A sex difference approach to evaluating resilience as a predictor of healthspan in mice

项目总结

Project Summary Aging of the human population has become the number one threat to human health globally as life expectancy is rising rapidly and because aging underlies nearly all major causes of death, disability, and degradation of the quality of later life. Hope for amelioration of this trend lies with the development of treatments that enhance and extend health. A major limitation on evaluating promising compounds for their senescence-inhibiting properties is the time it takes to perform lifespan studies in mice, the main preclinical animal model employed in biomedical research. Similarly, once compounds are ready for human testing, the time it takes to complete clinical trials will also become a bottleneck. In order to speed progress in the field then, it would be invaluable to develop a panel of short-term assays that could be administered to mice in early- to mid-life that would predict whether or not an intervention will extend healthspan in mice. The ability of an organism to recover from acute physical challenges or stresses is well-known to decline with age. If we define resilience as a quantitative metric which gauges the ability and speed of an organism to return to homeostasis after physical stress or challenge, then life- and health-extending interventions generally enhance resilience. The goal of the proposed research is to develop a standardized challenge or panel of challenges and their accompanying recovery metrics that will be informative about the healthspan impact of putative health-extending interventions when administered in early-to-mid life. The overarching hypothesis of the proposed research is that resilience assays can be developed that singly, or in combination, predict future life- and/or health-span. We propose to evaluate our overarching hypothesis purposely focusing on resilience assays with translational potential by performing the following specific aims (SAs). SA 1 will optimize resilience assay protocols, each consisting of an acute physical challenge and associated recovery metrics as to the best age and severity of challenge to use. SA 2 will determine whether the resilience assays optimized in specific aim 1 can identify the impact of known life- or health-span extension treatments. Three such treatments will be compared to untreated controls. These are: (a) dietary restriction (DR). This can be thought of as a positive control. To be informative, our resilience assays should predict longer life in both sexes; (b) rapamycin, our resilience assays should predict longer life in both sexes, but a greater effect in females; and (c) 17-α-estradiol. Our resilience assays should predict longer life in males only. SA 3 will evaluate the robustness of the most successful resilience assays identified in specific aim 2 across mouse genotypes. Because humans are so genetically and environmentally diverse, the generality of mouse assays should be maximized to the extent possible. Diverse mouse genotypes are available to access whether the assays developed in aim 2 are idiosyncratic to the original test genotype or robust as we would want for human trials.