Circadian rhythm disruption impairs ovarian follicular development via NAD

Summary

In a rat model mimicking increased light exposure, long-photoperiod disruption impaired folliculogenesis and ovulation, driven by NAD+ depletion that reduced SIRT3 activity and disrupted SOD2 deacetylation, causing oxidative and mitochondrial stress in granulosa cells. Multi-omics profiling and mechanistic assays supported this pathway, and nicotinamide mononucleotide supplementation rescued mitochondrial function and follicular outcomes.

Key Findings

• Long-photoperiod exposure reduced growing follicles and oocyte yield, indicating impaired folliculogenesis and ovulation.
• Mechanistically, circadian disruption decreased NAD+ levels, inhibited SIRT3 activity, and impaired SOD2 deacetylation, leading to oxidative and mitochondrial stress in granulosa cells.
• Nicotinamide mononucleotide (NMN) supplementation rescued mitochondrial function and improved follicular outcomes.

Clinical Implications

While preclinical, the data suggest targeting NAD+ metabolism (e.g., NMN or NAD+ boosters) and mitigating light-at-night could be explored to preserve follicular health in women with circadian disruption, warranting clinical trials in shift workers with subfertility.

Limitations

• Findings are from a rat model; human translational relevance requires validation
• Long-photoperiod is a proxy for circadian disruption and may not capture all real-world exposures

Future Directions

Prospective human studies in shift workers assessing circadian metrics, NAD+ status, and ovarian reserve; randomized trials of NAD+ boosters (e.g., NMN) and light hygiene interventions in women with subfertility.