域过表达，比较它们在延长寿命和延缓身体活动水平和生殖活力下降方面的效果。此外，系统地比较了长寿MSRA蝇与对照蝇的基因表达谱。该研究还将测试一种食品补充剂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。预期的结果在设计延长寿命的干预措施方面应该证明是有价值的。