Franny Jongbloed

11 1 GENERAL INTRODUCTION & AIMS AND OUTLINE OF THIS THESIS GENERAL INTRODUCTION Dietary restriction (DR) is defined as the reduction in food intake without causing malnutrition 1 . As from the 1930s, the beneficial effects of DR became known when McCay et al. showed that reducing calorie intake extended the lifespan of laboratory rats by at least 30% 2 (Table 1). Much later, their results were extended to other animal species including yeast, fruit flies and rodents as well as non-human primates 3,4 . These beneficial effects were seen by restricting calorie intake generally around 30%, starting from early adulthood. Although the extension of lifespan could not be replicated in every animal model, for instance in the normal housefly, the beneficial effects are thought to be derived from evolutionary conserved mechanisms 3,5 . The average extension rate of the median lifespan by DR in healthy animals was around 30% 3 . This percentage was shown to be even higher in mice with deficiencies causing accelerated aging, including the Ercc1(∆/-) mouse, in which the median and maximum lifespan could be tripled by DR 6 . Shortly after the effects of DR on aging were discovered, scientists also demonstrated a reduction in incidence and severity of age-related diseases . One of the first acknowledgements of this was made in the 1940s, when Tannenbaum et al. demonstrated a reduction of both initiation and progression of spontaneous tumors in small rodents on long-term DR 7 . Indeed, various studies confirmed these results and showed a marked decrease in the incidence of tumor development and progression 8-11 . Other well-established effects of DR are the decreased incidence and reversal of the metabolic syndrome, including insulin resistance and diabetes mellitus 4,12 . Recently, two studies showed and compared these effects in non-human primates, demonstrating that rhesus monkeys on a normal diet had a three times higher and earlier rate of dying from an age-related cause, including cancer, cardiovascular disease and diabetes mellitus, than did monkeys on DR 13,14 . The beneficial and reproducible effects of long-termDR triggered scientists to search for the mechanisms inducing these benefits. Until now, the exact mechanisms underlying DR are still largely unknown. One of the effects of DR that has been established is a reduction of the formation of reactive oxygen species (ROS) and increased resistance against oxidative stress 15 . ROS, which are natural byproducts of the metabolism of oxygen, are overly present in times of increased oxidative stress which occurs for example during metabolic disturbances as hyperinsulinemia as well as chronic inflammation 16 .