Franny Jongbloed

252 CHAPTER 9 We are the first to show the beneficial effect of protein deprivation for only three days and this diet could be further narrowed down by showing the beneficial effects of individual essential amino acid deprivation on hepatic IRI, suggesting an essential role of amino acid sensing in the increased stress resistance. As a final step, transcriptome analyses of all these diets enabled us to study their induced changes on mRNA level. However, these data did not reveal one mechanism in particular but instead a network of multiple pathways activated by a number of transcription factors, evoking the protective response of short-term nutrient deprivation. In all studies, we could disentangle a similar pattern of pathway regulation. Future studies focusing on overexpression and knock-down of transcription factors such as FOXO3, should further elucidate the role of these transcription factors and the pathways they activated in the protection of DR. We examined the effects of morbid obesity on aging of the immune system, in particular the T-cell immune system. Our data suggest that that morbid obesity in combination with the presence of metabolic syndrome indeed leads to premature aging of the immune system as determined by attrition of telomere length and an increase in T-cell maturation in peripheral white blood cells. These changes could be forestalled by applying obesity- reducing bariatric surgery, and were already present in the first three to six months following surgery. This pilot study indicates that morbid obesity is a risk factor for premature aging of the immune system, and that bariatric surgery is a valuable treatment to counteract this effect. Studying the effects of morbid obesity, the metabolic syndrome and bariatric surgery in a larger cohort and on a molecular level in tissue collected during surgery, could increase our understanding of the effects of obesity and inflammation on aging as well as on stress resistance during a situation of food deprivation, either via DR or via surgery. In addition, extending the follow-up period after bariatric surgery could give insight whether the decrease in telomere length at 12 months postoperatively is an indication of the short- term effect of bariatric surgery on immunological aging or the effect of the small sample size and therefore not representative. We showed the safety, feasibility and objective adherence to the diet in two surgical patient populations, namely living kidney donors and bariatric surgery patients. We were able to show the beneficial effects of a mild adaptation of this diet in living kidney donors, and showed vast improvement of kidney function in both donors and recipients. Transcriptome profiles of human kidney biopsies revealed high overlap with our preclinical data, and highlighted the importance of gender on the effects on stress resistance. Future studies are needed in order to validate these results, and these studies should focus on larger cohorts, different patient populations as well as other DR regimens.