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ABSTRACT One of the primary limitations to translating studies from animals to humans is that lifespan is not a reasonable or feasible end-point to use in determining if a manipulation retards aging in humans. Therefore, the goal of this RFA is to determine if measures of resilience in mice can be found that are surrogates for increased longevity and healthspan. Resilience is defined as the ?ability of an organism to respond to physical challenges or stresses and return to homeostasis?, i.e., resilience is not simply a measure of the ability of a cohort of animals to survive a toxic stress. Based on the goals of this RFA, we hypothesize that increased resilience to various stresses in mid-life can be used to predict the ability of a manipulation to increase the lifespan of mice. In this application. we will test a battery of seven measures of resilience based on; (1) assays that are relatively simple, inexpensive, and non-invasive and can be performed in whole animals in vivo; (2) assays that measure a range of physiological domains; (3) assays that are integrative, i.e., the response to the stress involves a series of pathways and/or multiple organs to maintain homeostasis; and (4) assays that can potentially be translated to humans. The ability of these assays to predict which manipulations will increase lifespan will be tested in the following aims. 1: To develop in vivo assays that will measure resilience in mice. We will develop seven assays of resilience to maximize their sensitivity to detect changes in resilience in mice. These assays will measure the response to: (1) a foreign protein/antigen, (2) treadmill endurance exercise capacity, (3) recovery from anesthesia, (4) carrageenan-induced inflammation in the paw, (5) heat stress, (6) hypoxia, and (7) restraint stress. 2: To determine whether our measures of resilience predict the longevity of cohorts of mice known to have increased longevity. We will measure resilience in cohorts of mice that have been shown to have a robust increase in both mean and maximum lifespan. For example, dietary restriction and growth hormone (GH) deficiency (Ames dwarf mice) as well as mice treated with compounds, which the NIA-funded Intervention Testing Program (ITP) has shown to robustly increase lifespan: rapamycin, acarbose, and 17-?-estradiol. 3. To determine if the tests of resilience predict increased longevity and healthspan in individual mice. Using a cohort of genetic diverse mice (diversity out cross), we will determine whether the assays in Aim 2 predict how long an animal will live. Using global pathology at the end of life as a measure of the health of each animal, we will also determine if resilience is predictive of health status.
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