Metabolic Regulation in Aging and Caloric Restriction

热量限制（CR）已经成为延长许多实验生物寿命的最成功的方法。 CR减缓了生理衰退和一些与年龄相关的动物病理学的发生。 提出的机制包括减少由活性氧化物质引起的氧化损伤、减慢代谢速率、降低体温、改变基因表达和减少DNA损伤。 主要的变化包括代谢的转变，特别是葡萄糖、蛋白质和脂质。奇怪的是，寿命延长的分子机制尚未被揭示。我们已经确定了Indy（我还没死）基因的突变，它延长了成年果蝇的寿命。该基因是人、小鼠和大鼠二羧酸钠协同转运蛋白的果蝇同源基因，参与三羧酸循环中间产物的摄取、利用和储存。这表明Indy在能源生产中可能发挥作用。 Indy在脂肪体、卵母细胞和消化道中表达，这些部位是果蝇的中间代谢场所。 根据预测的作用，该基因在能源生产和其组织表达，我们认为，在Indy突变破坏正常的能源生产，并导致在苍蝇的条件类似于CR。 Indy突变体的寿命延长机制可能与热量限制相同或相似。 我们将确定葡萄糖，糖原，海藻糖，甘油三酯和蛋白质的水平在低热量和高热量食物的正常苍蝇的老龄化群体的关键变化，并将它们与Indy老龄化苍蝇的代谢变化进行比较。 在Indy果蝇中观察到的变化应该与在低热量食物的对照果蝇中观察到的代谢变化相似，这支持了我们的假设，即Indy是CR的遗传模型。在我们的提案中描述的数据将提供新的信息与衰老和CR在果蝇的关键代谢变化。其次，我们将获得Indy突变果蝇在延长寿命期间的代谢谱。 这项研究将提供Indy基因在中间代谢中的作用和与寿命延长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了解热量限制的分子和遗传机制及其对延长寿命的影响。

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.