Epigenetic deciphering of ovarian aging: multilayer interactive mechanisms and targeted reversal strategies

Ovarian aging leads to the progressive loss of reproductive and endocrine functions. As an upstream regulatory hub, epigenetic modifications synergistically impair these two functions through multi-dimensional mechanisms, collectively contributing to the occurrence of clinical phenotypes. Current therapies (e.g., hormone replacement therapy) are difficult to reverse functional decline and carry long-term risks. This review systematically elaborates on the core roles of three major epigenetic mechanisms in ovarian aging: DNA methylation (mediated by DNMTs/TET), histone modification (dynamic balance of HATs/HDACs), and non-coding RNA (miRNA/lncRNA/circRNA network). Dysregulation of DNA methylation reprogramming drives the imbalance between dormancy and activation of primordial follicles and impairs steroidogenesis. Dysregulated histone modification induces spindle assembly defects, meiotic arrest, and a vicious cycle of apoptosis and autophagy in granulosa cells. ncRNAs regulate oocyte maturation through the ceRNA mechanism and epitranscriptomic reprogramming (e.g., m6A). These mechanisms synergistically accelerate ovarian aging through multiple pathways, including interfering with the HPG axis, aggravating oxidative stress-mitochondrial dysfunction, and disrupting apoptosis/autophagy homeostasis. Although epigenetic interventions still face potential transgenerational genetic safety risks, against the backdrop of high incidence and global population aging, the development of novel therapies that specifically target somatic cells or can avoid such risks has become an urgent need. In the future, targeting key epigenetic nodes is still expected to open up new avenues for extending female reproductive lifespan and alleviating long-term health risks associated with ovarian aging.