Franny Jongbloed

25 2 FASTING PROTECTS AGED-OVERWEIGHT MICE INTRODUCTION The rate of morbidity andmortality in patients with end-stage renal disease (ESRD) is greatly decreased by kidney transplantation, although it brings along its own set of complications like delayed graft function (DGF) and rejection 1 . DGF, defined as the need of dialysis in the first week after transplantation, occurs in almost 25% of all kidney transplantations in the USA 2 . Because elderly patients also benefit from a renal transplant, the number of transplantations performed in these patients has increased 3 . With the already existing shortage of donors, this has widened the gap between organ availability and demand. In an attempt to overcome this shortage, guidelines for extended donation are developed 4 . These extended criteria donors (ECD) are generally of older age, with existing morbidities like obesity and diabetes mellitus 5 . ECD kidneys show higher risks of DGF, acute rejection and graft failure, with recipient and donor age as independent risk factors 6,7 . Hence, practices improving transplantation success rates are urgently needed. Ischemia-reperfusion injury (IRI) is an unavoidable consequence of organ transplantation leading to a deleterious activation of cellular oxidases causing oxidative damage, tissue injury and inflammation 8,9 . IRI has been identified as a major risk factor for the development of DGF and rejection, with ECD kidneys being even more vulnerable to ischemic damage 10 . A potentially protective intervention against IRI is dietary restriction (DR), a short-term reduction in caloric intake before induction of ischemia. Long-term DR has been shown to prolong both health- and lifespan 11,12 . Although its mechanisms have not yet been elucidated, increased resistance to oxidative stress is likely to be involved. In addition, short- term DR and fasting as a more acute approach of DR have been found to increase resistance against oxidative damage as well, including IRI 9,13 . Previously, we have shown that both three days of fasting and two weeks of 30% DR induce robust protection against renal IRI in mice 9,14,15 . However, these studies have been conducted with healthy young-lean male mice. The relevance of these findings for a heterogeneous group of patients which are generally older and suffer from disease is uncertain since the response induced by fasting and DR under these conditions is unknown 16,17 . Therefore, the aim of this study is to examine the effect of age, body weight, gender, and genetic background on the protection against renal IRI induced by fasting. We show that preoperative fasting protects against the effects of IRI in aged-overweight male and female mice comparable to young-lean mice. Subsequently, we compared gene expression profiles of kidneys of young-lean mice with those of aged- overweight mice before and after fasting and identified several metabolic processes including fatty acid oxidation and retinol metabolism as well as pathways involved in the oxidative stress response as likely candidates involved in the induction of increased stress resistance by fasting.