Genes Specifying Aging and Longevity in the Mouse

描述（由申请人提供）：饮食限制（DR）是延长啮齿动物寿命和减缓衰老的最有效方法。多种生理反应后，DR的实施和许多这些已被提出作为潜在的因果因素，在生产DR的寿命延长的好处。我们已经发现，DR的几个生理效应有大量的遗传成分，并适合遗传分析。此外，这些性状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有反应的各种性状内部和之间的关系，并建立这些性状与作为DR标志的长寿之间的关系。我们建议绘制这些性状的基因（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，符合因果关系。 将此表述为一种假设，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与对DR的显著寿命延长相关。使用LSXSS RI面板，我们已经获得了对DR的几种反应的初步数据，包括降低体温，减轻体重，减慢生长速度，并且在DR期间降低雌性生育力，并且在恢复自由（AL）条件后延长雌性生育力。 目前正在进行进一步研究，以促进这些发现。在这里，我们建议确定和地图QTL指定的寿命和寿命结束的病理条件下AL和DR。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。这些QTL将使用LXS RI菌株、新的RI组和有史以来构建的最大的RI组（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).