Project Summary: P4 The goal of P4 is to improve our ability to discover “geroprotectors,” i.e. drugs that can slow aging and extend lifespan by postponing age-dependent changes that impair health and lead to death. The plan makes use of new ideas and methods in complementary in silico and in experimental approaches. The chemoinformatics group headed by Thomas Girke will develop and use strategies for identifying drugs and targets likely to show effects on aging and and age-dependent declines, based on LC research and data in the public domain (Aim 1). The second team, headed by Richard Miller, will evaluate candidate geroprotectors in mice (Aim 2), and in exploratory studies in humans (Aim 3) and dogs (Aim 4). The plan for mouse work is based on the concept of “Aging Rate Indicators (ARI),” defined as molecular tests that discriminate slow-aging animals from normal controls. Unlike the familiar “biomarkers of aging,” which are surrogates for biological age and interpretable only if tested at multiple ages in older subjects, ARIs are surrogates for the rate of aging. They can therefore be evaluated at a single time point, even in young and middle-aged individuals. Past LC work has discovered a set of ARIs, measured in plasma, fat, muscle, liver, and brain, that are altered significantly in 10 different varieties of slow-aging mice, including four in which aging was slowed by anti-aging drugs. Aim 2a will refine the ARI battery using tissue samples from 40 drugs for which lifespan effects will be known by Year 2 of the proposed award, to improve the set of ARI assays that discriminate effective from ineffective candidate geroprotectors. Aim 2b will use known geroprotectors to document the time course over which ARIs change after drug exposure. Aim 2c, the heart of P4, will then evaluate the candidate geroprotectors selected under Aim 1 using the optimized test conditions developed in Aim 2b, to see which ones resemble authentic anti- aging drugs in their ability to alter ARIs. The results of Aim 2c will help us validate and improve the selection algorithms of Aim 1 in an iterative, reciprocal process involving both lab teams. Aim 2d extends these concepts to normal mice, to test the predictions that ARIs can identify adult mice destined (a) for long lifespan; and (b) for preservation of cognitive ability at older ages. Aim 2d will also include plasma metabolomic data and extensive analysis of brain histochemistry to test a range of inter-related hypotheses. Aim 3 will evaluate plasma ARIs and fat/muscle mRNA data obtained from healthy human septuagenarians, to see if ARIs can discriminate subjects with unusually good preservation of youthful abilities. Aim 4 will conduct similar analyses on plasma of dogs involved in the Dog Aging Project. Anticipated outcomes of P4 include (a) a list of candidate geroprotectors that deserve testing in mouse lifespan protocols and in human and mouse disease models; (b) optimized in silico methods for nominating pr...