The Meiotic Spindle, Mechanisms of Chromosome Segregation and Aneuploidy in Aging Human Oocytes: An Update Review

The meiotic spindle is essential for accurate chromosome segregation during oocyte maturation and fertilization, and its alteration might be considered a major contributor to age-related aneuploidy and reproductive failure. Spindle formation is inherently vulnerable to errors and contributes to the unusually high frequency of chromosome segregation defects observed in human eggs. Human oocytes are particularly prone to aneuploidy; the presence of an abnormal chromosome number, which represents one of the leading causes of infertility, recurrent pregnancy loss, implantation failure, and congenital disorders in neonates. Previous studies have reported a U-shaped relationship between maternal age and aneuploidy rates, with relatively higher rates observed in both very young females and in women of advanced maternal age. Conversely, aneuploidy rates appear comparatively lower during the intervening reproductive-age period, particularly between approximately 25 and 35 years of age. Because most aneuploid embryos fail to develop successfully after fertilization, chromosome segregation errors in oocytes have profound consequences for female reproductive success. Aneuploidy primarily arises from defects during meiotic chromosome segregation. Faithful chromosome segregation depends on the accurate assembly and function of the meiotic spindle, a dynamic microtubule-based structure that aligns and separates homologous chromosomes during meiosis I and sister chromatids during meiosis II. Growing evidence indicates that chromosome mis-segregation results from the combined effects of impaired sister chromatid cohesion, altered kinetochore architecture, defective microtubule dynamics, weakened spindle assembly checkpoint activity, and age-related metabolic decline. Together, these defects compromise spindle integrity and reduce the fidelity of chromosome separation. Furthermore, the intrinsic instability of the acentrosomal spindle increases the likelihood of incorrect microtubule-kinetochore attachments, a defect that becomes more prevalent with maternal aging due to progressive deterioration of chromosome organization and kinetochore function. This review summarizes the current understanding of the molecular mechanisms regulating meiotic spindle assembly and function in human oocytes and examines how their disruption contributes to chromosome segregation errors and embryonic aneuploidy. We discuss the interplay between spindle abnormalities and upstream cellular defects, distinguish meiotic from post-zygotic origins of chromosomal abnormalities, and evaluate the clinical significance of spindle assessment in assisted reproductive technologies. Finally, we critically examine emerging strategies aimed at preserving chromosome segregation fidelity, including approaches targeting mitochondrial function and spindle regulation, while distinguishing interventions supported by mechanistic evidence from those that remain preclinical or speculative.