VDR-Spermidine Axis Protects Against Age-Related Granulosa Cell Dysfunction and Follicular Decline via DNMTs-Mediated p53 Methylation

Ovarian aging, marked by a decline in follicle quantity and quality, is a complex process whose underlying mechanisms remain elusive. Here, we identify the vitamin D receptor (Vdr) as a key anti-aging transcription factor whose expression in granulosa cells (GCs) declines with age. Using GCs-specific Vdr knockout (cVKO) mice and a Vdr-knockout (VKO) human granulosa-like cell line, we demonstrate that loss of Vdr triggers GCs aging and disrupts ovarian function. Integrated transcriptomic and metabolomic analyses from VKO and WT cells revealed that Vdr loss downregulates the de novo spermidine (SPD) biosynthesis by directly suppressing the transcription of ornithine decarboxylase (ODC1). This led to SPD depletion, which in turn inhibited DNA methyltransferase (DNMTs) activity, resulting in hypomethylation of the p53 promoter and activation of the p53/p21 pathway. Crucially, supplementation with either SPD or its upstream methyl donor S-adenosylmethionine (SAM) rescued cVKO and VKO cell aging, improved hormonal profiles and promoted follicular development in cVKO mice. Furthermore, both supplements effectively delayed ovarian aging and improved fertility in naturally aged mice. Our study unveils the Vdr-spermidine-DNMTs axis as a fundamental mechanism safeguarding against ovarian aging, highlighting SPD and SAM as promising therapeutic agents for age-related female infertility.