Reproductive aging is a complex biological process, characterized by infertility, hormonal perturbations and metabolic dysregulation. Medical advances have resulted in increased life expectancy; however, menopause still occurs at the age of 50. After menopause, estradiol levels decrease, affecting the function of the reproductive system as well as downstream organs, such as the bones (osteoporosis). The development of new approaches to delay reproductive aging will enhance reproductive longevity and delay general adverse health outcomes of aging. So far, most research on reproductive aging has focused on infertility and the well-known age-associated reduction in oocyte quantity and quality. However, our lab discovered that the ovarian microenvironment or stroma in which the gamete develops changes with age. Specifically, collagen I/III accumulates, resulting in fibrosis. Concurrently, a pro-inflammatory milieu develops with a significant increase in pro-inflammatory cytokine production, including interleukin-6 (IL-6). These changes create a reactive matrix that likely influences oocyte quality. In this proposal, we will test the hypothesis that targeting stromal fibrosis and inflammation we can extend reproductive longevity, maintain endocrine function, and improve overall health outcomes. We expect that mitigating fibrotic and inflammatory pathways will preserve the homeostatic matrix of the ovarian stroma. To test this hypothesis, we will establish a preclinical pipeline using CD1 mice to test whether anti-fibrotic and anti-inflammatory drugs can delay reproductive aging phenotypes. Beginning at 7 months, when fibrosis starts in the ovarian stroma, we will transplant an osmotic pump to continuously deliver a broad spectrum anti-fibrotic drug (Esbriet®), an anti-inflammatory drug (IL-6 receptor blocking antibody, Tocilizumab®) or the combination of both directly to the ovary. After a 6-week treatment, mice in each experimental cohort (N=5) will be harvested at 0-, 2- and 4-months post-treatment to evaluate fibrosis and inflammation (Aim 1) and reproductive longevity and overall health (Aim 2). In the first aim we will quantify collagen deposition and fibrillar structure, macrophage phenotypes, and inflammatory gene expression changes in the ovaries. In the second aim, we will perform follicle counts, focusing on the ovarian reserve as an indicator of reproductive lifespan. We will also monitor the estrous cycle of the mice, which is dysregulated with age. Blood will be collected to profile estradiol and anti-Mullerian hormones levels and the bones to analyze their mineralization as a readout of overall health. This work has translational potential because fibrosis and inflammation are hallmarks of the aging ovarian microenvironment also in humans. Furthermore, this work will establish a pre-clinical model to screen drugs which enhance reproductive longevity and overall health, which could be used in the future to test new therapeutic approaches.
|Effective start/end date||8/1/20 → 8/1/22|
- Buck Institute for Research on Aging (GCRLE-1720)