Fertile insights into fertility
Fertility declines significantly in women after the age of 35 due to the reduced quantity and quality of oocytes, the immature eggs in the ovaries. Also, advanced reproductive age is associated with pregnancy complications and higher risk of birth defects. The incidence of couples postponing childbearing is increasing, particularly in high-income countries. Understanding the biological process underpinning reproductive decline is therefore critical to develop effective interventions that ensure a successful pregnancy.
Ageing impact on gametogenesis
The EU-funded GermAge project investigated various pathways implicated in the process of gametogenesis, the production of oocytes and sperm cells. “Our goal was to define the determinants and factors responsible for age-dependent infertility and set the stage for future therapeutic or preventive strategies,” explains project coordinator Rolf Jessberger. During meiotic cell division, chromosomes bind on a spindle to ensure their correct segregation into the resultant germ cells. Failure to do so leads to aneuploidy, a condition with an abnormal number of chromosomes per cell. This often results in miscarriage or birth defects. Researchers focused on the basic mechanisms underlying meiotic division including key chromosome proteins, control checkpoints and mutational load in aging stem cells. They employed a battery of innovative molecular and cell biology techniques and animal models to analyse mouse and human germ cells. Notable is their technique for live oocyte chromosome imaging at remarkably high resolution as well as 3D oocyte chromosome tracking. GermAge developed a novel fluorescent labelling approach, enabling them to mark and study relevant meiotic spindle structures in oocytes. Scientists observed that increasing oocyte age weakens the spindle assembly checkpoint responsible for correct chromosome segregation during meiosis. They successfully identified the proteins responsible for maintaining chromosomal integrity and spindle attachment. GermAge characterised RNA-modifying and monitoring factors critical for gametogenesis and fertility. A key finding, the protein complex cohesin deteriorates in ageing oocytes, leading to meiotic errors. As cohesins keep chromosomes properly structured and ordered in dividing germ cells, cohesin loss also causes damage to chromosome ends, further contributing to genomic instability. Ageing oocytes exhibit a decreased ability to correct aberrant attachments to the spindle.
The impact of GermAge findings
GermAge has identified new risk factors for age-dependent male and female germ cell failure and age-dependent aneuploidy. These are important avenues for further research into reliable diagnostic biomarkers for human reproductive medicine. The project has developed highly innovative tools to study germ cell integrity with a focus on chromosome and chromosome-related aberrations. “In addition to advancing our understanding of the biology of germ cell aging, GermAge provides important insight into the genetic risk to children of older parents,” emphasises Jessberger. These tools could form the basis of improved diagnostics in assisted reproductive technologies with better cryopreservation of male and female germ cells and accurate evaluation of the risk of inherited diseases through personalised genomics. The team has devoted significant effort towards disseminating GermAge findings to the scientific community and raising public awareness on the risks associated with parenthood at an advanced age.
Keywords
GermAge, oocyte, germ cell, reproductive, spindle, meiotic, infertility, cohesin, aneuploidy, chromosome segregation, chromosome imaging, chromosome tracking
