DNA methylation differences underlying female reproductive aging

点击翻译按钮获取中文摘要

PROJECT SUMMARY Reproductive aging occurs earlier than systemic aging as a person with ovaries’ ovarian reserve is depleted as they approaches menopause. There is considerable variability around when a person with ovaries reaches menopause, yet few contributing factors have been identified. Assessment of reproductive age involves measuring ovarian reserve and oocyte function, which has clearly-defined parameters in in vitro fertilization. As ovarian reserve declines, Anti-Mullerian hormone levels fall and women produce fewer oocytes after ovarian stimulation. Oocyte function also declines, as fewer mature oocytes are produced and have the capacity to be fertilized. The mechanisms of these age-related declines are unclear, but may involve changes in DNA methylation, which are known to occur with age and may reflect the biological processes underlying reproductive aging. We hypothesize that DNA methylation patterns will be associated with ovarian reserve and oocyte function, and that people with ovaries with poor ovarian reserve and oocyte function will experience epigenetic age acceleration and will accumulate more stochastic epigenetic mutations. To test this hypothesis, we will first perform an epigenome-wide association to examine DNA methylation patterns associated with each measure of ovarian reserve and oocyte function. Then, we will calculate epigenetic age and age acceleration, which are indicators of biological aging, and stochastic epigenetic mutations, which increase with age and may disrupt key biological pathways in an individual. If successful, this proposal will provide a better understanding of the genes and processes associated with reproductive aging, would allow for future development of targeted treatments to slow or reverse aging, and would help identify women at increased risk of chronic disease later in life. This proposal will provide focused training opportunities that will be crucial for my success as an independent, NIH-funded researcher. I will work with experts in the fields of aging biology and reproductive aging, epigenetic aging, and clinical and translational research. Finally, I will seek additional training in grant and manuscript writing. This training will position me to apply for future R01 funding and become an independent investigator.