New study finds a novel explanation for female age-related infertility.
Infertility is recognized as a disease both in the U.S. and worldwide. It is clinically defined as the inability to get pregnant, or to successfully carry a pregnancy to term, after 1 year of unprotected sex.
Approximately 1 in 8 U.S. couples are struggling to get pregnant or maintain a pregnancy. One third of infertility is typically attributed to men, another third to women, and a final third is thought to be caused by a combination of problems in both partners.
Age is thought to play a crucial role in the ability to procreate. For a woman, the number of oocytes - that is, female egg cells before they fully develop into ova - naturally declines with age. Additionally, the quality of the eggs also decreases, particularly after a woman reaches the age of 37.
New research, carried out by scientists at the University of Montreal Hospital Research Center (CRCHUM) in Canada, uses state-of-the-art microscopy technology in order to examine the genetics behind this aging process.
The findings - published in the journal Current Biology - point to errors in chromosomal segregation as a new mechanism for explaining female age-related infertility.
Faulty microtubules in chromosome segregation cause infertility
Eggs with an abnormal number of chromosomes are called aneuploid eggs, explain the researchers. As a woman ages, and particularly as she ages beyond 35 years, the number of aneuploid eggs increases.
Until now, the widely accepted hypothesis for this increase in abnormal eggs stated that the glue-like substance - made of protein complexes called cohesins - that keeps the chromosomes unified starts to malfunction. This hypothesis has been called the "cohesion-loss" hypothesis.
The new research does not contradict this theory, but it does find an additional problem.
In the new study, the microtubules - which are small cylindrical structures within the cell that are responsible for cell movement and which organize themselves into a spindle - were found to be dysfunctional in older mice.
Microtubules pull the chromosomes together around their spindle-like structure and "sort" them when it is time for the cells to divide. After cell division, microtubules send out these chromosomes to the opposite poles of the nucleus of the daughter cells in a process commonly known as chromosome segregation.
CRCHUM researcher and Université de Montréal professor Greg Fitzharris explains the findings:
"We found that the microtubules that orchestrate chromosome segregation during cell division behave abnormally in older eggs. Instead of assembling a spindle in a controlled symmetrical fashion, the microtubules go in all directions. The altered movement of the microtubules apparently contributes to errors in chromosome segregation, and so represents a new explanation for age-related infertility."
In fact, Fitzharris says that "approximately 50 percent of the eggs of older females have a spindle with chaotic microtubule dynamics."
The researchers learned this by micromanipulating the eggs of mice, a classic approach whereby the oocytes were swapped among young mice (aged between 6 and 12 weeks) and old ones (aged 60 weeks).
"We swapped the nuclei of the young eggs with those of the old eggs and we observed problems in the old eggs containing a young nucleus," explains Shoma Nakagawa, a postdoctoral research fellow at CRCHUM and the Université de Montréal. "This shows that maternal age influences the alignment of microtubules independently of the age of the chromosomes contained in the nuclei of each egg."
The findings also hold for humans, the authors explain. Chromosomal defects due to spindle malfunctioning occur in women as well, so age-related infertility does not seem to be caused by the age of the chromosomes themselves.
In the future, the authors hope that their findings will help women to become pregnant despite their older age.
"We are currently exploring possible treatments for eggs that might one day make it possible to reverse this problem and rejuvenate the eggs," says Fitzharris.