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--卡路里限制和长寿印地突变--相关的分子遗传、生化和生理变化。卡路里限制(CR)是延长动物寿命和延缓年龄相关症状发生的最成功的方法。在一些不同的实验生物体中，CR可以减缓生理衰退和与年龄相关的病理的发生。果蝇Indy基因的突变在不降低代谢率、体力活动或生育能力的情况下，显著延长了寿命。Indy是一种Krebs循环中间产物的二羧酸转运体，主要存在于中肠、脂肪体和单核细胞的质膜上，这些组织对苍蝇的中间代谢很重要。减少Indy活动的延长寿命的效果被认为是由与CR相关的变化引起的。我们将通过比较死亡率、代谢特征(例如，血脂、葡萄糖、糖原等)来测试Indy长寿命突变是否导致了CR状态。以及印地长寿果蝇和卡路里限制果蝇的基因组转录反应。在这些研究过程中，我们将重点确定卡路里限制导致果蝇寿命延长的生理和分子反应，以实现我们了解衰老过程中潜在的分子遗传学机制的长期目标。

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.