Dietary restriction as treatment modality : inducing resistance to ischemic and chemotherapy related stress

There is a pressing necessity for improving the knowledge about the etiology and clinical applicability of dietary restriction to optimize the effects of dietary restriction on surgical and disease-related stress resistance and postoperative outcome. The aims of this thesis were to assess the effects of current and novel short-term dietary regimens in different models, to gain more insight into the mechani

Preoperative fasting protects against renal ischemia-reperfusion injury in aged and overweight mice

Ischemia-reperfusion injury (IRI) is inevitable during kidney transplantation leading to oxidative stress and inflammation. We previously reported that preoperative fasting in young-lean male mice protects against IRI. Since patients are generally of older age with morbidities possibly leading to a different response to fasting, we investigated the effects of preoperative fasting on renal IRI in aged-overweight male and female mice. Male and female F1-FVB/C57BL6-hybrid mice, average age 73 weeks weighing 47.2 grams, were randomized to preoperative ad libitum feeding or 3 days fasting, followed by renal IRI. Body weight, kidney function and survival of the animals were monitored until day 28 postoperatively. Kidney histopathology was scored for all animals and gene expression profiles after fasting were analyzed in kidneys of young and aged male mice. Preoperative fasting significantly improved survival after renal IRI in both sexes compared with normal fed mice. Fasted groups had a better kidney function shown by lower serum urea levels after renal IRI. Histopathology showed less acute tubular necrosis and more regeneration in kidneys from fasted mice. A mRNA analysis indicated the involvement of metabolic processes including fatty acid oxidation and retinol metabolism, and the NRF2-mediated stress response. Similar to young-lean, healthy male mice, preoperative fasting protects against renal IRI in aged-overweight mice of both genders. These findings suggest a general protective response of fasting against renal IRI regardless of age, gender, body weight and genetic background. Therefore, fasting could be a non-invasive intervention inducing increased oxidative stress resistance in older and overweight patients as well

A signature of renal stress resistance induced by short-Term dietary restriction, fasting, and protein restriction

During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-Term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate-or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-Analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-Term DR

Relative body weight and survival.

<p>Relative body weight (A) and survival (B) of male and female mice undergoing 37 and 60 minutes of renal ischemia-reperfusion injury (IRI), respectively, preceded by 3 day fasting or ad libitum feeding. In the first week after surgery, both fasted groups gradually lost weight after which they slowly gained weight in the weeks thereafter. Both fasted groups show a significantly improved survival: p = 0.0171 for males, p = 0.0040 for females. M = male, F = female, Adlib = ad libitum fed.</p

Top 15 canonical pathways overlapping in aged and young mice in response to fasting compared with ad libitum.

<p>Canonical pathways overlapping in aged and young mice after 3 days of fasting with their corresponding geometric mean p-value and the percentage of regulated genes.</p

Histopathological analysis of kidneys after renal ischemia-reperfusion injury.

<p>Histopathological analysis of kidneys of male and female mice after IRI. Mice sacrificed at the end of the experiment showed significantly less acute tubular necrosis (A) and significantly more tubular epithelial regeneration (B). Divided by intervention, both male and female fasted mice also showed less necrosis (C) and more regeneration (D). Fasted male mice sacrificed at day 7 showed similar pathology scores as the fasted mice at day 28 (mice indicated by the red symbols).*  =  significance (p<0.05) compared to the group ‘Found dead’, **  =  compared to the group ‘Moribund’, ***  =  compared to ad libitum fed males, ****  =  compared to ad libitum fed females.</p