Genetic Bases of Sarcopenia and Muscle Healthspan in C.*

肌肉减少症是不可避免地伴随着人类衰老的肌肉质量和肌肉力量的下降。 损失开始于中年（即使是健康的人），并进展到几乎每个人都可以 预计随着时间的推移，肌肉力量会显著下降（到90岁时，力量下降50%）。 不幸的是，这种普遍现象往往足以使人丧失能力， 生活活动，如行走和举重，变得必要。尽管在这场战争中 肌肉减少症，相对较少了解肌肉减少症如何以及为什么发生，特别是在分子水平上。 水平迄今为止，尚未利用遗传模型来研究肌肉减少症的分子机制。 我们发现C. elegans衰老的特征是与年龄相关的肌肉衰退， 人类肌肉减少症此外，我们已经确定了一个在这个过程中起关键作用的基因-AGE-1 PI 3激酶（已知作用于影响寿命的β 2胰岛素样信号通路）。向下- 单基因活性的调节可以显著延迟肌肉减少症的发作是非常令人鼓舞的。 我们研究的总体目标是确定遗传对C。雅利安人肌肉减少症和定义 使肌肉年轻化的分子策略。我们将追求3个目标：I）分子表征 胰岛素样信号对C.二）评价氧化应激对小鼠骨骼肌的影响， 损伤和热量限制对肌肉健康的影响; III）执行全基因组，无偏见 RNAi筛选以鉴定影响肌肉减少症的新基因。 在我们建议的研究完成后，我们希望提供一个详细的分子描述， 线虫胰岛素和经典胰岛素β 2信号通路的组分影响线虫 肌肉减少症我们还将定义氧化应激和热量限制协议如何影响细胞 肌肉衰退的原因。此外，我们希望确定新的遗传因素， 肌肉老化最终的结果应该是在分子和机制水平上的重大进展 我们了解C. elegans模型我们的希望是， 预期将刺激对哺乳动物中保守过程的研究，我们产生的数据可能会 影响设计新的治疗干预策略，以对抗人类肌肉减少症。

Sarcopenia is the decline in muscle mass and muscle strength that inevitably accompanies human aging. Loss initiates at middle age (even in healthy individuals) and progresses such that virtually everyone can expect to experience significant decline in muscle strength over time (- 50% strength loss by age 90). Unfortunately, this universal phenomenon is often sufficiently incapacitating such that assistance in basic life activities, such as walking and lifting, becomes necessary. Despite the substantial toll taken by sarcopenia, relatively little is understood about how and why sarcopenia occurs, especially at the molecular level. To date, genetic models have not been exploited to investigate molecular mechanisms of sarcopenia. We have found that C. elegans aging features age-related muscle decline that shares striking similarities to human sarcopenia. Moreover, we have identified one gene that plays a critical role in the process--AGE-1 PI3 kinase (known to act in the DAF-2 insulin-like signalling pathway that influences longevity). That down- regulation of a single gene activity can markedly delay the onset of sarcopenia is highly encouraging. The overall goal of our research is to identify the genetic influences on C. elegans sarcopenia and to define molecular strategies that "youthenize" muscle. We will pursue 3 aims: I) The molecular characterization of the effects of insulin-like signalling on C. elegans sarcopenia; II) The evaluation of the impacts of oxidative damage and caloric restriction on muscle healthspan; III) The execution of a genome-wide, non-biased RNAi screen to identify novel genes that influence sarcopenia. At the completion of the study we propose, we expect to provide a detailed molecular description of how nematode insulins and components of the canonical DAF-2 insulin signalling pathway influence nematode sarcopenia. We will also define how oxidative stress and caloric restriction protocols influence cellular aspects of muscle decline. Furthermore, we expect to identify novel genetic factors with major impacts on muscle aging. The end result should be a significant advance in the level of molecular and mechanistic detail with which we understand sarcopenia in the C. elegans model. Our hope is that the novel insight we anticipate will stimulate the search for conserved processes in mammals, and that data we generate may influence design of new therapeutic intervention strategies for combating human sarcopenia.