GENETIC MODIFIERS AND LONGEVITY OF MNSOD MUTANT MICE

这一建议的前提是，氧自由基参与线粒体衰老，进而导致整个生物体的衰老。线粒体中产生的超氧阴离子自由基可导致大分子损伤，导致线粒体缺陷。这一过程向下的级联最终导致生物体的衰老和死亡。我们推测，保护线粒体免受自由基损伤的因子有可能维持能量产生和组织功能，最终延缓衰老的开始，延长生物体的寿命。基因敲除(KO)小鼠缺乏线粒体超氧化物歧化酶(MnSOD)，是线粒体超氧阴离子自由基增加、组织损伤加速和过早死亡的动物模型。我们观察到不同遗传背景的KO小鼠的平均存活时间和表型有显着差异。短寿种群和长寿种群的平均寿命和最长寿命分别相差7倍和5倍。除了寿命上的差异，长寿的KO小鼠的组织损伤程度比短寿的动物要低。数据表明，与长寿人群共分离的遗传成分具有减缓组织损伤的能力，从而延长寿命。因此，识别这些遗传修饰物并了解它们保护线粒体免受超氧化物损伤的功能可能会导致在人类衰老动物模型中分离出延长寿命的基因。为实现这些目标，提出了以下具体目标。目的对导致MnSOD突变小鼠寿命延长的主要遗传修饰因子进行精细定位。目的II-体内和体外比较Sod2-/+和+/+动物使用和不使用遗传修饰剂后的寿命和年龄相关变化。目的通过对Sod2-/-小鼠的表型分析，研究遗传修饰物的功能。目的IV-鉴定导致MnSOD突变小鼠寿命延长的主要修饰基因。

This proposal is based on the premise that oxygen free radicals are involved in mitochondrial aging and in turn, aging of the whole organism. Superoxide radicals generated in the mitochondria can lead to damage of macromolecules and result in defective mitochondria. The downward cascade of this process ultimately leads to the state of senescence and the demise of the organism. We hypothesize that factors that can protect the mitochondria from free radical damage have the potential to maintain energy production and tissue function and ultimately to delay the onset of senescence and prolong the lifespan of the organism. Knockout (KO) mice lacking the mitochondrial superoxide metabolizing enzyme, Mn superoxide dismutase (MnSOD), represent an animal model with increased mitochondrial superoxide radicals, accelerated tissue damage, and early demise. We observed a remarkable difference in the mean survival time and the phenotype of the KO mice on different genetic backgrounds. The mean and maximum lifespan difference between the short-lived and the long-lived population is 7 and 5 fold respectively. In addition to the lifespan difference, the long-lived KO mice have a lower level of tissue damage than the short-lived animals. The data indicate that genetic components that cosegregate with the long-lived population have the ability to decelerate tissue damage and consequently, prolong the lifespan. Therefore, identification of these genetic modifiers and understanding their functions protecting mitochondria from superoxide damages may lead to the isolation of genes that can extend lifespan in animal models for human aging. To achieve these goals, the following specific aims are proposed. Aim I - Fine mapping of the major genetic modifier leading to prolonged lifespan in MnSOD mutant mice. Aim II - In vivo and in vitro comparison of lifespan and age- related changes between Sod2-/+ and +/+ animals with and without the genetic modifier. Aim III - Functional studies of the genetic modifier by phenotype analyses of Sod2-/- mice. Aim IV - Identification of the major modifier gene leading to prolonged lifespan in MnSOD mutant mice.