EXTREME LONGEVITY IN NEMATODES: GENES & ENVIRONMENTS

线虫的极长寿命：基因

• 批准号: 6737113
• 负责人: Thomas E. Johnson
• 金额: $ 27.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6737113
• 关键词: Caenorhabditis elegans; aging; animal mortality; biological models; developmental genetics; environmental stressor; gene environment interaction; human mortality; longevity; mathematics; model design /development; mutant; nutrient intake activity; reproduction; statistics /biometry

Project 6: Extreme Longevity in Nematodes: Genes & Environments This project will examine mortality and exceptional survival in the nematode Caenorhabditis elegans. Our overarching hypothesis is that longevity is extremely plastic. Corollaries of this hypothesis are that both genetic and environmental factors can work independently in specifying mortality. Moreover, mortality is controlled segmentally: reduced mortality at one age does not automatically cause similar changes in mortality at all ages. We have some evidence in favor of our main hypothesis and its corollaries but we are not at all sure whether they generally hold, especially as longevity increases. Here we plan a series of experiments to test predictions of these hypotheses. Because of our interest in age-specific mortality and in extreme longevity, all will ultimately analyze populations of 100,000 or more nematodes in several ways. We intend also to build upon extremely exciting results that allow us to predict (on the second day of adult life) those worms destined to live longest in a population of genetically identical individuals. We actually have developed the capability of physically separating out a sub-cohort of long-lived individuals (all worms in the populations are genetically identical), using the COPAS "worm sorter", into a distinct population for subsequent analyses. These studies will reveal the dynamics of hidden heterogeneity of frailty. We will closely examine "late-life" reproductive capabilities in C. elegans with a goal of ascertaining whether "older" worms can reproduce under certain conditions or in certain genetic mutants. This capability also will allow direct assessment of possible artifacts resulting from the effects of induced sterility on subsequent mortality, observed in numerous studies of longevity mutants in C. elegans. We will ascertain the shape of the mortality curves throughout life, focusing on extreme longevity. We will analyze new longevity mutations and combinations of mutations that can quadruple life expectancy and maximum life span. We will study the effect of environmental determinants of extended longevity, such as caloric restriction, hormesis, and drug supplementation in large cohorts of the nematode. We will develop physiological and molecular predictors of extreme longevity.

项目6：线虫中的极端寿命：基因和环境 该项目将检查秀丽隐杆线虫线虫中的死亡率和出色的生存。我们的总体假设是寿命非常塑料。该假设的推论是遗传因素和环境因素都可以独立地指定死亡率。此外，死亡率是部分控制的：一个年龄的降低死亡率并不会自动在所有年龄段的死亡率上自动变化。我们有一些证据支持我们的主要假设及其推论，但我们根本不确定它们是否普遍存在，尤其是随着寿命的增加。在这里，我们计划了一系列实验，以测试这些假设的预测。由于我们对特定年龄的死亡率和极端寿命的兴趣，所有这些最终都会以多种方式分析100,000或更多线虫的人群。我们 也打算以极其令人兴奋的结果为基础，这使我们能够预测那些注定要在遗传相同的个体中生活最长的蠕虫。实际上，我们已经开发了将长寿命的子圆形分离出来的能力（种群中的所有蠕虫都是遗传上相同的），使用COPAS“蠕虫分类器”，分为不同的人群，以进行随后的分析。这些研究将揭示脆弱的隐藏异质性的动态。 我们将在秀丽隐杆线虫中仔细检查“后期”的生殖能力，其目的是确定在某些条件下还是在某些遗传突变体中“较老”的蠕虫可以繁殖。该能力还将允许直接评估因诱导的无菌性对随后死亡率的影响而导致的可能的伪影，这在秀丽隐杆线虫的寿命突变体的许多研究中都观察到。 我们将确定一生的死亡率曲线的形状，重点是极端寿命。我们将分析新的寿命突变和突变的组合，这些突变可以使预期寿命和最大寿命四倍。我们将研究延长寿命的环境决定因素的影响，例如在线虫的大量同类中，例如热量限制，刺激性和药物补充。 我们将开发极寿命的生理和分子预测指标。