Dissecting the mechanisms underlying lifespan extension in insulin signalling mutant mice

剖析胰岛素信号突变小鼠寿命延长的机制

基本信息

批准号：
BB/H012850/2
负责人：
Colin Selman
金额：
$ 15.78万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FH012850%2F2
关键词：
Dissecting mechanisms underlying lifespan extension

项目摘要

Our population is ageing rapidly, and by 2050 there will be an estimated 250000 centenarians in the UK compared to only 10000 in 2004. Ageing is accompanied by a physical decline which can result in disability, a profound loss of independence and a resultant decrease in quality of life. In addition, ageing is the major risk factor for a number of diseases including Alzheimer's, various cancers, osteoporosis and type-2 diabetes. Therefore, identifying the processes that cause ageing is of fundamental importance if we have any hope of maintaining quality of life into old age. Currently, it is not understood what processes cause ageing, although the ability of cells to withstand stress, the ability of cells to protect against damage and repair this damage, and how the cells consume energy all appear important. To examine this I will use a novel mouse model in which a specific gene (insulin receptor substrate protein 1, Irs1 null) has been removed from all tissues. I have previously shown that these mice are exceptionally long-lived and are resistant to the infirmities of old age. In addition I will expose these mice to caloric restriction (CR). CR also extends lifespan and improves health in many animals and by using this comparative approach I will identify common genes and pathways across both life-extending treatments. I suggest that these overlapping genes/pathways are likely to be central to ageing in mammals. The information generated by this proposal will provide new insights into the fundamental biology of mammalian ageing and may ultimately help identify potential therapeutic pathways for treatment of the diseases of ageing in humans.

我们的人口正在迅速衰老，到2050年，英国估计将有250000年的百岁老人，而2004年仅10000人。衰老伴随着身体的下降，可能导致残疾，严重失去独立性和产生的生活质量。此外，衰老是多种疾病的主要危险因素，包括阿尔茨海默氏症，各种癌症，骨质疏松症和2型糖尿病。因此，如果我们希望将生活质量保持到老年，那么确定导致衰老的过程至关重要。目前，尽管细胞承受压力的能力，防止损坏和修复这种损害的能力以及细胞消耗的能量如何看上去很重要，但尚不了解什么过程会导致衰老。为了检查这一点，我将使用一种新型的小鼠模型，其中特定基因（胰岛素受体底物蛋白1，IRS1 null）已从所有组织中删除。我以前已经表明，这些小鼠的寿命异常长，并且对老年患病有抵抗力。此外，我将使这些小鼠暴露于热量限制（CR）。 CR还可以延长寿命并改善许多动物的健康，并通过使用这种比较方法，我将在两种延长生命的治疗方法中确定常见的基因和途径。我建议这些重叠的基因/途径可能是哺乳动物衰老的核心。该提案产生的信息将为哺乳动物衰老的基本生物学提供新的见解，并最终可能有助于确定治疗人类衰老疾病的潜在治疗途径。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fibroblasts derived from long-lived insulin receptor substrate 1 null mice are not resistant to multiple forms of stress.

DOI：
10.1111/acel.12255
发表时间：
2014-10
期刊：
Aging cell
影响因子：
7.8
作者：
Page MM;Sinclair A;Robb EL;Stuart JA;Withers DJ;Selman C
通讯作者：
Selman C

Lifespan modulation in mice and the confounding effects of genetic background.

小鼠的寿命调节和遗传背景的混杂影响。

DOI：
10.1016/j.jgg.2014.06.002
发表时间：
2014
期刊：
Journal of genetics and genomics = Yi chuan xue bao
影响因子：
0
作者：
Mulvey L
通讯作者：
Mulvey L

Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production.

DOI：
10.1016/j.cmet.2017.05.003
发表时间：
2017-06-06
期刊：
Cell metabolism
影响因子：
29
作者：
Hine C;Kim HJ;Zhu Y;Harputlugil E;Longchamp A;Matos MS;Ramadoss P;Bauerle K;Brace L;Asara JM;Ozaki CK;Cheng SY;Singha S;Ahn KH;Kimmelman A;Fisher FM;Pissios P;Withers DJ;Selman C;Wang R;Yen K;Longo VD;Cohen P;Bartke A;Kopchick JJ;Miller R;Hollenberg AN;Mitchell JR
通讯作者：
Mitchell JR

Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice.