PhD defence J. (Jacinta) van de Grint

Below is a brief summary of the dissertation: 

Over the past century, people have started living much longer—but this has come with a rise in age-related diseases like cancer, dementia, and frailty. To improve healthy aging, we need to better understand what drives the aging process. This thesis focuses on one key culprit: damage to our DNA.
DNA damage builds up over time and can block important processes like transcription—the first step in turning genes into proteins. Using a mathematical model, this thesis shows how such damage especially disrupts long genes, gradually upsetting the balance of messages inside cells as we age. This imbalance, called transcriptional stress, was then linked to frailty, a condition of increased vulnerability in older adults. Studies in people and in mice with faulty DNA repair systems revealed shared gene patterns that connect DNA damage to physical decline.
The thesis also looks at reproductive aging. A specific genetic change in the DNA repair gene MCM8 delays menopause but also raises the risk of breast cancer. Lab-grown cells with this mutation showed impaired DNA repair, suggesting that longer fertility might come at a cost.
Finally, the work tackles cellular senescence—a state where damaged cells stop dividing but linger, contributing to aging and inflammation. A new tool was developed to track these senescent cells in real time, helping researchers better understand and potentially target them.
Together, these findings reveal how DNA damage ties together key features of aging and may help guide future strategies to extend healthspan and prevent age-related diseases.