Harnessing Redox Regulation of Proteasome Function to Promote Healthy Aging - PROJECT SUMMARY For half a century, groups across the world have been investigating the hypothesis that reactive oxygen species influence the biology of aging. However, technical limitations have, until recently, heavily limited the precision at which studies can interrogate this hypothesis. For example, reactive oxygen species are known to post-translationally modify cysteine residues on proteins throughout the proteome, however, only recently have proteomic techniques been developed allowing for deep and quantitative analysis of cysteine oxidation on proteins in a biological sample. This proposal will develop preliminary data which identified a broad increase in cysteine oxidation across 10,970 cysteines in the proteome in C. elegans during aging and begin to link these events to regulation of the biology of aging. Specifically, this proposal will focus on redox regulation of proteasome activity during aging. First, this proposal will determine the relative contribution of cysteine oxidation to regulating age-dependent changes to proteasome activity. Second, this proposal will identify and define regulatory cysteines involved in redox regulation of the proteasome and determine their influence in the maintenance of longevity. Third, this proposal will generate new cysteine oxidation data sets to determine how longevity interventions influence the trajectory of age-dependent cysteine oxidation. Finally, this proposal will evaluate the intriguing hypothesis that reactive oxygen species can be carefully titrated to promote fitness through stimulating dormant proteasome activity in aged organisms. This work will synergistically employ the skillsets of multiple investigators to perform impactful, cutting-edge research. In addition to providing significant insights into important areas of cell biology, the proposed work will also contribute to the development of a future academic scientist at Harvard’s T.H. Chan School of Public Health, one of the best places to receive scientific training in the world. These studies will both develop a research program which the trainee can use to establish an independent, academic scientific research group as well as equip the trainee with the skillset needed to be successful in this professional domain. The trainee will receive experience in all areas required of a successful academic investigator, such as mentoring, scientific communication, grant writing, project management and budgeting and receive significant technical training in a new model system, new fields and many new techniques. Together, this work will define fundamental mechanisms contributing to development of the biology of aging with broad implications for human health and disease and provide strategies to promote healthy aging.
