Abstract
It has been widely reported that advanced maternal age impairs oocyte quality. To date, various molecules have been discovered to be involved in this process. However, prevention of fertility issues associated with maternal age is still a challenge. In the present study, we find that both in vitro supplement and in vivo administration of melatonin are capable of alleviating the meiotic phenotypes of aged oocytes, specifically the spindle/chromosome disorganization and aneuploidy generation. Furthermore, we identify SIRT2 as a critical effector mediating the effects of melatonin on meiotic structure in old oocytes. Candidate screening shows that SIRT2-controlled deacetylation of histone H4K16 is essential for maintaining the meiotic apparatus in oocytes. Importantly, non-acetylatable-mimetic mutant H4K16R partially rescues the meiotic deficits in oocytes from reproductive aged mice. In contrast, overexpression of acetylation-mimetic mutant H4K16Q abolishes the beneficial effects of melatonin on the meiotic phenotypes in aged oocytes. To sum up, our data uncover that melatonin alleviates advanced maternal aged-associated meiotic defects in oocytes through the SIRT2-depenendet H4K16 deacetylation pathway.
Highlights
The reproductive aging process is thought to be dominated by a gradual decrease in both the quantity and the quality of the oocytes residing within the follicles present in the ovarian cortex [1]
Melatonin administration alleviates the meiotic defects of oocytes from old mice It has been widely reported that aged oocytes are more likely to produce abnormal spindle and aneuploidy, which lead to a decreasing chance of fertilization and an increasing risk of miscarriage or of a child with birth defects [24,25,26]
Only 15.7% of meiotic defects were detected in metaphase oocytes from reproductive aged mice administrated with melatonin, which is significantly reduced as compared to those old oocytes (Figure 1A– 1B)
Summary
The reproductive aging process is thought to be dominated by a gradual decrease in both the quantity and the quality of the oocytes residing within the follicles present in the ovarian cortex [1]. The age-related decline in oocyte quality is associated with increased spindle abnormalities and aneuploidy [2]. Recent findings suggest that melatonin influences the autophagy processes due to its role as a metabolic regulator and mitochondrial www.aging-us.com protector [15]. Sirtuins are a family of NAD+-dependent deacetylases (SIRT1-7) that catalyze post-translational modifications of proteins. They have been reported to respond to metabolic challenges or oxidative stress associated with aging [17]. Histone acetylation is crucial for cell cycle control, DNA repair, gene expression, and chromosome architecture/stability [19,20,21,22]. SIRT2 has been found to regulate cell differentiation via deacetylating various transcription factors [23]
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