Reversible oxidation of methionine in aging

说明(申请人提供)：被活性氧氧化的氨基酸被认为是加速衰老的。蛋氨酸很容易被氧化成两种同分异构体：蛋氨酸-R-亚硫醚(MET-R-O)和蛋氨酸-S-亚硫醚(MET-S-O)。蛋氨酸亚砜还原酶A(MSRA)能还原MET-S-O，蛋氨酸亚砜还原酶B(MSRB)能还原MET-R-O。现在已知多种形式的MSRA和MSRB在组织和亚细胞分布上不同。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一个重要决定因素。然而，MET-R/S含量和MSRA/B活性如何随年龄变化尚无系统资料。此外，目前还不清楚不同的MSR形式在衰老过程中是否起到类似的作用。利用模式生物果蝇，这项研究将提供蛋氨酸氧化和MSRs在正常衰老生物学中的作用的全面观点。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活性随年龄的变化。不同形式的MSR在不同的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的开始方面的有效性。此外，系统地比较了长寿命MSRA果蝇和对照果蝇的基因表达谱。这项研究还将测试食物补充剂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的寿命。预期的结果应该在设计延长寿命的干预措施方面证明是有价值的。

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.