GENETIC MODIFIERS AND LONGEVITY OF MNSOD MUTANT MICE

该建议基于氧自由基参与线粒体衰老并进而参与整个生物体衰老的前提。线粒体内产生的超氧自由基可导致大分子物质的损伤，导致线粒体缺陷。这一过程的向下级联最终导致衰老状态和有机体的死亡。我们假设，可以保护线粒体免受自由基损伤的因素有可能维持能量产生和组织功能，并最终延迟衰老的发生和延长生物体的寿命。敲除（KO）小鼠缺乏线粒体超氧化物代谢酶，锰超氧化物歧化酶（MnSOD），代表了一种动物模型，增加线粒体超氧化物自由基，加速组织损伤，和早期死亡。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存在显著差异。短寿命和长寿命人群之间的平均和最大寿命差异分别为7倍和5倍。除了寿命差异外，长寿的KO小鼠的组织损伤水平低于短命的动物。这些数据表明，与长寿种群共分离的遗传组分具有减缓组织损伤的能力，从而延长寿命。因此，鉴定这些遗传修饰剂并了解它们保护线粒体免受超氧化物损伤的功能，可能会导致分离出可以延长人类衰老动物模型寿命的基因。为实现这些目标，提出了以下具体目标。目的I -精细定位导致MnSOD突变小鼠寿命延长的主要遗传修饰因子。目的II -在体内和体外比较具有和不具有遗传修饰剂的Sod 2-/+和+/+动物之间的寿命和年龄相关变化。目的III -通过Sod 2-/-小鼠的表型分析进行遗传修饰剂的功能研究。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.