Molecular mechanisms underlying lifespan extension by dietary restriction

描述（由申请人提供）：饮食限制（DR）可以延长寿命并延缓年龄依赖性疾病的发作。本提案的总体目标是确定DR对长寿益处的分子机制。能量感应amp激活的蛋白激酶（AMPK）在细胞能量水平下降时被激活，这是DR的直接后果，提高了AMPK介导DR延长寿命的可能性。我们最近发现，DR延长蠕虫的寿命需要AMPK， AMPK磷酸化并激活FoxO转录因子，FoxO转录因子是几种已知的调节物种寿命的蛋白质。基于最近的工作，我们确定了受FoxO转录因子调控的基因对AMPK激活的响应，我们假设能量敏感的AMPK将DR信号转化为基因表达程序的长期变化，至少部分是通过FoxO转录因子的激活。为了解决AMPK如何调节DR对寿命延长的反应，我们提出以下具体目标：分析AMPK家族在DR信号感知中的作用。为了确定AMPK延长寿命的分子机制，将遗传学和生化方法结合起来研究秀丽隐杆线虫（C. elegans）。破译AMPK在DR作用下控制寿命的机制，将增加我们对控制寿命的重要基因和细胞反应的认识。了解AMPK-FoxO通路在秀丽隐杆线虫寿命中的作用，也将为研究DR对哺乳动物寿命的影响机制提供分子基础。

DESCRIPTION (provided by applicant): Dietary restriction (DR) increases lifespan and delays the onset of age-dependent diseases. The overarching goal of this proposal is to identify the molecular mechanisms underlying the benefits of DR on longevity. The energy-sensing AMP-activated protein kinase (AMPK) is activated in response to decreased cellular energy levels, a direct consequence of DR, raising the possibility that AMPK mediates lifespan extension in response to DR. We recently showed that AMPK is required for DR to extend lifespan in worms and that AMPK phosphorylates and activates FoxO transcription factors, proteins that are known to regulate lifespan in several species. Based on recent work in which we identified genes regulated by FoxO transcription factors in response to AMPK activation, we hypothesize that the energy-sensing AMPK translates DR signals into long-term changes in gene expression programs, at least partly through the activation of FoxO transcription factors. To address the question of how AMPK regulates the extension of lifespan in response to DR, we propose the following specific aims: Aim 1. To dissect the role of the AMPK family in sensing DR signals Aim 2. To determine the molecular mechanisms by which AMPK extends lifespan A combination of genetics and biochemical approaches in Caenorhabditis elegans (C. elegans) will be used to develop these aims. Deciphering the mechanisms by which AMPK controls longevity in response to DR will increase our knowledge of the genes and the cellular responses that are important to control lifespan. Understanding the role of the AMPK-FoxO pathway in longevity in C. elegans will also provide a molecular foundation for studying the mechanisms underlying DR benefits on lifespan in mammals.