权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Overactivity in growth and its effects on rates of ageing

生长过度活跃及其对衰老速度的影响

基本信息

批准号：
BB/L019884/1
负责人：
Andre Pires Da Silva
金额：
$ 46.59万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL019884%2F1
关键词：
Overactivity growth its effects rates

项目摘要

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.

卡路里限制(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，是为数不多的延缓从酵母到哺乳动物等多种动物衰老的治疗方法之一。营养感知遗传通路的下调，如高度保守的TOR激酶和胰岛素通路，被认为介导了CR的效应。营养感应通路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，高新陈代谢会导致自由基的产生，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，认为氧化损伤是衰老的原因。这项研究将使用另一种理论框架来解决衰老的机制。根据最近发展的一种理论，衰老是发育程序无意中过度功能的结果。因此，在生命后期继续生长可能会导致病理和最终死亡。这一理论可以解释氧化损伤理论中报道的许多悖论，也可以解释为什么CR延缓衰老。这一新理论与汽车相提并论，认为老化就像是一辆没有刹车和驾驶员的汽车，而不是因为“生锈”而老化。我们建议研究一种线虫(蛔虫)，这种线虫产生遗传上相同的兄弟姐妹，但寿命不同；这种线虫的两性一直比雌性多活三分之一。性别之间没有遗传差异将有助于对造成寿命差异的原因进行适当的对照实验。线虫是研究衰老的理想选择，因为它们的寿命相对较短，而且很容易在实验室培养和操作。我们假设，在我们的线虫模型中，雌两性以不同的速度老化，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速度来检验这一假设。我们的模式物种为研究衰老的机制提供了一个强大的系统，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、昆虫和哺乳动物都有一些相同的衰老机制。因此，我们预计这项提议的结果将适用于其他生物体。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phenotypic plasticity and developmental innovations in nematodes.

线虫的表型可塑性和发育创新。

DOI：
10.1016/j.gde.2016.05.018
发表时间：
2016
期刊：
Current opinion in genetics & development
影响因子：
4
作者：
Tandonnet S
通讯作者：
Tandonnet S

Sex- and Gamete-Specific Patterns of X Chromosome Segregation in a Trioecious Nematode.

X染色体隔离的性别和配子特异性模式。

DOI：
10.1016/j.cub.2017.11.037
发表时间：
2018-01-08
期刊：
Current biology : CB
影响因子：
0
作者：
Tandonnet S;Farrell MC;Koutsovoulos GD;Blaxter ML;Parihar M;Sadler PL;Shakes DC;Pires-daSilva A
通讯作者：
Pires-daSilva A

Description of two three-gendered nematode species in the new genus Auanema (Rhabditina) that are models for reproductive mode evolution.

DOI：
10.1038/s41598-017-09871-1
发表时间：
2017-09-11
期刊：
Scientific reports
影响因子：
4.6
作者：
Kanzaki N;Kiontke K;Tanaka R;Hirooka Y;Schwarz A;Müller-Reichert T;Chaudhuri J;Pires-daSilva A
通讯作者：
Pires-daSilva A

Reproduction: Sperm with Two X Chromosomes and Eggs with None.

繁殖：带有两条 X 染色体的精子和没有一条 X 染色体的卵子。

DOI：
10.1016/j.cub.2017.12.026
发表时间：
2018
期刊：
Current biology : CB
影响因子：
0
作者：
Shen,Yongquan;Ellis,RonaldE
通讯作者：
Ellis,RonaldE

Mating dynamics in a nematode with three sexes and its evolutionary implications.

DOI：
10.1038/srep17676
发表时间：
2015-12-03
期刊：
Scientific reports
影响因子：
4.6
作者：
Chaudhuri J;Bose N;Tandonnet S;Adams S;Zuco G;Kache V;Parihar M;von Reuss SH;Schroeder FC;Pires-daSilva A
通讯作者：
Pires-daSilva A