Mechanistic understanding of female reproductive aging based on the chicken model

Abstract

Female reproductive aging is a fundamental biological process characterized by a progressive decline in ovarian function, oocyte quality, and endocrine homeostasis, ultimately leading to reduced fertility and increased susceptibility to age-related diseases. Accumulating evidence indicates that reproductive aging is not merely a passive consequence of time but rather a tightly regulated process governed by complex genetic, epigenetic, and metabolic mechanisms. However, mechanistic dissection and translational exploration of female reproductive aging remain constrained by the limited availability of suitable animal models that faithfully recapitulate the human reproductive trajectory. In this review, we synthesize the current advances in understanding the molecular regulatory networks underlying female reproductive aging, with particular emphasis on key signaling pathways, cellular senescence, epigenetic regulation, hormonal control, and mitochondrial dysfunction coupled with oxidative stress. We highlight how the dysregulation of these interconnected mechanisms contributes to ovarian reserve depletion, follicular atresia, and declining oocyte competence across species. We propose that laying hens are a powerful and underutilized model for studying female reproductive aging. Laying hens exhibit a well-defined and highly reproducible reproductive lifespan characterized by distinct phases of peak and declining reproductive output, closely paralleling the age-related fertility decline in women. At the molecular level, hens share conserved regulatory features with humans, including hormonal signaling via the hypothalamic–pituitary–ovarian axis, age-associated oxidative stress, mitochondrial dysfunction, and epigenetic modulation of reproductive tissues. The daily ovulation cycle, measurable reproductive output, and responsiveness to metabolic and environmental interventions in hens further facilitate high-resolution and high-throughput investigations into aging-related mechanisms. By integrating evidence from human studies, mammalian models, and avian systems, this review highlights the translational value of laying hens in elucidating conserved genetic and epigenetic drivers of female reproductive aging. We discuss the current limitations and future perspectives for cross-species validation and multi-omics integration, aiming to facilitate the identification of actionable targets for delaying reproductive aging and improving female reproductive health. Abs1