Genes Specifying Aging and Longevity in the Mouse

描述(申请人提供)：饮食限制(DR)是最有效的延长啮齿动物寿命和减缓衰老的方法。在施加DR后，可以看到多种生理反应，其中许多被认为是产生DR延长寿命益处的潜在原因。我们发现，DR的几种生理效应具有实质性的遗传成分，可以进行遗传分析。此外，这些特征中有几个是由不同的基因集指定的。我们建议利用这一大量的初步结果来建立对DR反应的各种性状内部和之间的关系，并建立这些性状与延寿之间的关系，这是DR的标志。我们建议定位这些性状的基因(QTL)，并确定DR诱导的寿命延长是否在遗传上与这些反应中的一个或多个有关，与因果关系一致。 作为一种假设，我们提出存在可识别的QTL，这些QTL是DR生理反应变化的基础，其中一些QTL与DR的反应显著延长有关。使用LSXSS RI小组，我们获得了DR反应的几个反应的初步数据，包括DR期间的体温降低、体重减轻、生长速度减慢、女性生育力下降以及恢复即刻(AL)条件后女性生育力的延长。 进一步推进这些发现的其他研究正在进行中。在这里，我们建议识别和定位在AL和DR条件下指定寿命和生命终结病理的QTL。我们还将评估血糖、胰岛素和IGF-1的水平，并绘制这些特征的QTL图。这些QTL将使用LXS RI菌株、一个新的RI集合和有史以来构建的最大RI集合(77个菌株)进行定位。

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).