THE ROLE OF PROTEIN TURNOVER IN AGING

描述(由申请人提供)：我们的长期目标是澄清 蛋白质合成和周转在衰老中的作用。我们特别是 对蛋白质周转在分子机制中的作用感兴趣(S) 负责卡路里限制的抗衰老作用。我们有 发现了一种新的蛋白激酶，延伸因子-2(EEF-2)激酶， 可以调节动物细胞中蛋白质合成的速度(Ryazanov et.艾尔， (1988)自然334：170-173；Ryazanov等人，(1997)Proc.娜塔莉。阿卡德。SCI。94： 4884-4889)。我们发现在炎中EEF-2激酶基因被敲除 秀丽能增加蛋白质周转率，延长寿命。 相反，在转基因线虫中过表达EEF-2激酶会缩短 寿命。长期以来，人们一直在讨论蛋白质的合成和周转可以 在衰老过程中起到致病作用。我们的结果提供了第一个直接的 对这一假设的实验支持。从我们的初步实验来看，我们 提示EEF-2激酶的失活以及由此导致的 蛋白质的合成和降解导致更有效地去除 氧化损伤的蛋白质，从而延长寿命。此外，UP- 通过抑制EEF-2激酶调节蛋白质合成可能 有助于卡路里限制的抗衰老作用。 在这项赠款申请中，我们将同时使用线虫和小鼠作为模型 系统。我们计划阐明蛋白质合成的分子机制。 在衰老过程中的抑制作用，并探讨EEF-2激酶和 蛋白质周转中卡路里限制的抗衰老作用。我们会 同时还分析了EEF-2在正常衰老和热量消耗中的作用 我们最近利用EEF-2激酶基因敲除小鼠对哺乳动物的限制 获得。本拨款申请中所描述的实验旨在 为开发新型治疗试剂提供基础 可以模拟卡路里限制，避开一些有害的 老龄化的后果。

DESCRIPTION (provided by applicant): Our long-term goal is to elucidate the role of protein synthesis and turnover in aging. We are particularly interested in the role of protein turnover in the molecular mechanism(s) responsible for the anti-aging effect of caloric restriction. We have identified a novel protein kinase, elongation factor-2 (eEF-2) kinase, that can modulate the rate of protein synthesis in animal cells (Ryazanov et. al., (1988) Nature 334: 170-173; Ryazanov et al., (1997) Proc. Natl. Acad. Sci. 94: 4884-4889). We found that a knockout of eEF-2 kinase in Caenorhabditis elegans results in an increase in protein turnover, and extends life span. Conversely, overexpression of eEF-2 kinase in transgenic nematodes shortens life span. It has long been discussed that protein synthesis and turnover can play a causative role in aging. Our results provide the first direct experimental support of this hypothesis. From our preliminary experiments, we suggest that inactivation of eEF-2 kinase and the resulting increase in protein synthesis and degradation leads to a more efficient removal of oxidatively damaged proteins, and thus extends life span. In addition, up- regulation of protein synthesis through inhibition of eEF-2 kinase may contribute to the anti-aging effect of caloric restriction. In this grant application, we will use both C. elegans and mice as model systems. We plan to elucidate the molecular mechanism of protein synthesis inhibition during aging and to investigate the role of eEF-2 kinase and protein turnover in the anti-aging effect of caloric restriction. We will also analyze the rote of eEF-2 kinase in normal senescence and caloric restriction in mammals using the eEF-2 kinase knockout mice we recently obtained. The experiments described in this grant application are designed to provide a foundation for the development of novel therapeutic reagents that can mimic caloric restriction, circumventing some of the deleterious consequences of aging.