IDENTIFYING MECHANISMS TO SLOW REPRODUCTIVE DECLINE USING A CAENORHABDITIS ELEGANS MODEL

Abstract

Reproductive decline is one of the first systems to decline with age in women and has become increasingly important as the average maternal age increases. In this thesis work, I sought to 1) uncover novel regulators of reproductive aging, 2) investigate reproductive longevity mutants to reveal new mechanisms that promote reproductive longevity, and 3) identify therapeutics that slow reproductive decline. To achieve these goals, we have used the model organism C. elegans. C. elegans is an ideal model to study reproductive aging because it has a short generation time and many genetic tools. Importantly, key regulators of aging and longevity are conserved from worms to humans. Furthermore, work from our lab and others has established that, like women, worms spend at least half of their lifespans in a post-reproductive period; therefore, reproductive decline begins early in life. Also, the loss of oocyte quality with age, not the declining number of oocytes, governs reproductive decline, and genes that decline with age in oocytes are similar in worms, mice, and humans. In this thesis, I describe the following findings: 1) mitochondria are key regulators of reproductive longevity and rely on mitophagy to slow reproductive decline, 2) the mitophagy-promoting metabolite Urolithin A slows reproductive decline by improving oocyte quality, and 3) a novel mechanism that regulates the reproductive span requires communication between the hypodermis and the germline using Notch signaling. Further, we have designed and verified a microfluidic chip that simplifies and improves reproductive and lifespan assays and tracks healthspan metrics simultaneously on an individual worm level. Using this device, we have uncovered that 1) drugs and supplements that promote somatic longevity also promote reproductive longevity and 2) a novel role for conserved serum glucocorticoid-induced kinase 1 (SGK-1) in reproductive span regulation. The findings reported here aim to have implications for humans and to further the research and interest in the reproductive aging field.