Franny Jongbloed

12 CHAPTER 1 Table 1. A list of the durations of dietary restriction (DR), maximum lifespan extension and health span benefits described in various animal species Species DR (%) Maximum lifespan extension (%) Health span References Yeast 20-60% 300% Increased reproductive period 3 Worms 10-35% 200-300% Increased stress resistance 3 Flies 20-30% 200% None reported 3 Fish 33-58% 33% Decrease in age-dependent learning and memory 17 Mice 30-60% 30-60% Decrease in age-associated diseases, auto- immune, increased stress resistance 3 Rats 30-60% 30-60% Decrease in age-associated diseases, increased stress resistance 18 Monkeys 25% 30% Decrease in age-associated diseases, prevention of obesity 4,13,14 Increased oxidative stress is also induced by ischemia-reperfusion injury (IRI), a phenomenon occurring for instance during organ transplantation and which is a major risk factor for damage to or even failure of the transplanted organ. After organ retrieval, cessation of the blood flow, ischemia, leads to hypoxia, nutrient deprivation, and thereby accumulation of metabolic waste products. Reperfusion of the ischemic organ increases the generation of reactive oxygen species, triggers apoptotic cell death, and starts an inflammatory response which may result in profound tissue injury 19,20 . Especially the reperfusion period is thought to be a major player in the increased ROS production, which leads to high levels of oxidative stress 21 . Several studies have tried to use the increased stress resistance by DR in a therapeutic fashion. For instance, Sun et al. showed that rats subjected to 6 months of 40% DR are protected against the oxidative damage induced by a high dose of paraquat 22 . In addition, mice offered 40% DR during 8 months were protected against the toxicity of high doses of paracetamol 23 . However, the therapeutic use of DR to protect against oxidative stress in humans was hampered by the long period of DR that was applied. Since the kinetics of onset of oxidative stress resistance against IRI induced by DR were not yet known at this time, colleagues investigated whether short and clinically applicable periods of DR were able to induce resistance against oxidative stress induced by renal IRI in the mice. It was shown that both four and two weeks of 30%DRwere capable of ameliorating renal IRI in mice 1 . Mice showed significantly improved survival rate and kidney function after induction of IRI compared to mice that were allowed to eat ad libitum. Subsequently, a short period of 100% DR, namely three days of fasting, induced similar protective effects against renal IRI. Antioxidant and cytoprotective molecules, including heme oxygenase-1 (HO-1) and glutathione reductase (Gsr) were significantly induced by three days of fasting