Declining Autophagy in Aging Females Compromises Vital Early Embryonic Development

AMA significantly impairs female fertility and reduces the success of assisted reproductive technology (ART) by compromising early embryonic development. Autophagy, a vital process in embryogenesis, has been shown to decline with increasing maternal age. This reduction is thought to disrupt key metabolic pathways essential for normal embryonic development. However, the mechanistic link between autophagy-mediated metabolic regulation and the developmental potential of embryos from aged females remains insufficiently understood.

To address this gap, the research team led by Prof. Jingyu Li, Prof. Shimeng Guo, Prof. Guoning Huang at Chongqing Medical University, and Shaorong Gao at Tongji University finds a decreased autophagy in embryos from aged female mice and that supplementation with Rapamycin (an autophagy activator) in the culture medium improved early embryonic development, suggesting that impaired autophagy may be one of the essential reasons for the decline in development of embryos from aged female mice. 

The non-targeted lipidomics and proteomics suggest an enhanced fatty acid β-oxidation (β-FAO) in embryos from aged female mice or low-autophagy embryos. With RIP-qPCR and RNA pull-down, the research team reveals that decreased autophagy in low-autophagy embryos hinders LC3B-dependent degradation of Acox1, elevating ACOX1 expression, thereby enhancing β-FAO. Overexpression of Acox1 reduces blastocyst formation rates, while knockdown of Acox1 partially rescues embryonic development in low-autophagy embryos, suggesting that autophagy-mediated regulation of β-FAO plays a pivotal role in the developmental potential of embryos from aged female mice.

Subsequently, RNA-seq, Cut&Tag, and ATAC-seq analyses suggest that abnormally active β-FAO in low-autophagy embryos excessively consumes oxidized nicotinamide adenine dinucleotide (NAD⁺), leading to failure in H3K9ac erasure, thereby interfering with the timely exit of minor zygotic genome activation, ultimately causing developmental defects. Furthermore, this evolutionarily conserved mechanism is confirmed in embryos derived from women with advanced age, indicating the significant clinical relevance of the metabolic intervention targets identified in this study.

Future Prospects

This work investigates the molecular mechanisms underlying autophagy-driven lipid metabolic dysregulation in embryos from aged female mice and humans, and elucidates how these metabolic alterations impair embryonic developmental competence. The findings may offer a potential clinical strategy to mitigate the decline in early embryonic development associated with maternal aging.