Overactivity in growth and its effects on rates of ageing

热量限制（CR）是在不改变营养成分或营养不良的情况下减少营养摄入量，是为数不多的已知治疗方法之一，可以延缓各种动物的衰老，从酵母到哺乳动物。营养感应遗传途径的下调，如高度保守的TOR激酶和胰岛素途径，被认为介导CR的作用。营养感应途径的活动究竟如何导致更快的衰老尚不清楚。一种流行的理论认为，高代谢导致自由基的产生，从而导致分子损伤。然而，有一些证据与氧化损伤理论相矛盾，氧化损伤理论是衰老的原因。这项研究将使用另一种理论框架来解决衰老的机制。根据最近发展起来的一种理论，衰老是一个发展程序意外功能亢进的结果。因此，在以后的生活中继续增长可能导致病理学和最终死亡。这一理论可以解释氧化损伤理论中的许多悖论，也可以解释为什么CR可以延缓衰老。用汽车来类比，不是因为“生锈”而老化，这个新理论提出，老化就像一辆没有刹车和司机的汽车。我们建议研究一种线虫（蛔虫），这种线虫产生基因相同的兄弟姐妹，但寿命不同;这种线虫的雌雄同体总是比雌性长三分之一。性别之间没有遗传差异，这将有助于对寿命差异的原因进行适当的控制实验。线虫是研究衰老的理想工具，因为它们的寿命相对较短，并且易于在实验室中培养和操作。我们假设我们的线虫模型的雌雄同体的雌性以不同的速度衰老，因为它们积累了与年龄相关的病理，这些病理是成年期不同时间功能亢进的结果。我们将通过使用性别修饰治疗、基因表达和基因敲除分析来操纵衰老率来测试这一假设。我们的模式物种提供了一个强大的系统来研究衰老的机制，因为我们可以大量培养它们，并从基因上操纵它们的基因组和性别。最近的研究表明，线虫、昆虫和哺乳动物有一些相同的衰老机制。因此，我们预计这项建议的结果将适用于其他生物。

Caloric restriction (CR), which is the reduction of nutrient intake without change in nutrient composition or malnutrition, is one of the few known treatments that delay ageing in a wide variety of animals, from yeast to mammals. The down-regulation of nutrient-sensing genetic pathways, such as the highly conserved TOR kinase and insulin pathways, are thought to mediate the effects of CR. How exactly the activity of nutrient-sensing pathways leads to faster ageing is not known. A popular theory suggests that high metabolism results in the production of free radicals, which causes molecular damage. However, there is some evidence that contradicts the oxidative damage theory as the cause of ageing. This research will address the mechanisms of ageing using an alternative theoretical framework. According to a theory developed recently, ageing is the result of an unintended hyperfunction of a developmental program. Thus, growth that continues later in life could lead to pathology and eventual death. This theory can explain many of the paradoxes reported for the oxidative damage theory, as well as explain why CR delays ageing. Making an analogy with a car, instead of ageing due to "rusting", this new theory proposes that ageing is like a car that drives without any brakes and driver. We propose to study a species of nematode (roundworm) that produces genetically identical siblings, but that show different lifespan; hermaphrodites of this nematode consistently live a third longer than females. The absence of genetic differences between genders will facilitate proper control experiments for the cause of differences in lifespan. Nematodes are ideal for studying ageing because they have a relatively short lifespan, and are easy to culture and to manipulate in the laboratory. We hypothesize that females of hermaphrodites of our nematode model are ageing at different rates because they accumulate age-related pathologies that are the result of hyperfunction at different times during adulthood. We will test this hypothesis by manipulating the ageing rates using gender-modifying treatments, gene expression and gene knock-out analysis. Our model species provides a powerful system to study the mechanisms underlying ageing, because we can culture them at large numbers and genetically manipulate their genomes as well as genders. Recent research showed that nematodes, insects and mammals share some of the same mechanisms of ageing. Therefore, we anticipate that the results of this proposal will be applicable to other organisms.