The reproductive potential of mammals decreases with aging, until reaching infertility. One reason for aging-related infertility is the decrease of the reproductive capability of old oocytes. It was found previously that gene expression, histone acetylation, and protein function are altered by aging in metaphase II (MII) stage oocytes. MII oocytes develop from germinal vesicle (GV)-stage oocytes. Here, we hypothesized that the defects of old MII oocytes arise at the GV stage. To prove this hypothesis, we examined the acetylations of histone H4 at lysines 5 (H4K5), 8 (H4K8), 12 (H4K12), and 16 (H4K16) in old GV and MII oocytes. We found that acetylation of H4K12 and H4K16 decreased in old GV oocytes. Acetylation of H4K12 later increased in old MII oocytes. We also examined expression of Cdc2a, a gene related to H4K12 acetylation. Cdc2a expression increased in old nonsurrounded nucleolus (NSN) oocytes but decreased in old MII oocytes. On the other hand, the protein and kinase activities of CDC2A decreased in both GV and MII old oocytes. Finally, we showed that correction of the histone deacetylation of old oocytes at the GV stage restores younglike levels of H4K12 acetylation and CDC2A protein at the MII stage. These data support our hypothesis that abnormalities of histone acetylation at the GV stage are the cause of alterations at the MII stage. Our study provides evidence for strategies targeting the GV stage of oocytes to overcome aging-induced infertility.