Molecular Genetics of Caloric Restriction in Aging Flies

描述（由申请人提供）：本提案的目标是确定与两种相关的延长寿命干预措施（热量限制和长寿命Indy突变）相关的分子遗传，生化和生理变化。在动物中，热量限制（CR）是延长寿命和延缓年龄相关症状发作的最成功方法。在许多不同的实验生物体中，CR减缓了生理衰退和年龄相关病理的发生。果蝇（Drosophila melanogaster）体内Indy基因的突变，在不降低代谢率、身体活动或生育能力的情况下，显著延长了寿命。INDY是克雷布斯循环中间体的二羧酸转运体，主要存在于果蝇中肠、脂肪体和细胞的质膜中，这些组织对中间代谢很重要。降低Indy活性的延长寿命效应被认为是由类似于CR相关的变化引起的。我们将通过比较Indy长寿果蝇和热量限制果蝇的死亡率、代谢谱（如脂质、葡萄糖、糖原等）和基因组转录反应来测试Indy长寿突变是否诱导了CR状态。在这些研究过程中，我们将专注于确定导致果蝇寿命延长的热量限制的生理和分子反应，以实现我们理解衰老过程背后的分子遗传机制的长期目标。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the molecular genetic, biochemical and physiological changes associated with two related life-extending interventions, caloric restriction and the long-lived Indy mutation. Caloric restriction (CR) is the most successful way to increase life span and delay the onset of age-related symptoms in animals. CR slows down the physiological decline and occurrence of age-related pathologies in a number of different experimental organisms. Mutations in the Indy gene in the fruit fly, Drosophila melanogaster, dramatically extend life span without a decrease in metabolic rate, physical activity or fertility. INDY is a dicarboxylate transporter of Krebs cycle intermediates and is primarily found in the plasma membrane of midgut, fat body, and oneocytes, tissues important for intermediary metabolism in the fly. The life extending effect of reducing Indy activity has been proposed to result from changes similar to those associated with CR. We will test whether Indy long-lived mutations have induced a state of CR by comparing the mortality rate, metabolic profile (e.g. lipids, glucose, glycogen, etc.) and genomic transcriptional responses of Indy long-lived flies and calorically restricted flies. In the course of these studies we will focus on determining the physiological and molecular responses to caloric restriction that lead to life span extension in the fly in order to achieve our long-term goal of understanding the molecular genetic mechanisms underlying the process of aging.