Extreme Protein Longevity in the Ovary: Implications for Reproductive Aging

Advanced maternal age (>35 years) is associated with an increased risk of fetal chromosomal abnormalities and pregnancy complications. With the average maternal age at conception continuing to increase, there is an immediate need to understand the molecular mechanisms driving reproductive aging and identify novel therapeutic targets and biomarkers. Long-lived proteins represent an emerging feature of cellular proteostasis, with distinct molecular signatures and mechanisms contributing to their exceptional stability. In the oocyte, protein turnover has long been implicated in maintaining quality, while age-associated loss of long-lived proteins such as cohesins can compromise reproductive function. Recent studies have begun to define the long-lived proteome of the mammalian oocyte and ovary and reveal broader trends in protein persistence across the reproductive lifespan. This review discusses the molecular features associated with protein longevity, examples of long-lived proteins, the relationship between protein turnover and oocyte aging, and recent studies characterizing long-lived proteins in the ovary and oocyte. We conclude by considering the implications of protein longevity for reproductive aging and proteostasis in aging cells.