Summary: Researchers have uncovered a metabolic mechanism that helps explain why advanced maternal age (AMA) impairs female fertility and lowers assisted reproductive technology (ART) success. Using non-targeted lipidomics and proteomics alongside multi-omic sequencing (RNA-seq, Cut&Tag, and ATAC-seq), the team found that embryos from older females show a marked decline in autophagy. This decline prevents the normal degradation of the enzyme ACOX1, causing an abnormal increase in fatty acid beta-oxidation (β-FAO). The resulting metabolic overactivity depletes oxidized nicotinamide adenine dinucleotide (NAD+), blocks critical histone modification erasure (H3K9ac), and prevents embryos from properly exiting minor zygotic genome activation, ultimately causing early developmental arrest.
Key Facts
- Autophagy declines with age: Autophagy is a conserved cellular recycling process essential for removing damaged proteins and maintaining metabolic balance during early embryogenesis. The researchers demonstrated that autophagy activity progressively decreases as maternal age increases, compromising embryonic cellular homeostasis.
- ACOX1 accumulates when recycling fails: Molecular assays including RIP-qPCR and RNA pull-down showed that in young embryos the autophagy-related protein LC3B targets the peroxisomal enzyme ACOX1 for degradation. When autophagy is reduced in embryos from aged females, LC3B-dependent clearance of ACOX1 is impaired and ACOX1 levels rise dramatically.
- Excessive lipid burning (β-FAO): Elevated ACOX1 drives a hyper-activated state of fatty acid β-oxidation. While β-FAO is an important energy pathway, its abnormal over-activation in low-autophagy embryos produces metabolic imbalance rather than benefit.
- NAD+ depletion: The hyperactive β-FAO consumes oxidized NAD+ at high rates. NAD+ is required for numerous cellular reactions, including those that enable chromatin remodeling and histone modification. Severe NAD+ depletion undermines these processes.
- Epigenetic consequences: Because NAD+ levels fall, embryos fail to erase the histone acetylation mark H3K9ac at the proper time. This epigenetic defect prevents timely exit from minor zygotic genome activation, leaving the embryo genetically trapped in an earlier transcriptional state and blocking blastocyst formation.
- Pharmacological rescue: Adding the autophagy activator rapamycin to embryo culture restored autophagic activity, reduced ACOX1 accumulation, normalized lipid metabolism and improved blastocyst formation rates in aged mouse models, supporting a causal chain from autophagy loss to developmental failure.
- Clinical relevance: The same molecular sequence—reduced autophagy, ACOX1 accumulation, β-FAO overactivation, NAD+ depletion and H3K9ac persistence—was observed in human embryos from women of advanced maternal age, indicating strong translational potential for targeted metabolic interventions in ART.
The investigation was led by Prof. Jingyu Li, Prof. Shimeng Guo and Prof. Guoning Huang at Chongqing Medical University together with Shaorong Gao at Tongji University. Their integrated approach combined lipidomics, proteomics and multiple genomic assays to map how age-related declines in autophagy rewire embryonic lipid metabolism and alter chromatin states that are essential for development.
Experimental highlights
- Non-targeted lipidomics and proteomics revealed elevated β-FAO signatures in embryos from aged females or experimentally low-autophagy embryos.
- Molecular interaction assays (RIP-qPCR and RNA pull-down) identified LC3B-mediated targeting of Acox1 as a critical regulatory node that is lost when autophagy declines.
- Genetic manipulation showed that overexpressing Acox1 reduced blastocyst formation, while Acox1 knockdown partially restored development in low-autophagy embryos, linking ACOX1 levels causally to developmental competence.
- RNA-seq, Cut&Tag and ATAC-seq demonstrated that excess β-FAO depletes NAD+, interferes with H3K9ac erasure and blocks the normal transition out of minor zygotic genome activation.
Future prospects
By defining how age-associated declines in autophagy disrupt lipid metabolism and chromatin remodeling in early embryos, this work points to metabolic and pharmacological strategies to protect or restore embryonic developmental potential. The rapamycin rescue experiments suggest that controlled activation of autophagy or other interventions that rebalance β-FAO and preserve NAD+ pools could improve blastocyst formation in ART settings. Because the mechanism appears conserved in human embryos from older women, the findings provide a clear rationale for further preclinical and clinical investigation of metabolic additives and culture optimizations aimed at increasing IVF success for patients of advanced maternal age.
Key Questions Answered:
A: Maternal aging impairs autophagy, the cellular recycling system that normally removes specific enzymes and keeps metabolism balanced. When autophagy declines, ACOX1 accumulates and drives excessive fat burning, which triggers downstream metabolic and epigenetic failures that halt early development.
A: Hyper-active β-FAO consumes oxidized NAD+ needed for chromatin-modifying reactions. With NAD+ depleted, embryos fail to erase histone marks such as H3K9ac at the right time, preventing the transition out of minor zygotic genome activation and blocking progression to the blastocyst stage.
A: The rapamycin experiments demonstrate that stimulating autophagy in culture can reverse the pathological cascade—lowering ACOX1, rebalancing lipid metabolism and rescuing blastocyst development in aged mouse embryos. Because the mechanism was also identified in human embryos from older women, these results open a plausible path toward metabolic interventions to improve IVF outcomes, pending safety and clinical testing.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The referenced journal paper was reviewed in full.
- Additional context was added by editorial staff.
About this neurodevelopment and aging research news
Author: Siyun Qin
Source: Science China Press
Contact: Siyun Qin – Science China Press
Image: The image is credited to Neuroscience News
Original Research: Open access. “Autophagy-dependent disruption of β-FAO-mediated histone acetylation in embryos during maternal aging” by Dongmei Deng, Chong Li, Ling Zhu, Yin Tian, Jie Wang, Chenshi Li, Mo Chen, Guoning Huang, Shaorong Gao, Shimeng Guo, and Jingyu Li. Science Bulletin. DOI: 10.1016/j.scib.2026.02.053
Abstract
Autophagy-dependent disruption of β-FAO-mediated histone acetylation in embryos during maternal aging
Advanced maternal age (AMA) impairs fertility and lowers ART success largely by compromising early embryonic development. Autophagy, essential for embryogenesis, declines with maternal age and disrupts metabolic pathways necessary for normal development. This study maps how autophagy loss drives ACOX1 accumulation, hyper-activated β-FAO, NAD+ depletion and failure of H3K9ac erasure, which together prevent timely exit from minor zygotic genome activation and lead to developmental arrest. The mechanism was validated in both mouse models and human embryos from older women, suggesting potential clinical strategies to mitigate age-related declines in embryonic development.