The long-term objective of this project is to identify the mechanism by which damage, in particular damage to the nuclear genome that arises spontaneously as a consequence of endogenous processes, promotes aging-related degenerative changes. The current model is that stochastic damage promotes aging via a cell autonomous mechanism, i.e., by driving cell senescence or cell death. We seek to challenge this model by carefully examining how spontaneous DNA damage drives aging in a mouse model of a human progeriod syndrome caused by a defect in DNA repair. The approach will be to combine unique genetic and mass spectrometry tools to accomplish the following aims: 1) To use highly sensitive LC-MS/MS/MS assays to measure endogenous oxidative DNA lesions in tissues of progeroid and wild-type mice at multiple ages and determine if the level of damage predicts the extent of aging-related pathology in each of these tissues. 2) To genetically deplete DNA repair in one tissue or cell type at a time and determine the impact on those cells, neighboring cells and distant tissues, to determine if damage drives aging via a cell-autonomous or non-autonomous mechanism. 3) To use parabiosis between normal and progeroid mice to determine if circulating factors can overcome accelerated aging due to too much DNA damage. 4) To use unbiased and targeted proteomics approaches to identify systemic signals activated in response to genotoxic stress and old age. Successful completion of these aims is anticipated to yield novel information about the aging process and if there are common underlying mechanisms for multiple aging-related diseases. The proteomics work may yield new biomarkers of biologic age. In addition, extension of our preliminary work via this project is anticipated to yield rational strategies to extend healthspan ofthe elderly by reducing stochastic damage and/or inhibiting the damage responses that promote aging.

Public Health Relevance

;This project seeks to identify the mechanism by which normal wear-and-tear causes aging and the inevitable loss of function that accompanies aging. The work is anticipated to yield novel biomarkers that can predict if someone is aging well or poorly. The work is also anticipated to yield novel strategies for preventing wear-and-tear and/or its consequences to improve the health ofthe elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-2)
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Scripps Research Institute
La Jolla
United States
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