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减缓了动物的生理衰退和一些与年龄相关的病理的发生。可能的机制包括活性氧化物质引起的氧化损伤减少、代谢速率减慢、体温降低、基因表达改变和DNA损伤减少。主要的变化包括新陈代谢的变化，尤其是葡萄糖、蛋白质和脂质。矛盾的是，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，这种突变可以延长成年果蝇的寿命。该基因是人类、小鼠和大鼠二羧酸钠共转运体的苍蝇同源基因，参与克雷布斯循环中间体的吸收、利用和储存。这表明印度可能在能源生产中发挥作用。Indy在果蝇的脂肪体、卵巢细胞和消化道、中间代谢部位表达。基于该基因在能量产生及其组织表达中的预测作用，我们认为Indy突变破坏了正常的能量产生，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。我们将确定低热量和高热量食物下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关键变化，并将其与印度衰老果蝇的代谢变化进行比较。在Indy果蝇中观察到的变化应该与对照果蝇在低热量食物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。我们的提案中描述的数据将为果蝇衰老和CR相关的关键代谢变化提供新的信息。其次，我们将获得Indy突变蝇在其延长寿命期间的代谢谱。该研究将为Indy基因在中间代谢中的作用与与寿命延长相关的代谢变化之间的直接联系提供依据。我们的研究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.