Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer's disease, and Parkinson's disease

Mitochondrial decay due to oxidative damage is a contributor to brain aging and age-related neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). One type of mitochondrial decay is oxidative modification of key mitochondrial enzymes. Enzyme dysfunction, that is due to poor binding of substrates and coenzymes may be ameliorated by supplementing adequate levels of substrates or coenzyme precursors. Such supplementation with mitochondrial nutrients (mt-nutrients) may be useful to prevent or delay mitochondrial decay, thus prevent or treat AD and PD. In the present review, we survey the literature to identify mt-nutrients that can (1) protect mitochondrial enzymes and/or stimulate enzyme activity by elevating levels of substrates and cofactors; (2) induce phase-2 enzymes to enhance antioxidant defenses; (3) scavenge free radicals and prevent oxidant production in mitochondria, and (4) repair mitochondrial membrane. Then, we discuss the relationships among mt-nutrient deficiency, mitochondrial decay, and cognitive dysfunction, and summarize available evidence suggesting an effect of mt-nutrient supplementation on AD and PD. It appears that greater effects might be obtained by longer-term administration of combinations of mt-nutrients. Thus, optimal doses of combinations of mt-nutrients to delay and repair mitochondrial decay could be a strategy for preventing and treating cognitive dysfunction, including AD and PD.     

Spermidine Supplementation Protects the Liver Endothelium from Liver Damage in Mice

Chronic liver diseases are multifactorial and the need to develop effective therapies is high. Recent studies have shown the potential of ameliorating liver disease progression through protection of the liver endothelium. Polyamine spermidine (SPD) is a caloric restriction mimetic with autophagy-enhancing properties capable of prolonging lifespan and with a proven beneficial effect in cardiovascular disease in mice and humans. We evaluated the use of dietary supplementation with SPD in two models of liver disease (CCl₄ and CDAAH diet). We analyzed the effect of SPD on endothelial dysfunction in vitro and in vivo. C57BL/6J mice were supplemented with SPD in the drinking water prior and concomitantly with CCl₄ and CDAAH treatments. Endothelial autophagy deficient (Atg7endo) mice were also evaluated. Liver tissue was used to evaluate the impact of SPD prophylaxis on liver damage, endothelial dysfunction, oxidative stress, mitochondrial status, inflammation and liver fibrosis. SPD improved the endothelial response to oxidative injury in vitro and improved the liver endothelial phenotype and protected against liver injury in vivo. SPD reduced the overall liver oxidative stress and improved mitochondrial fitness. The absence of benefits in the Atg7endo mice suggests an autophagy-dependent effect of SPD. This study suggests SPD diet supplementation in early phases of disease protects the liver endothelium from oxidative stress and may be an attractive approach to modify the chronic liver disease course and halt fibrosis progression.     

Effect of selenium depletion and repletion on plasma glutathione and glutathione-dependent enzymes in the rat

Selenium deficiency has several known biochemical effects. In the rat, these effects include loss of glutathione peroxidase (GSH-Px) activity, increased plasma glutathione concentration and increased liver glutathione S-transferase (GSH S-Tr) activity. The time course of the development of these changes in rats fed selenium-deficient diets and the time course of reversal of these changes in selenium-deficient rats fed graded levels of selenium were determined. As selenium deficiency was produced, liver cytosolic and plasma GSH-Px activities decreased first and were less than 5% of control when plasma glutathione concentration and liver GSH S-Tr activity began to increase. Elevated liver GSH S-Tr activity in selenium-deficient rats was corrected by refeeding selenium at the lowest level of supplementation (0.015 ppm) for 4 wk. GSH-Px activity required a supplementation of 0.10 ppm selenium for correction to control levels in 4 wk. Based on these studies a classification of the severity of selenium deficiency into mild, moderate and severe categories is proposed. In addition, the effect of dietary sulfur amino acid supplementation on plasma glutathione concentration was studied.     

Oral Cholecalciferol Supplementation in Sahara Black People with Chronic Kidney Disease Modulates Cytokine Storm,Oxidative Stress Damage and Athero-Thromboembolic Risk

