Molecular basis of ovarian aging and reproductive outcomes: biomarker exploration based on follicular fluid

Ovarian aging reduces oocyte quality and is a major limiting factor in assisted reproductive technologies (ART) such as IVF and ICSI. This review highlights the role of follicular fluid (FF) as a mirror of the oocyte microenvironment and summarizes molecular alterations linked to aging and ovarian dysfunction. We focus on metabolites, proteins, microRNAs, and exosomes within FF that influence oocyte quality and reproductive outcomes, aiming to identify novel clinical biomarkers. Follicular fluid contains diverse biomolecules-including hormones, growth factors, cytokines, oxidative stress markers, and exosomes-that shape oocyte maturation, fertilization capacity, and embryonic competence. Recent multi-omics studies suggest that metabolic and redox-related molecules, amino acid and lipid profiles, and exosomal microRNAs are associated with ART outcomes. Mitochondrial DNA (mtDNA) and cell-free mtDNA (cf-mtDNA) also emerge as promising indicators of mitochondrial function and oocyte developmental potential. However, variations in patient background, sample handling, and analytical methods limit reproducibility. Overall, FF provides a valuable, minimally invasive source for assessing the oocyte environment and understanding ovarian aging. Future studies should integrate metabolomic, proteomic, transcriptomic, and exosomal data through multi-omics and functional analyses to establish reliable clinical biomarkers. Such advances may enable precise assessment of oocyte quality, prediction of ART success, and early diagnosis of ovarian aging.