Caenorhabditis Intervention Testing Program Renewal--Project Summary Health challenges linked to human aging take a tremendous toll on society. Physical and cognitive decline limit the quality of life for the elderly and their caregivers. Aging is the major risk factor for, and possible cause of, cancer, diabetes, and neurodegenerative disease. Without question, the promotion of healthy aging with extended resistance to decline and disease should be a major objective of current medical research. Fortunately, tremendous progress has been made in the biology of aging field and the science is poised to be translated into preclinical and clinical science. Simple animals models such as the nematode Caenorhabditis elegans have been at the heart of this success. Many genes and chemical compound interventions that modulate aging processes are likely to act similarly in humans. The goal of the proposed work is to continue, and expand, efforts of a co-operative scientific group involving three closely interacting laboratories who coordinately test pharmacological interventions for their ability to extend healthy aging and promote longevity in nematodes. A specific emphasis of this integrated super-group is to test promising compound on a collection of natural variants of the Caenorhabditis genus, which together represent the extensive genetic heterogeneity in the human population. The idea is that treatments that confer positive outcomes across a diverse population will have an increased chance of being effective in humans. The emphasis of this specific proposal is the screening of test compounds for the capacity to promote longevity and health across a genetically diverse test set. We will consider compounds via a public access portal, from leads in the literature, and from high throughput chemical screens for longevity. Our labs will also develop and test utility of engineered deletions of genes encoding fundamental executors of proteostasis, metabolism, intercellular signaling and mitochondrial maintenance in diverse genetic backgrounds for compound evaluation. By creating “at risk’ strains impaired in conserved hallmarks of aging, we might increase the dynamic range for identifying anti-aging therapies. We will expand understanding of mechanisms for the most effective compounds, aiding their translation. Overall, we will participate in a unique team project that has the power to define pharmacological interventions that robustly promote strong healthspan across a varied population, with implications for development of therapies that promote healthy human aging.