Primary fibroblast resiliency as a predictor of health and lifespan in mice

响应RFA-AG-17-040，“身体弹性的短期测量作为 预测小鼠的健康寿命”，我们建议用一组 不同的细胞损伤作为预测个体小鼠寿命和健康寿命的手段。概述的 根据RFA的资金公告，有必要开发这些标准化测试， 在老龄化社区中使用，以加速研究，揭示 衰老的生理衰退我们以前已经表明，从人皮肤中分离的原代成纤维细胞， 小鼠的尾部皮肤可能保留了小鼠体内环境（或其它环境）的特征 他们所创造的物种。例如，我们在一系列研究中发现皮肤- 衍生的原代成纤维细胞分离自生长激素/胰岛素缺乏的长寿小鼠， Like生长因子1水平对多种细胞毒性和代谢损伤具有弹性。这些差异 即使在使用与成纤维细胞相同的条件培养的多次群体倍增后， 来自对照小鼠的线。此外，我们已经在这个成纤维细胞模型中表明， 预测了单个细胞系对多种其他形式的损伤的弹性。我们的整体 一种假说认为皮肤来源的原代成纤维细胞的细胞弹性代表了 个体在体内，并预测个体小鼠的健康寿命和寿命。我们设计了 本研究旨在验证这一假设，并达到RFA概述的目标。在我们的第一个目标中，我们测试 成纤维细胞弹性是否是正常衰老的个体寿命和健康寿命的预测 一组遗传异质性小鼠。由于独特的成纤维细胞弹性测试小组 我们已经概述了，我们可以测试小鼠的身体弹性，对整体健康几乎没有影响 和动物的寿命。也就是说，在单个小鼠中，我们将测量成纤维细胞的弹性， （包括整个中年的重复评估）和寿命，并使用这些数据， 建立预测模型。在我们的第二个目标中，我们测试了 在已知会改变寿命和/或健康寿命的小鼠中进行干预。这将考验这一模式能否 预测可能改变人群中这些参数的新干预措施。因为我们目前 缺乏标准化的研究工具来探测细胞水平上的免疫力，这是恢复力的标志。 在小鼠研究中，它有可能成为健康寿命和长寿的一个非常重要的标志。

In response to RFA-AG-17-040, “Short-term Measurements of Physical Resilience as a Predictor of Healthspan in Mice”, we propose testing primary fibroblast resilience with a panel of different cellular insults as a means to predict individual mouse longevity and healthspan. As outlined by the funding announcement for this RFA, there is a need to develop these standardized tests for use among the aging community to accelerate research towards revealing mechanisms that underly the physiological decline of aging. We previously have shown that primary fibroblasts isolated from the tail skin of mice likely retain characteristics of the in vivo environment of the mouse (or other species) from which they were established. For example, we showed in a series of studies that skin- derived primary fibroblasts isolated from long-lived mice with deficiencies in growth hormone/insulin- like growth factor 1 levels are resilient to multiple cytotoxic and metabolic insults. These differences persist even after numerous population doublings in culture using identical conditions as fibroblast lines from control mice. In addition, we have shown in this fibroblast model that resiliency to one form of insult predicts resiliency to multiple other forms of insult in an individual cell line. Our overall hypothesis is that cellular resiliency of skin-derived primary fibroblasts represents the vitality of an individual in vivo and predicts both healthspan and longevity of individual mice. We have designed this study to test this hypothesis and meet the goals outlined by this RFA. In our first aim, we test whether fibroblast resiliency is predictive of individual longevity and healthspan in a normally aging group of genetically heterogeneous mice. Because of the unique fibroblast resiliency panel of tests we have outlined, we can test physical resiliency of mice with little to no effect on the overall health and longevity of the animals. That is, in an individual mouse we will measure fibroblast resilience (including repeated assessments throughout middle age) and longevity and use these data to develop a predictive model. In our second aim, we test the effect on fibroblast resiliency of interventions in mice known to alter longevity and/or healthspan. This will test whether this model can predict novel interventions that may alter these parameters within a population. Because we currently lack standardized research tools to probe resiliencies at the cellular level, this marker of resilience has the potential to be a highly important marker of healthspan and longevity in mouse studies.