Metabolic consequences of DNA damage and cellular senescence

Over the past decades, life expectancy has rapidly increased. At the same, the prevalence of obesity has reached epidemic proportions with over 50% of all adults being overweight or obese. As a consequence, the number of people that suffer from diabetes type 2, non-alcoholic fatty liver disease, and cardiovascular disease is rising dramatically. In addition to obesity, age is one of the greatest risk factors for developing cardiometabolic diseases. One of the mechanisms that contributes to ageing is the accumulation of DNA damage over time. DNA damage can cause cellular dysfunction and induce cell death or cellular senescence. Senescent cells are damaged cells that accumulate in the body during ageing and promote inflammation. In this thesis, Postmus investigated if DNA damage and cellular senescence can contribute to the development of cardiometabolic diseases.

First of all, Postmus investigated if DNA damage could cause diabetes type 2. By using mice with a deficiency in one of the DNA repair systems, Postmus showed that DNA damage in insulin-producing cells can drive the development of diabetes.

In addition, Postmus explored if senescent cells could play a causal role in the development of cardiometabolic diseases after cancer therapy. Treatment of atherosclerosis-prone mice with the chemotherapeutic agent doxorubicin did, however, not exacerbate senescent cell accumulation nor cardiometabolic disease development.

Collectively, the results in this thesis contribute to a better understanding of the metabolic consequences of DNA damage and cellular senescence and provide new therapeutic targets for age-related cardiometabolic diseases.