THE ROLE OF PROTEIN TURNOVER IN AGING

描述（由申请人提供）：我们的长期目标是阐明 蛋白质合成和周转在衰老中的作用。 我们特别 对蛋白质周转在分子机制中的作用感兴趣 负责热量限制的抗衰老效果。 我们有 鉴定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率（Ryazanov et.例如， （1988）Nature 334：170-173; Ryazanov等人，等人（1997）Proc. Acad. Sci.九十四： 4884-4889）。 我们发现，在小杆线虫中敲除eEF-2激酶， 线虫导致蛋白质周转增加，并延长寿命。 相反，eEF-2激酶在转基因线虫中的过表达缩短了 寿命 长期以来，人们一直在讨论蛋白质的合成和周转可以 在衰老中起着重要的作用。 我们的研究结果提供了第一个直接的 实验证明了这一假设。 根据初步实验，我们 表明eEF-2激酶失活和导致的 蛋白质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，上- 通过抑制eEF-2激酶调节蛋白质合成可以 有助于热量限制的抗衰老效果。 在本申请中，我们将同时使用C。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 抑制衰老过程中，并研究eEF-2激酶的作用， 限制热量的抗衰老作用中的蛋白质周转。 我们将 并分析了eEF-2激酶在正常衰老和高热量饮食中的作用 最近，我们使用eEF-2激酶敲除小鼠在哺乳动物中进行了限制， 得到了 本申请中描述的实验旨在 为开发新的治疗试剂提供了基础， 可以模仿热量限制，规避一些有害的 老化的后果。

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.