Genes Specifying Aging and Longevity in the Mouse

描述（由申请人提供）：饮食限制（DR）是最有效的延长啮齿动物寿命和延缓衰老的方法。在实施DR后，可以看到多种生理反应，其中许多已被提出作为产生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，这些特征中的一些是由不同的基因组指定的。我们建议使用这些大量的初步结果来建立对DR作出反应的各种特征之间的关系，并建立这些特征与DR的标志长寿之间的关系。我们建议绘制这些特征背后的基因（qtl），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遗传相关，是否与因果关系一致。

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).