Caenorhabditis Intervention Testing Program at Oregon

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Caenorhabditis Intervention Testing Program Renewal at Oregon—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 animal 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 to capitalize upon the very high temporal resolution provided by our automated lifespan approach to expand upon our existing analytical framework to include an analysis of variation in rates of aging using more general statistical models that allow for changes in the rate of mortality over an individual’s lifespan. This approach provides a unique hypothesis testing framework that is particularly well suited for compound interventions. In addition, we will build upon our translational capacity by using RNA- seq to identify genetic pathways targeted by longevity-extending compounds and to understand which molecular systems maintain early-life function later in life as a hallmark of healthy aging. Mapping these changes onto known mammalian genetic regulatory systems will allow us to determine which interventions are most likely to serve as targets for rapid 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.