Novel Age-Dependent DNA Modifications

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Life expectancy has increased dramatically over the last century, bringing world-wide epidemics of age- related diseases. Although there have been many theories proposed for aging, the mechanisms by which cells record time or mark time are largely unknown. Recent developments in the field of epigenetics have shown that methylation in specific regions closely correlates to age. However, the epigenome is a malleable molecular product that is regulated by many external factors. Additional mechanisms by which cells can track long periods of time chronologically remain undefined. We propose that specific DNA damage products can accumulate over time, and that this DNA damage is affected by metabolic events. Identifying specific DNA adducts that accumulate at later stages of life would open a new view of disease onset that directly interfaces genetics and metabolism. Although the concept of time tracking through DNA damage is not new, we now have the technology to measure specific DNA lesions at high resolution and sensitivity, and to discover new lesions--allowing a rigorous and quantitative test of this hypothesis. In fact, our preliminary data reveal at least 3 as-yet-unidentified DNA products in DNA of old mammalian brains that are present in substantially higher quantities compared in DNA of young mammalian brains. Identification of these and other DNA adducts that accumulate with aging would be broadly groundbreaking, but particularly for understanding why diverse diseases strike at specific times of life. In the experiments in this project, we will identify the 3 DNA products that accumulate in mammalian brains with aging. We will also discover new DNA products in other tissues with aging. We will synthesize the unknown DNA molecules and use isotope dilution mass spectrometry to quantitate the new DNA molecules in any biological system. Performing this biochemistry will open the door for major downstream questions. Do these new DNA molecules escape DNA repair? Are they mutagenic, or do they affect gene expression? What metabolic biochemistry regulates the formation of these age-related DNA molecules? Once we define these new DNA molecules as “long term clocks”, and we provide the structures and rigorous measurement methods to the scientific community, scientists can begin to ask interesting questions about whether these molecules could function in biological systems as “alarm clocks”.