The 25-hydroxyvitamin D₃ (25OHD₃) deficiency in chronic kidney disease (CKD) is associated with immune system dysfunction (pro-inflammatory cytokines storm) through macrophages renal infiltration, oxidative stress (OxS) damage and athero-thromboembolic risk. Conversely, cholecalciferol supplementation (25OHD-S) prevents kidney fibrosis by inhibition of vascular calcification and nephrotic apoptosis (nephrons reduction). The objective of this study was to investigate the pleiotropic effects of 25OHD-S on immunomodulation, antioxidant status and in protecting against thromboembolic events in deficiency CKD Black and White individuals living in the Southern Sahara (SS). The oral 25OHD-S was evaluated in 60,000 IU/month/36 weeks versus in 2000 IU/day/24 weeks in Black (n = 156) and White (n = 150). Total serum vitamin D was determined by liquid chromatography-tandem mass spectrometry. All biomarkers of pro-inflammatory cytokines (PIC) were assessed by ELISA tests. OxS markers were assessed by Randox kits. Homocysteine and lipoproteine (a) were evaluated by biochemical methods as biomarkers of atherothromboembolic risk. All statistical analyses were performed with Student’s t-test and one-way ANOVA. The Pearson test was used to calculate the correlation coefficient. The means will be significantly different at a level of p value < 0.05. Multiple logistic regressions were performed using Epi-info and Statview software. Vitamin D deficiency alters the PIC profile, OxS damage and atherothrombogenic biomarkers in both SS groups in the same manner; however, these disorders are more acute in Black compared to White SS individuals. The results showed that the serum 25OHD₃ concentrations became normal (>75 nmol/L or >30 ng/mL) in the two groups. We have shown that the dose and duration of 25OHD-S treatment are not similar in Black SS residents compared to White SS subjects, whilst the same inhabit the south Sahara environment. It appears that a high dose intermittent over a long period (D60: 36 weeks) was more efficient in Black people; while a lower dose for a short time is sufficient (D2: 24 weeks) in their White counterparts. The oral 25OHD-S attenuates PIC overproduction and OxS damage, but does not reduce athero-thromboembolic risk, particularly in Black SS residents.     

IGF-1 Signaling Regulates Mitochondrial Remodeling during Myogenic Differentiation

Skeletal muscle is essential for locomotion, metabolism, and protein homeostasis in the body. Mitochondria have been considered as a key target to regulate metabolic switch during myo-genesis. The insulin-like growth factor 1 (IGF-1) signaling through the AKT/mammalian target of rapamycin (mTOR) pathway has a well-documented role in promoting muscle growth and regeneration, but whether it is involved in mitochondrial behavior and function remains un-examined. In this study, we investigated the effect of IGF-1 signaling on mitochondrial remodeling during myogenic differentiation. The results demonstrated that IGF-1 signaling stimulated mitochondrial biogenesis by increasing mitochondrial DNA copy number and expression of genes such as Cox7a1, Tfb1m, and Ppargc1a. Moreover, the level of mitophagy in differentiating myoblasts elevated significantly with IGF-1 treatment, which contributed to mitochondrial turnover. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) were identified as two key mediators of IGF-1-induced mitochondrial biogenesis and mitophagy, respectively. In addition, IGF-1 supplementation could alleviate impaired myoblast differentiation caused by mitophagy deficiency, as evidenced by increased fusion index and myosin heavy chain expression. These findings provide new insights into the role of IGF-1 signaling and suggest that IGF-1 signaling can serve as a target for the research and development of drugs and nutrients that support muscle growth and regeneration.     

Protective Effect of Mitophagy Regulated by mTOR Signaling Pathway in Liver Fibrosis Associated with Selenium

Background: As a central organ of energy metabolism, the liver is closely related to selenium for its normal function and disease development. However, the underlying roles of mitochondrial energy metabolism and mitophagy in liver fibrosis associated with selenium remain unclear. Methods: 28 rats were randomly divided into normal, low-selenium, nano-selenium supplement-1, and supplement-2 groups for a 12-week intervention. We observed pathological and ultrastructural changes in the liver and analyzed the effects of selenium deficiency and nano-selenium supplementation on liver metabolic activities and crucial proteins expression of mammalian target of the rapamycin (mTOR) signaling pathway. Results: Selenium deficiency caused liver pathological damage and fibrosis with the occurrence of mitophagy by disrupting normal metabolic activities; meanwhile, the mTOR signaling pathway was up-regulated to enhance mitophagy to clear damaged mitochondria. Furthermore, nano-selenium supplements could reduce the severity of pathological damage and fibrosis in livers and maintain normal energy metabolic activity. With the increased concentrations of nano-selenium supplement, swelling mitochondria and mitophagy gradually decreased, accompanied by the higher expression of mTOR and phosphorylation-modified mTOR proteins and lower expression of unc-51 like autophagy activating kinase 1 (ULK1) and phosphorylation-modified ULK1 proteins. Conclusions: Mitophagy regulated by the mTOR signaling pathway plays a dual protective role on low-selenium inducing liver fibrosis and nano-selenium supplements preventing liver fibrosis. Mitochondrial energy metabolism plays an important role in these processes as well.     

Arginine enhances In vivo immune responses in young, adult and aged mice

Arginine supplementation enhances in vitro lymphocyte proliferation in healthy adult humans and in rodent models. Studies examining the effect of arginine supplementation on in vivo immune responses are lacking. The purpose of this study was to determine whether arginine supplementation could enhance in vivo immune responses in adult mice and reverse known age-associated alterations in immune function of young and aged mice. Mice (1, 10 and 33 mo old) were fed a 2% arginine or an isonitrogenous diet for 2 wk. Delayed-type hypersensitivity to 2,4-dinitrofluorobenzene-challenged ears and changes in popliteal lymph node weights to injected sheep red blood cells were measured. The mean percentage of increase in ear thickness in challenged vs. unchallenged ears was 27, 35 and 24% with arginine supplementation and 7, 12 and 0% with the isonitrogenous diet in the 1-, 10- and 33-mo-old mice, respectively (P 相似文献   

Effect of dietary selenium and magnesium on human mammary tumor growth in athymic nude mice.

