Critical roles of m6A demethylase FTO in ovarian aging

Ovarian aging, recognized as one of the initial signs of systemic aging, is marked by a progressive reduction in both the number and quality of oocytes, which has a profound effect on female fertility. In spite of the advancements in assisted reproductive technologies, these methods fail to tackle the fundamental molecular mechanisms that drive ovarian senescence. Recent surveys have underscored the significant role of epitranscriptomic regulation, especially the N6-methyladenosine (m6A) modification, in regulating RNA stability, translation, and cellular functionality. Fat mass and obesity-associated (FTO), a m6A demethylase, has been identified as a crucial regulator of granulosa cell homeostasis, influencing pathways related to oxidative stress, mitochondrial integrity, apoptosis, and cellular senescence. A decrease in FTO expression in aging ovaries is associated with increased m6A levels, destabilization of heterochromatin, dysregulation of transposable elements, and the upregulation of senescence-associated genes such as FOS. Moreover, regulation of genes such as MFN2, MMP2, and P53 by FTO has been shown to sustain mitochondrial function, uphold ERK signaling, and prevent apoptosis in granulosa cells. In summary, these discoveries position FTO as a pivotal element in the molecular framework governing ovarian aging, presenting promising opportunities for therapeutic strategies aimed at preserving female reproductive capacity.