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：线虫的极长寿命：基因与环境 该项目将研究线虫秀丽隐杆线虫的死亡率和异常存活率。我们的首要假设是，寿命具有极强的可塑性。这一假设的推论是，遗传因素和环境因素都可以独立地影响死亡率。此外，死亡率是分段控制的：某一年龄段死亡率的降低不会自动导致所有年龄段死亡率的类似变化。我们有一些证据支持我们的主要假设及其推论，但我们完全不确定它们是否普遍成立，尤其是随着寿命的延长。在这里，我们计划进行一系列实验来检验这些假设的预测。由于我们对特定年龄死亡率和极端寿命的兴趣，最终将通过多种方式分析 100,000 或更多线虫种群。我们 还打算建立在极其令人兴奋的结果的基础上，使我们能够预测（在成年后的第二天）那些注定在基因相同的个体群体中寿命最长的蠕虫。实际上，我们已经开发出使用 COPAS“蠕虫分类器”将长寿个体子群（种群中的所有蠕虫在基因上都相同）物理分离成不同种群的能力，以进行后续分析。这些研究将揭示脆弱的隐藏异质性的动态。 我们将仔细研究线虫的“晚年”繁殖能力，目的是确定“老年”蠕虫是否可以在某些条件下或在某些基因突变体中繁殖。这种能力还可以直接评估诱导不育对随后死亡率的影响可能产生的假象，这在对秀丽隐杆线虫长寿突变体的大量研究中观察到。 我们将确定一生中死亡率曲线的形状，重点关注极端长寿。我们将分析新的长寿突变和突变组合，它们可以使预期寿命和最大寿命增加四倍。我们将研究延长寿命的环境决定因素的影响，例如热量限制、兴奋作用和大群线虫的药物补充。 我们将开发极端长寿的生理和分子预测因子。