Molecular mechanisms underlying lifespan extension by dietary restriction

描述(申请人提供)：饮食限制(DR)可延长寿命并延缓与年龄相关的疾病的发病。这项建议的首要目标是确定DR对长寿的益处背后的分子机制。能量敏感的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，增加了AMPK介导寿命延长的可能性。我们最近发现，AMPK是DR延长蠕虫寿命所必需的，AMPK磷酸化并激活FoxO转录因子，这些蛋白质已知在几个物种中调节寿命。根据我们最近的工作，我们发现了受FoxO转录因子调控的基因，以响应AMPK的激活，我们假设能量敏感的AMPK将DR信号翻译成基因表达程序的长期变化，至少部分通过FoxO转录因子的激活。为了解决AMPK如何调节DR引起的寿命延长的问题，我们提出了以下具体目标：目的1.剖析AMPK家族在感知DR信号中的作用目的2.确定AMPK延长寿命的分子机制将结合秀丽线虫的遗传学和生物化学方法来开发这些目标。破译AMPK在DR反应中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了解。了解AMPK-FoxO通路在线虫寿命中的作用也将为研究哺乳动物DR延长寿命的机制提供分子基础。公共卫生相关性：饮食限制(DR)延长了寿命，推迟了年龄依赖性疾病的发病，包括癌症和神经退行性疾病。确定DR对寿命的益处的分子基础将有助于揭示DR方案的重要组成部分，从而可能模仿DR的效果，使其在预防和治疗年龄依赖性疾病方面具有实际应用价值。

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. PUBLIC HEALTH RELEVANCE: Dietary restriction (DR) extends lifespan and delays the onset of age-dependent diseases, including cancer and neurodegenerative disorders. Identifying the molecular basis by which DR exerts its benefits on lifespan will help uncover the important components of the DR regimen to possibly mimic the effects of DR to make it of practical use for preventing and treating age-dependent pathologies.