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

• 批准号: BB/H012850/1
• 负责人: Colin Selman
• 金额: $ 51.5万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH012850%2F1
• 关键词: Dissecting; mechanisms; underlying; lifespan; extension

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老龄化，到2050年，英国预计将有25万名百岁老人，而2004年只有1万人。衰老伴随着身体衰退，可能导致残疾、严重丧失独立性并导致生活质量下降。此外，老龄化是一些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，如果我们有希望在老年时保持生活质量，确定导致衰老的过程至关重要。目前，人们还不知道是什么过程导致衰老，尽管细胞承受压力的能力，细胞保护免受损伤和修复这种损伤的能力，以及细胞如何消耗能量都很重要。为了检验这一点，我将使用一种新的小鼠模型，其中一个特定的基因（胰岛素受体底物蛋白1，Irs 1 null）已被删除的所有组织。我以前已经证明，这些小鼠寿命特别长，并且对老年的虚弱有抵抗力。此外，我将这些小鼠暴露于热量限制（CR）。CR还延长了许多动物的寿命并改善了健康状况，通过使用这种比较方法，我将确定两种延长寿命治疗方法的共同基因和途径。我认为这些重叠的基因/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础生物学提供新的见解，并可能最终帮助确定治疗人类衰老疾病的潜在治疗途径。

项目成果

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

Evidence of a metabolic memory to early-life dietary restriction in male C57BL/6 mice.

• DOI: 10.1186/2046-2395-1-2
• 发表时间: 2012
• 期刊: Longevity & healthspan
• 作者: Selman C;Hempenstall S
• 通讯作者: Hempenstall S

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.

• DOI: 10.18632/aging.101446
• 发表时间: 2018-05-20
• 期刊: Aging
• 作者: Page MM;Schuster EF;Mudaliar M;Herzyk P;Withers DJ;Selman C
• 通讯作者: Selman C

Dietary restriction and the pursuit of effective mimetics

饮食限制和追求有效的模仿

• DOI: 10.1017/s0029665113003832
• 发表时间: 2014
• 期刊: Proceedings of the Nutrition Society
• 影响因子: 7
• 作者: Selman C