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.

根据RFA-AG-17-040的要求，“身体复原力的短期测量 小鼠健康寿命的预测指标“，我们建议用一组 不同的细胞侮辱作为预测小鼠个体寿命和健康寿命的一种手段。如上所述 根据这个RFA的资金声明，有必要为以下方面开发这些标准化测试 在老龄化社区中使用，以加快研究，以揭示 衰老的生理性衰退。我们之前已经证明，从 小鼠的尾部皮肤可能保留了小鼠(或其他动物)体内环境的特征 物种)，它们就是从这些物种建立起来的。例如，我们在一系列研究中表明，皮肤- 从生长激素/胰岛素缺乏的长寿小鼠分离的原代成纤维细胞- 像生长因子1一样，水平对多种细胞毒性和新陈代谢的侮辱具有弹性。这些差异 即使在使用与成纤维细胞相同的条件的培养中进行多次群体倍增后，仍然存在 来自对照小鼠的线条。此外，我们已经在这个成纤维细胞模型中展示了对一种形式的弹性 在一个单独的细胞系中，对多种其他形式的侮辱的恢复力。我们的整体 假说是，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 这项研究旨在检验这一假设，并达到这一RFA概述的目标。在我们的第一个目标中，我们测试 在正常衰老中，成纤维细胞的弹性是否可以预测个体的寿命和健康寿命 一组遗传上不同的小鼠。因为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，而对整体健康几乎没有影响 以及动物的长寿。也就是说，我们将在单个小鼠身上测量成纤维细胞的弹性 (包括中年期间的重复评估)和寿命，并使用这些数据 开发一个预测性模型。在我们的第二个目标中，我们测试了对成纤维细胞弹性的影响 对已知可改变寿命和/或健康寿命的小鼠的干预。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索细胞水平的弹性，这是弹性的标志 在小鼠研究中有可能成为健康和长寿的一个非常重要的标志。