Interactions between DNA damage and metabolism

Over the past decades, life expectancy has dramatically increased worldwide. Because of this, the causes of mortality have shifted from infectious diseases towards chronic metabolic diseases such as type 2 diabetes and cardiovascular disease. While some of the causes underlying the development of chronic metabolic diseases can be changed, such as dietary and physical behavior, other causes such as genetics, ethnicity and aging cannot be changed. Although the knowledge of the mechanisms driving aging is still limited, progeroid syndromes have shown that inadequate repair of DNA damage contributes to features of accelerated aging.
In this thesis, we have investigated the interactions between DNA damage and metabolism as a potential underlying mechanism for the age-related risk to develop metabolic diseases. Using mouse models with a deficiency in DNA damage repair, we have shown that accumulation of DNA damage can lead to metabolic impairments. Moreover, we provide evidence that DNA damage in specific cell populations can be sufficient to drive systemic impairments. This is highlighted by mice with a deficiency in DNA damage repair in pancreatic beta-cells which develop impairments in insulin secretion and glucose tolerance but also develop obesity, inflammation and senescence in peripheral tissues. Collectively, the research performed in this thesis provides evidence of a tight link between DNA damage, cell function and the development of chronic metabolic diseases.