Genes Specifying Aging and Longevity in the Mouse

小鼠衰老和长寿的基因

• 批准号: 6818198
• 负责人: Thomas E. Johnson
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818198
• 关键词: aging; blood glucose; dietary restriction; family genetics; gene environment interaction; genetic mapping; genetic regulation; genetic strain; genetic susceptibility; insulin; insulin sensitivity /resistance; insulinlike growth factor; laboratory mouse; longevity; longitudinal animal study; nutrition related tag; pathology; quantitative trait loci

DESCRIPTION (provided by applicant): Dietary restriction (DR) is the most validated method of extending longevity and slowing aging in rodents. Multiple physiological responses are seen after imposition of DR and many of these have been put forth as potential causal factors in producing the life-extension benefits of DR. We have found that several of the physiological effects of DR have a substantial genetic component and are amenable to genetic analysis. Moreover, several of these traits are specified by distinct sets of genes. We propose to use this substantial body of preliminary results to establish a relationship within and among various traits that respond to DR and to establish the relationship between these traits and the longevity-extension that is the hallmark of DR. We propose to map the genes (QTLs) underlying these traits and determine whether DR-induced life extension is genetically associated with one or more of these responses, consistent with a causal relationship. Phrasing this as a hypothesis, we propose that there are identifiable QTLs that underlie variation in the physiological responses to DR and that some of these QTLs are associated with significant life extension in response to DR. Using the LSXSS RI panel, we have obtained preliminary data for several responses to DR, including lowered body temperature, reduced body weight, slower growth rate, and reduced female fertility during DR and extended female fertility after restoring ad lib (AL) conditions. Additional studies to further these findings are underway. Here we propose to identify and map QTLs specifying life span and end-of-life pathology under both AL and DR conditions. We also will assess levels of blood glucose, insulin, and IGF-1 and map QTLs for these traits. These QTLs will be mapped using the LXS RI strains, a new RI set and the largest set of RIs ever constructed (77 strains).

描述（由申请人提供）：饮食限制（DR）是啮齿动物延长寿命和延缓衰老的最有效方法。实施 DR 后会出现多种生理反应，其中许多已被认为是产生 DR 延长寿命益处的潜在因果因素。我们发现 DR 的一些生理效应具有重要的遗传成分，并且可以进行遗传分析。此外，其中一些性状是由不同的基因组指定的。我们建议利用这一大量初步结果来建立对 DR 做出反应的各种特征内部和之间的关系，并建立这些特征与作为 DR 标志的寿命延长之间的关系。我们建议绘制这些性状背后的基因（QTL）图谱，并确定 DR 诱导的寿命延长是否与这些反应中的一种或多种在遗传上相关，并符合因果关系。 将此作为一个假设，我们提出存在可识别的 QTL，这些 QTL 是对 DR 的生理反应变化的基础，并且其中一些 QTL 与响应 DR 的显着寿命延长相关。使用 LSXSS RI 面板，我们获得了 DR 的几种反应的初步数据，包括 DR 期间体温降低、体重减轻、生长速度减慢、女性生育力降低以及恢复自由 (AL) 条件后女性生育力延长。 进一步的研究正在进行中。在这里，我们建议在 AL 和 DR 条件下识别和绘制指定寿命和临终病理学的 QTL。我们还将评估血糖、胰岛素和 IGF-1 的水平，并绘制这些性状的 QTL 图谱。这些 QTL 将使用 LXS RI 菌株、新的 RI 组和有史以来构建的最大 RI 组（77 个菌株）进行定位。