Franny Jongbloed

243 9 SUMMARY AND DISCUSSION SUMMARY AND DISCUSSION An increase in oxidative stress and inflammation has a negative influence on overall quality and quantity of life leading to accelerated development of age-associated diseases and a decrease in lifespan. An acute induced stress response leads to worse outcome of organ transplantation procedures due to the development of ischemia-reperfusion injury (IRI), creating a boundary for the possibilities of organ transplantation for patients with end- stage organ failure. A surgery-related stress response might also influence the outcome of patients undergoing elective surgery, especially when comorbidities as in morbid obesity are present. Dietary restriction (DR) has been shown to improve lifespan and reduce age- associated diseases as well as to improve outcome of IRI in various healthy laboratory animal models. Many aspects of DR are still unknown, including which components of the calories are responsible for the effects of DR, the mechanisms underlying DR, as well as the overall applicability of DR in different animal models involving acute stress-related injury. Foremost, the translation of DR into a clinical setting has been proven difficult and evidence of effects in patients is therefore limited. There is a pressing necessity for improving the knowledge about the etiology and clinical applicability of DR to optimize the effects of DR on surgical and disease-related stress resistance and postoperative outcome. The aims of this thesis were three-fold: One, to assess the effects of current and novel short- term DR regimens in different mouse models of acute stress; two, to gain more insight into the mechanisms underlying DR; and three, to search for a clinically applicable dietary intervention in the surgical setting. Current and novel short-term dietary restriction regimens Previously, colleagues showed that two weeks of 30%DR and three days of fasting are able to significantly improve survival and kidney function in male C57BL/6 mice that underwent renal IRI as compared to ad libitum (AL) fed mice 1 . These results were among the first that showed a beneficial effect of a short-term DR on a model of acute stress and several questions arose calling for follow-up research. In this section I will subsequently address questions related to the effective components and regimens of short-term DR drawing in part on the results in this thesis. The aforementioned results were obtained in an optimal model for laboratory research with young-lean male mice 1 . However, this model is less suitable to examine whether DR has a broader applicability when it comes to differences in age, gender, obesity and genetic background. The results in chapter 2 taught us that three days of fasting can indeed be reproduced in an optimal model to study aging and obesity. In this study, fasted hybrid mice showed improvement of both survival and kidney after induction of IRI, which was