PRIMARY FIBROBLAST RESILIENCY AS A PREDICTOR OF HEALTH AND LIFESPAN IN MICE

In response to RFA-AG-17-040, ?Short-term Measurements of Physical Resilience as aPredictor of Healthspan in Mice?, we propose testing primary fibroblast resilience with a panel ofdifferent cellular insults as a means to predict individual mouse longevity and healthspan. As outlinedby the funding announcement for this RFA, there is a need to develop these standardized tests foruse among the aging community to accelerate research towards revealing mechanisms that underlythe physiological decline of aging. We previously have shown that primary fibroblasts isolated fromthe tail skin of mice likely retain characteristics of the in vivo environment of the mouse (or otherspecies) 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 differencespersist even after numerous population doublings in culture using identical conditions as fibroblastlines from control mice. In addition, we have shown in this fibroblast model that resiliency to one formof insult predicts resiliency to multiple other forms of insult in an individual cell line. Our overallhypothesis is that cellular resiliency of skin-derived primary fibroblasts represents the vitality of anindividual in vivo and predicts both healthspan and longevity of individual mice. We have designedthis study to test this hypothesis and meet the goals outlined by this RFA. In our first aim, we testwhether fibroblast resiliency is predictive of individual longevity and healthspan in a normally aginggroup of genetically heterogeneous mice. Because of the unique fibroblast resiliency panel of testswe have outlined, we can test physical resiliency of mice with little to no effect on the overall healthand 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 todevelop a predictive model. In our second aim, we test the effect on fibroblast resiliency ofinterventions in mice known to alter longevity and/or healthspan. This will test whether this model canpredict novel interventions that may alter these parameters within a population. Because we currentlylack standardized research tools to probe resiliencies at the cellular level, this marker of resiliencehas the potential to be a highly important marker of healthspan and longevity in mouse studies.