EXTREME LONGEVITY IN NEMATODES: GENES & ENVIRONMENTS

项目6：线虫的超长寿命：基因和环境 该项目将研究线虫线虫的死亡率和特殊存活率。我们最重要的假设是，长寿极具可塑性。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：一个年龄段的死亡率下降并不会自动导致所有年龄段的死亡率发生类似的变化。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成立，特别是随着寿命的延长。在这里，我们计划进行一系列实验来测试这些假说的预测。由于我们对特定年龄的死亡率和极长寿的兴趣，所有人最终都将以几种方式分析10万或更多的线虫种群。我们 也意欲建立在极其令人兴奋的结果的基础上，使我们能够预测(在成年生命的第二天)那些注定在基因相同的个体群体中存活时间最长的蠕虫。实际上，我们已经开发出一种能力，可以使用COPAS“蠕虫分类器”将一群长寿的个体(种群中的所有蠕虫在基因上都是相同的)物理地分离出来，分成一个不同的种群，以供后续分析。这些研究将揭示脆弱性隐藏的异质性的动态。 我们将仔细研究线虫“晚年”的繁殖能力，目的是确定“较老”的线虫是否可以在特定条件下或在某些基因突变中繁殖。这一能力还将允许直接评估诱导性不孕对随后死亡率的影响所造成的可能的人工制品，这是在对线虫长寿突变的众多研究中观察到的。 我们将确定整个生命中死亡曲线的形状，重点是极端长寿。我们将分析新的长寿突变和可以使预期寿命和最长寿命翻两番的突变组合。我们将研究延长寿命的环境决定因素的影响，如卡路里限制、兴奋作用和在线虫大群中补充药物。 我们将开发出极长寿的生理和分子预测指标。

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.