果蝇长寿基因methuselah的研究进展

果蝇Drosophila 3号染色体上methuselah （mth）基因发生突变后， 成年果蝇的平均寿命会延长约35%， 并且对一系列外界胁迫因素如饥饿、 高温、 百草枯（可产生强氧化性自由基）的耐受性会显著增强。研究表明mth编码的Mth蛋白属于B家族G蛋白偶联受体（G protein-coupled receptor, GPCR）， 其内源性配体是sun基因编码的小分子肽Stunted。现已发现敲除sun基因或者过表达Mth受体的肽类拮抗剂均能延长果蝇的寿命。Mth受体是目前发现的首个与动物衰老调控相关的GPCR， 该受体除了具有GPCR典型的7次跨膜结构外， 还具有其独特的胞外结构域， 该胞外结构域能够与多种配体结合。Mth受体的生理功能主要体现为： 维持生物体内环境稳态和新陈代谢的平衡， 参与调控果蝇的寿命、 应激反应、 雄性种系干细胞数量和感知运动能力等。目前对Mth受体的研究尚处于起步阶段， 其工作机理的解析对于我们揭示GPCR如何参与寿命的调节具有重要意义， 为我们开发延长人类寿命的新药提供了可能。鉴于此， 本文主要对果蝇Mth受体的结构功能、 配体及其寿命调控信号转导通路等方面做了总结， 并对Mth受体寿命调控信号通路的实用研究价值做了一些展望。

Research progress on the longevity gene methuselah in Drosophila

The mutation of the gene methuselah (mth) in Drosophila chromosome 3 leads to a 35% increase in average lifespan of adults and enhances their resistance to various forms of stress, such as starvation, high temperature, and paraquat, a superoxide-generating drug. The gene methuselah (mth) encodes a family B G protein-coupled receptor (GPCR) Mth and its endogenous ligand is Stunted, a small peptide encoded by the sun gene. The sun gene knockout or overexpression of peptide antagonists of Mth receptor also extends life span of fruit flies. Mth receptor characterized by a signature seven-trans-membrane configuration is thought to be the first GPCR associated with the control of animal ageing. The unique ectodomain of Mth receptor makes contact with multiple ligands. Its biological functions include maintaining the balance of homeostasis and metabolism and participating in the regulation of lifespan, stress response, male germline stem cell population, sensorimotor function, etc. At present, researches of Mth receptor are still in the initial stage. Its working mechanism is of great significance to reveal how GPCR participates in lifespan control. Moreover, it may help us develop new drugs to extend life. Therefore, the structure, function, ligand and signal transduction pathway of the Drosophila Mth receptor were mainly summarized in this article and the outlook for the practical research value of its signal pathway were also reviewed.