SAT-150 - Age-Related Accumulation of Advanced Glycation End-Products in the Follicles Impairs CPEB1-Dependent Translation Regulation in Oocytes

Introduction:
Female fertility declines with age, largely due to deterioration in oocyte quality. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) is a master regulator of translation control of mRNA in oocytes, and is essential for meiotic progression and developmental competence. Although age-related reduction of CPEB1 expression has been reported, the underlying mechanism remains unknown. Aging is accompanied by chronic inflammation, oxidative stress, and the accumulation of advanced glycation end-products (AGEs), which disrupts tissue homeostasis. This study investigated whether AGE accumulation in the follicular microenvironment affects CPEB1 expression and oocyte developmental competence.

Methods:
AGE concentrations in human follicular fluid were measured and compared between non-advanced age group (27–34 years) and advanced age group (35–43 years) undergoing oocyte retrieval. Ovaries harvested from 8-week-old and 48-week-old mice were examined by immunostaining to evaluate AGE accumulation, RAGE expression, and stage-specific CPEB1 expression in oocytes. Using a mouse follicle culture system, we mimicked age-related AGE accumulation and assessed changes in CPEB1 expression and translation activity. To determine whether AGEs directly affect oocytes, denuded oocytes were exposed to AGE stress and evaluated for CPEB1 expression and translation activity. Furthermore, the rescue effect of a RAGE inhibitor during AGE-loaded follicle culture was examined.

Results:
AGE concentrations in human follicular fluid were significantly higher in the advanced age group. In old mice, AGEs accumulated in ovaries and granulosa cells across follicular stages, accompanied by increased RAGE expression. CPEB1 expression in oocytes was maintained in early secondary follicles but declined at the antral stage in old mice. In follicle culture, AGE exposure decreased CPEB1 expression and increased translation activity in oocytes. In contrast, AGE treatment of denuded oocytes did not alter CPEB1 expression or translation activity, indicating that the effects of AGEs on oocytes are mediated through granulosa cells. The addition of a RAGE inhibitor restored CPEB1 expression and suppressed aberrantly increased translational activity under AGE stress.


Conclusion:
Age-related accumulation of AGEs in the follicular environment disrupts oocyte translation regulation by reducing CPEB1 expression, ultimately impaired oocyte maturation. Targeting AGE–RAGE signaling may represent a promising strategy to mitigate AGE-induced dysfunction and improve oocyte developmental competence. Inhibition of RAGE signaling has the potential to mitigate AGE-induced dysfunction and improve oocyte developmental competence.

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