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

原代成纤维细胞弹性作为小鼠健康和寿命的预测因子

• 批准号: 9422077
• 负责人: Adam Salmon
• 金额: $ 30.94万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9422077
• 关键词: Address; Adult; Adverse effects; Aging; Aging-Related Process; Animals; Biological Assay; Cell Line; Cells; Characteristics; Communities; Data; Development; Environment; Estradiol; Fatty acid glycerol esters; Female; Fibroblasts; Funding; Future; Goals; Growth Hormone Receptor; Health; Individual; Insulin-Like Growth Factor I; Intervention; Lead; Length; Life; Longevity; Measurable; Measurement; Measures; Metabolic; Metabolic stress; Modeling; Mus; Mutant Strains Mice; Organism; Outcome; Pathology; Pattern; Physiological; Population; Process; Research; Resistance; Series; Sirolimus; Skin; Somatotropin; Standardization; Stress; Tail; Testing; Time; assay development; cohort; cytotoxic; design; end of life; feeding; healthy aging; improved; in vivo; innovation; male; middle age; normal aging; novel; predictive modeling; resilience; response; senescence; tool; translational impact; young adult

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.

为了响应RFA-AG-17-040，“物理弹性的短期测量 小鼠健康跨的预测指标”，我们建议用一组面板测试一级成纤维细胞弹性 不同的细胞损伤是一种预测单个小鼠寿命和健康状态的手段。如概述 通过此RFA的资助公告，有必要开发这些标准化测试 在衰老社区中使用以加速研究朝着基本的机制揭示机制 衰老的身体下降。我们以前已经表明，主要的成纤维细胞从 小鼠的尾皮可能保留小鼠体内环境的特征（或其他 它们是从中建立的物种。例如，我们在一系列研究中表明皮肤 从长寿命小鼠中分离出患有生长马/胰岛素 - 像生长因子1水平一样，对多种细胞毒性和代谢侮辱也有弹性。这些差异 即使在使用与成纤维细胞相同的条件下，文化中的人口加倍之后，也持续存在。 来自控制小鼠的线。此外，我们在这个成纤维细胞模型中显示了对一种形式的弹性 侮辱性预测对单个细胞系中多种其他形式的侮辱的弹性。我们的整体 假设是皮肤衍生的原代成纤维细胞的细胞弹性代表了 个体体内和预测单个小鼠的健康范围和寿命。我们已经设计了 这项研究以检验这一假设并满足此RFA概述的目标。在我们的第一个目标中，我们测试 成纤维细胞的弹性是否可以预测通常老化的个体寿命和健康状态 一组遗传异质小鼠。由于具有独特的成纤维细胞弹性测试面板 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，在单独的鼠标中，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 开发一个预测模型。在第二个目标中，我们测试对成纤维细胞弹性的影响 已知会改变寿命和/或健康范围的小鼠的干预措施。这将测试该模型是否可以 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的弹性，这是这种弹性的标志 在小鼠研究中，有可能成为健康范围和寿命的非常重要的标志。