Metabolic Regulation in Aging and Caloric Restriction

卡路里限制(CR)已经成为延长许多实验生物寿命的最成功的方法。CR延缓了生理性衰退和某些动物年龄相关病理的发生。提出的机制包括减少由反应性氧化物种引起的氧化损伤，降低新陈代谢速度，降低体温，改变基因表达和减少DNA损伤。主要的变化包括新陈代谢的变化，特别是葡萄糖、蛋白质和血脂。矛盾的是，延长寿命背后的分子机制还没有被揭示。我们已经确定了Indy(我还没有死)基因的突变，这种基因可以延长成年果蝇的寿命。该基因是人、小鼠和大鼠二羧酸钠共转运体的果蝇同源基因，参与Krebs循环中间产物的吸收、利用和储存。这表明，印地可能会在能源生产中发挥作用。Indy在果蝇的脂肪体、卵母细胞和消化道表达，是果蝇中间代谢的部位。根据该基因在能量产生中的预测作用及其组织表达，我们认为Indy基因的突变扰乱了正常的能量产生，并导致果蝇出现类似CR的情况。Indy突变体的寿命延长机制可能与热量限制相同或相似。我们将测定食用低热量和高热量食物的正常果蝇衰老种群中葡萄糖、糖原、海藻糖、甘油三酯和蛋白质水平的临界变化，并将它们与印度衰老果蝇的代谢变化进行比较。在Indy果蝇身上观察到的变化应该类似于在低热量食物中观察到的对照果蝇的代谢变化，这支持了我们的假设，即Indy是CR的遗传模型。我们提案中描述的数据将提供与果蝇衰老和CR相关的关键代谢变化的新信息。其次，我们将获得Indy突变果蝇在延长寿命期间的代谢概况。这项研究将提供Indy基因在中间代谢中的作用与与延长寿命相关的代谢变化之间的直接联系。我们研究的目的是检查和理解卡路里限制的分子和遗传机制及其对寿命延长的影响。

Caloric restriction (CR) has emerged as the most successful way to extend the life span of a number of experimental organisms. CR slows down physiological decline and occurrence of some of the age-related pathology of animals. Suggested mechanisms include reduced oxidative damage caused by reactive oxidative species, slower metabolic rate, reduction in body temperature, alterations in gene expression and reduction in DNA damage. The main changes include a shift in metabolism, particularly glucose, protein and lipids. Paradoxically, the molecular mechanisms underlying life span extension have not been revealed. We have identified mutations in the Indy (I'm not dead yet) gene that extends life span of adult fruit flies. The gene, a fly homologue of a human, a mice and a rat sodium dicarboxylate cotransporter is involved in uptake, utilization and storage of Krebs cycle intermediates. This suggests a possible role of Indy in energy production. Indy is expressed in fat body, oenocytes and digestive tract, places of intermediary metabolism in flies. Based on the predicted role of the gene in energy production and its tissue expression we suggest that mutations in Indy disrupt normal energy production and result in a condition in flies similar to CR. The mechanism of life extension in Indy mutants may be the same as or similar to caloric restriction. We will determine the critical changes in the level of glucose, glycogen, trehalose, tryglyceride and proteins in aging populations of normal flies on low and high caloric food and compare them to metabolic changes in Indy aging flies. The changes observed in Indy flies should be similar to the metabolic changes observed for control flies on low caloric food supporting our hypothesis that Indy is a genetic model for CR. The data described in our proposal will provide new information on the critical metabolic changes associated with aging and CR in fruit flies. Second, we will obtain metabolic profile of Indy mutant flies during their extended life span. This study will provide a direct link between the role of Indy gene in intermediary metabolism and metabolic changes associated with life span extension. The goal of our studies is to examine and understand the molecular and genetic mechanisms of caloric restriction and its effect on life span extension.