長壽基因Indy影響老化的機制探討

Abstract

經研究證實限制飲食中的卡路里攝取可延長壽命，並可降低與延緩老化相關疾病如：神經退化性疾病、癌症與心血管疾病等的發生。許多卡路里限制影響的生理及細胞分子機轉已逐漸揭開，然而其延長壽命的機制並不十分清楚。儘管如此，卡路里限制的概念已被廣泛的運用於治療老化相關的疾病上。利用果蠅為研究模式，在我們之前的研究中顯示，I`m not dead yet (Indy) 的基因突變可顯著延長果蠅的壽命 (Wang et al., 2009a)；且發現Indy 基因大量表現在果蠅的消化道，其功能亦與Krebs cycle 的中間代謝物之運送有關。這些特性顯示， Indy 突變延長壽命的機轉可能是透過調控動物體內養分的吸收、利用及儲存，而達成類似卡路里限制的生理狀態。除了果蠅之外，人類及其他哺乳動物中亦有和Indy 相似的蛋白存在。因此，我們若能深入瞭解Indy 突變延長壽命的機轉，對於人類健康及老化相關疾病的治療將會有莫大幫助。本研究計畫的主要目標在於：探討卡路里限制與Indy 如何交互作用以及如何延長壽命的機轉，並應用於神經退化性疾病的治療。

Calorie restriction (CR) has been shown to increase lifespan and delay the onset of age-related diseases including neurodegenerative diseases, cancers, and cardiovascular diseases. Despite the fact that many downstream molecules and physiological systems have been shown to be regulated by CR, the mechanism by which CR extends lifespan remains unclear. Nevertheless, CR has been shown to be beneficial for treating several age-related diseases. We have previously shown that a single mutant gene called I`m not dead yet (Indy) can cause dramatic lifespan extension (Wang et al., 2009a) in Drosophila melanogaster. The function of the Indy protein is a transporter of Krebs cycle intermediates, and its preliminary localization to regions of the fly important in uptake, utilization and storage of nutrients suggests that Indy mutation may alter the metabolic state similarly to CR, to favor lifespan extension. Indy’s similarity to mammalian and human dicarboxylate transporters suggests that knowledge of how Indy extends lifespan in the fly will be valuable for treating agerelated diseases and for improving healthy lifespan in humans. The main goal of our research is to try to understand the mechanism by which Indy and CR extend lifespan, and their applications for treating neurodegenerative diseases.