Human aging is associated with physical and cognitive decline as well as a marked increase of susceptibility to cancer, diabetes, and neurodegenerative disease. As such, the promotion of healthy aging, with extended resistance to decline, is a major goal of medical research. To address this problem, simple animals models such as the nematode C. elegans have been studied, providing molecular insights into the genes and drug interventions that modulate conserved aging processes. The goal of the proposed work is to participate in a co-operative scientific group that tests drugs for the abilityto extend healthy aging and promote longevity in the C. elegans model. A specific emphasis will be to test promising drugs on a collection of natural variants of C. elegans, which will seek to represent the extensive genetic heterogeneity in the human population-those drugs that confer similar outcomes across a diverse population will be considered to have an increased change of being efficacious in higher organisms. Our first goal is to conduct a fast preliminary evaluation o how diverse species variants age, using two fast assays of aging quality that monitor conserved processes that accompany human aging: 1) analysis of auto fluorescent lipofuscin and advanced glycation end products, which accumulate to high levels in C. elegans reference strain N2 that age poorly but remain at low levels in animals that age gracefully;2) diminished locomotory capacity, which we evaluate with powerful computer vision analysis programs. We will use this preliminary data to select a test set of strains for our second goal: drug screening across a diverse population from the same species for promotion of longevity and healthspan. Our expertise in developing rapidly assessed healthspan measures should facilitate drug dose selection as well as healthspan evaluation. Overall, the proposed study will definitively shed insight into how natural variation within a species impacts longevity and healthspan. Pharmacological interventions that robustly promote strong healthspan across a varied population target should be identified.
This project will identify drug interventions that improve the length of life and/or the quality of aging in a simple animal model. Data obtained by testing a genetically diverse test set is anticipated to identify drugs with high potential to be efficaciousin a diverse human population. This study may lead to pharmacological interventions that protect against physical deterioration, cognitive decline, and disease susceptibility in the elderly human population.