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<p>Women of advanced age exhibit significant heterogeneity in ovarian reserve, categorized as normal (NOR) or diminished (DOR). This study aims to distinguish physiological age-related decline from pathological accelerated aging in DOR, and to explore underlying molecular mechanisms for optimizing assisted reproductive strategies. In vitro fertilization-embryo transfer (IVF-ET) outcomes were retrospectively compared in advanced-age women (≥ 40 years) with NOR or DOR treated at our center (January 2022 – December 2024). Simultaneously, follicular fluid (FF) was collected from both groups (<i>n</i> = 20). After centrifugation, metabolomic analysis was performed on metabolites, and transcriptomic sequencing on isolated granulosa cells (GCs). Despite comparable fertilization and cleavage-stage embryo quality, the DOR group showed significantly lower rates of oocyte maturation, blastocyst formation, clinical pregnancy, and live birth (<i>P</i> &lt; 0.05). Metabolomic analysis revealed 28 differential metabolites (DMs) in FF, primarily enriched in galactose metabolism. Transcriptomics of GCs identified 246 differentially expressed mRNAs (DEmRNAs), prominently enriched in immune-related pathways. Protein-protein interaction analysis highlighted five hub genes (CX3CR1, CD69, FCER1A, EOMES, SPRR2A). Integrated analysis of the top 50 DEmRNAs with the top 400 DEmRNA-DM correlation pairs identified five key genes—IGLC3, RNVU1-29, FAM110C, NPY2R, and KCNN4—bridging GC transcriptome and FF metabolome, with key pairs including RNVU1-29 with lysylhydroxyproline and a sterane derivative, and FAM110C with 16-hydroxyhexadecanoic acid. In conclusion, DOR in advanced age may represent a distinct pathological aging state characterized by a dysregulated follicular microenvironment potentially shaped by immune activation and metabolic reprogramming. The identified key gene-metabolite pairs offer candidate molecular links to compromised oocyte developmental competence.</p>

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Integrated Metabolomic and Transcriptomic Profiling Reveals a Distinct Pathological Aging State in Diminished Ovarian Reserve of Advanced Reproductive-Age Women

  • 期刊论文

  • 发表日期：

    2026年7月9日

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  • Zhengda Li,
  • Shikai Wang,
  • Xianbao Mao,
  • Xiaohui Zhang,
  • Pingpin Wei,
  • Liangshi Chen,
  • Lintao Xue,
  • Ziyun Ruan

摘要

Women of advanced age exhibit significant heterogeneity in ovarian reserve, categorized as normal (NOR) or diminished (DOR). This study aims to distinguish physiological age-related decline from pathological accelerated aging in DOR, and to explore underlying molecular mechanisms for optimizing assisted reproductive strategies. In vitro fertilization-embryo transfer (IVF-ET) outcomes were retrospectively compared in advanced-age women (≥ 40 years) with NOR or DOR treated at our center (January 2022 – December 2024). Simultaneously, follicular fluid (FF) was collected from both groups (n = 20). After centrifugation, metabolomic analysis was performed on metabolites, and transcriptomic sequencing on isolated granulosa cells (GCs). Despite comparable fertilization and cleavage-stage embryo quality, the DOR group showed significantly lower rates of oocyte maturation, blastocyst formation, clinical pregnancy, and live birth (P < 0.05). Metabolomic analysis revealed 28 differential metabolites (DMs) in FF, primarily enriched in galactose metabolism. Transcriptomics of GCs identified 246 differentially expressed mRNAs (DEmRNAs), prominently enriched in immune-related pathways. Protein-protein interaction analysis highlighted five hub genes (CX3CR1, CD69, FCER1A, EOMES, SPRR2A). Integrated analysis of the top 50 DEmRNAs with the top 400 DEmRNA-DM correlation pairs identified five key genes—IGLC3, RNVU1-29, FAM110C, NPY2R, and KCNN4—bridging GC transcriptome and FF metabolome, with key pairs including RNVU1-29 with lysylhydroxyproline and a sterane derivative, and FAM110C with 16-hydroxyhexadecanoic acid. In conclusion, DOR in advanced age may represent a distinct pathological aging state characterized by a dysregulated follicular microenvironment potentially shaped by immune activation and metabolic reprogramming. The identified key gene-metabolite pairs offer candidate molecular links to compromised oocyte developmental competence.