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Indy突变）相关的分子遗传、生化和生理变化。热量限制（CR）是延长动物寿命和延迟年龄相关症状发作的最成功方法。CR减缓了许多不同实验生物体中生理衰退和年龄相关病理的发生。果蝇（Drosophila melanogaster）中Indy基因的突变可以显著延长寿命，而不会降低代谢率、体力活动或生育能力。INDY是克雷布斯循环中间体的二羧酸转运蛋白，主要存在于中肠、脂肪体和单核细胞的质膜中，这些组织对果蝇的中间代谢很重要。已提出降低Indy活性的寿命延长效应是由与CR相关的变化类似的变化引起的。我们将通过比较死亡率、代谢特征（例如脂质、葡萄糖、糖原等）和死亡率来测试Indy长寿突变是否诱导了CR状态。和基因组转录反应的印第长寿苍蝇和热量限制苍蝇。在这些研究的过程中，我们将专注于确定导致寿命延长的果蝇对热量限制的生理和分子反应，以实现我们的长期目标，即了解衰老过程的分子遗传机制。

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.