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.
The goal of this proposal is to standardize tests of cellular resiliency using a skin-derived fibroblast model as a means to delineate the relationship between resiliency and mechanisms that regulate the aging process. We describe in depth a set of fibroblast resiliency assessments that we believe are representative of physiological cellular responses associated with longevity and test their correlation to natural mouse longevity and their ability to determine the potential of interventions to alter longevity. Because we currently lack standardized research tools to probe resiliency, this marker of resilience has the potential to be a highly important marker of healthspan and longevity in mouse studies.
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