Human Reproduction Update · Nov 6, 2026
From folate to the epigenetic clock: one-carbon metabolism in oocyte quality and ovarian ageing
By Fu X, Yang Y, Jiang L et al.
BACKGROUND: One-carbon metabolism (OCM) supports nucleotide synthesis and S-adenosylmethionine (SAM)-dependent methylation; its links to sulfur metabolism connect it to glutathione (GSH) synthesis and hydrogen sulfide (H2S) signalling. These functions are relevant to oocyte growth, epigenetic programming, and developmental competence, but their contribution to ovarian ageing remains incompletely understood. Existing reviews address pregnancy, embryo development, or female fertility broadly, leaving OCM in stage-specific oocyte biology and ageing insufficiently integrated. OBJECTIVE AND RATIONALE: This review examines OCM in oocyte development, epigenetic regulation, and ovarian ageing, focusing on substrate supply, enzyme regulation, and methyl-donor metabolism. It evaluates experimental and clinical evidence on metabolic disturbances and nutritional interventions, and identifies knowledge gaps that limit clinical translation. SEARCH METHODS: PubMed/MEDLINE was searched for English-language literature published from January 2008 to September 2026. OCM substrate, enzyme, and methylation terms were combined with oocyte, follicular, ovarian, embryo, and ART terms. Reference lists were hand-searched. Evidence was assessed by species, tissue, design, and outcome, prioritizing mechanistic perturbations, prospective cohorts, and clinical trials. OUTCOMES: Mouse studies indicate transient leucovorin uptake in growing oocytes and cumulus-supported serine transfer. Methylenetetrahydrofolate reductase (MTHFR) phosphorylation shows developmental regulation, whereas methionine adenosyltransferase 2A (MAT2A) inhibition after the eight-cell stage reduces bovine blastocyst development. DNA methylation supports imprint establishment; reducing methionine from 50 to 10 µM in bovine embryo culture altered methylation at more than 1600 genes. Porcine homocysteine (Hcy) exposure impaired mitochondrial and developmental endpoints, with an increased mitochondrial DNA 16S methylation signal whose causal role requires validation. Multi-component supplementation containing 5-methyltetrahydrofolate (5-MTHF) increased bovine blastocyst yield during maturation (34.9% vs 17.1%), without establishing a human protocol. In a selected recurrent-miscarriage/repeated-ART-failure cohort, over 40% were homozygous or compound heterozygous for common MTHFR variants, without appropriate controls establishing enrichment. Higher Hcy was associated with poorer implantation and clinical pregnancy in C677T TT carriers; a separate retrospective cohort associated hyperhomocysteinaemia with lower live birth (adjusted odds ratio [OR] approximately 0.45). Another retrospective study associated combined 5-MTHF/B12/B6 supplementation with higher clinical pregnancy (OR 2.03) and live birth (OR 1.83) than folic acid alone, without establishing causality. One study found optimal red-cell folate in 12% and adequate B12 in 44% of infertile women. Age-associated methylation remodelling varies across loci, cells, and models; blood/somatic methylation-age estimates are not oocyte-age measurements. Experimental reproductive studies suggest context-dependent H2S roles, but effects on chronological ovarian ageing and oocyte demethylation remain unestablished. Non-reproductive experiments on H2S-linked MTHFR persulfidation support further study of sulfur-dependent Hcy partitioning, without validating this mechanism in oocytes. WIDER IMPLICATIONS: OCM provides a rationale for investigating nutritional interventions, but predominantly animal and observational evidence does not establish improved human live birth or delayed ovarian ageing. Priorities include direct OCM flux and measurements of SAM and S-adenosylhomocysteine in ageing human oocytes, adequately powered randomized trials assessing reproductive outcomes and safety, and tissue-specific methylation measures as exploratory biomarkers. Common MTHFR variants alone should not determine treatment. REGISTRATION NUMBER: N/A.