PROJECT SUMMARY Aging has profound impacts on the development and progression of human diseases that are principal causes of mortality, including cardiovascular diseases, diabetes, neurodegenerative diseases, infectious diseases and cancer. Aberrant epigenetic alterations have been attributed to the development of many age- related disorders and have recently been found to be closely linked to aging itself. The long-term goal of this project is to determine the roles of epigenetic and chromatin regulatory pathways in the regulation of aging. Recently, through a novel histone mutant lifespan screen, we found that tri-methylation of histone H3 at lysine 36 (H3K36me3) promotes longevity by suppressing intragenic cryptic transcription. We have also shown that cryptic transcription, considered a form of transcription infidelity, increases with age in both yeast and worms; genetic manipulations that suppress cryptic transcription extend lifespan. These observations suggest that the age-associated increases in cryptic transcription and the resulting loss of transcription fidelity are evolutionarily conserved causes of aging. In the proposed project, we will test this hypothesis by investigating 1) the cause of increased cryptic transcription during aging; 2) how suppression of cryptic transcription extends lifespan; and 3) the functional conservation of this pathway during aging in higher eukaryotic systems, including worms and mammalian adult stem cells. This project examines the molecular causes of aging from a novel perspective and will lead to the discovery of new epigenetic mechanism of aging that could serve as potential therapeutic targets of aging and age-related diseases.

PROJECT NARRATIVE This project investigates the molecular basis of decreased gene expression fidelity during aging, including the cause of such changes and the mechanism of how such changes may accelerate aging. The successful execution of this project will lead to a better understanding of the molecular mechanisms of aging, in whole organisms as well as in mammalian adult stem cells. The new knowledge derived from this project will be useful for the future design of novel therapeutics aimed at reducing age-related diseases and promoting healthy aging.