Grant: Project Grant

The first most acute sign of advancing age experienced by women is a decline in fertility. Maternal age not only affects the risk of having a baby with chromosomal abnormalities (such as Down's syndrome), but also increases the frequency of suffering from various pregnancy complications such as pre-eclampsia or preterm birth. The reason why these latter complications are more prevalent in older women is not well understood, as they are not commonly associated with chromosomal defects of the baby. Advanced maternal age is an immense societal challenge as many women delay child bearing until later in their lives, with now well over 20% of babies born to women over 35 in Canada. Therefore it is extremely important to gain better insights into why these complications increase with age, and explore potential therapeutic avenues that may help mitigate this risk. Using the mouse as a model to study how age affects pregnancy outcome, we have found that the cells lining the womb (the so-called endometrium) undergo a significant decline in their ability to support pregnancy with age. Similar changes likely affect pregnancy in older women. These defects correlate with widespread changes to the regulatory layer of information that is imposed onto DNA (known as the epigenome) that controls which genes can be switched on and off. In aged cells many important genes have an altered epigenetic signature, which prevents them from being activated at the right time. In this proposal, we are aiming to gain fundamental novel insights into the precise nature and progression of these epigenetic alterations and how they affect endometrial cell function. This study will help elucidate why the womb is less capable of adapting to pregnancy in older females, and explore potential avenues how these changes can be prevented or reversed. This knowledge forms the stepping stone for future therapeutic interventions aimed at diminishing the risk of pregnancy complications in women of advanced age.