The effect of dietary selenium (Se) supplementation and low dietary magnesium (Mg) on growth of cells of the human mammary tumor cell line (HTB123/DU4475) and the tissue glutathione (GSH) content in female athymic nude mice was studied. Sixty three- to four-week-old female athymic nude mice were randomly divided into six dietary groups of 10 animals. The mice were fed a modified AIN-76A diet with two levels of Mg (100 and 665 mg/kg) and three levels of Se (0.04, 0.2, and 4.0 mg/kg). At the fourth week of dietary treatment, mice were subcutaneously inoculated with 2.5 x 10(6) viable tumor cells on the dorsal lumbar region and then fed their respective diets for another four weeks. Dietary Se supplementation had no significant effect on tumor growth or tissue GSH content. Low dietary Mg limited both tumor growth and tissue GSH synthesis but raised Mg and GSH levels in tumor tissues. The growth of mice fed the diet containing 100 mg/kg Mg and 4.0 mg/kg Se was significantly retarded. This study demonstrated that neither Se deficiency nor Se supplementation had any effect on mammary tumor growth or tissue GSH content in athymic nude mice. Low dietary Mg did retard tumor growth and inhibited GSH synthesis. Low dietary Mg also resulted in an apparent increase in Se toxicity in these animals.     

Dietary Cocoa Flavanols Enhance Mitochondrial Function in Skeletal Muscle and Modify Whole-Body Metabolism in Healthy Mice

Mitochondrial dysfunction is widely reported in various diseases and contributes to their pathogenesis. We assessed the effect of cocoa flavanols supplementation on mitochondrial function and whole metabolism, and we explored whether the mitochondrial deacetylase sirtuin-3 (Sirt3) is involved or not. We explored the effects of 15 days of CF supplementation in wild type and Sirt3^-/- mice. Whole-body metabolism was assessed by indirect calorimetry, and an oral glucose tolerance test was performed to assess glucose metabolism. Mitochondrial respiratory function was assessed in permeabilised fibres and the pyridine nucleotides content (NAD⁺ and NADH) were quantified. In the wild type, CF supplementation significantly modified whole-body metabolism by promoting carbohydrate use and improved glucose tolerance. CF supplementation induced a significant increase of mitochondrial mass, while significant qualitative adaptation occurred to maintain H₂O₂ production and cellular oxidative stress. CF supplementation induced a significant increase in NAD⁺ and NADH content. All the effects mentioned above were blunted in Sirt3^-/- mice. Collectively, CF supplementation boosted the NAD metabolism that stimulates sirtuins metabolism and improved mitochondrial function, which likely contributed to the observed whole-body metabolism adaptation, with a greater ability to use carbohydrates, at least partially through Sirt3.     

DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus

While some studies on dietary supplementation with docosahexaenoic acid (DHA, 22:6n-3) have reported a beneficial effect on memory as a function of age, others have failed to find any effect. To clarify this issue, we sought to determine whether supplementing mice with a DHA-enriched diet could alter the ability of synapses to undergo activity-dependent changes in the hippocampus, a brain structure involved in forming new spatial memories. We found that DHA was increased by 29%?± 5% (mean?± SE) in the hippocampus for the supplemented (DHA+) versus nonsupplemented (control) group (n = 5 mice per group; p?< 0.05). Such DHA elevation was associated with enhanced synaptic transmission (p?< 0.05) as assessed by application of a high-frequency electrical stimulation protocol (100?Hz stimulation, which induced transient (<2?h) increases in synaptic strength) to slices from DHA+ (n = 4 mice) hippocampi when compared with controls (n = 4 mice). Increased synaptic responses were evident 60?min poststimulation. These results suggest that dietary DHA supplementation facilitates synaptic plasticity following brief high-frequency stimulation. This increase in synaptic transmission might provide a physiological correlation for the improved spatial learning and memory observed following DHA supplementation.     

Naringin Improves Diet-Induced Cardiovascular Dysfunction and Obesity in High Carbohydrate,High Fat Diet-Fed Rats

Obesity, insulin resistance, hypertension and fatty liver, together termed metabolic syndrome, are key risk factors for cardiovascular disease. Chronic feeding of a diet high in saturated fats and simple sugars, such as fructose and glucose, induces these changes in rats. Naturally occurring compounds could be a cost-effective intervention to reverse these changes. Flavonoids are ubiquitous secondary plant metabolites; naringin gives the bitter taste to grapefruit. This study has evaluated the effect of naringin on diet-induced obesity and cardiovascular dysfunction in high carbohydrate, high fat-fed rats. These rats developed increased body weight, glucose intolerance, increased plasma lipid concentrations, hypertension, left ventricular hypertrophy and fibrosis, liver inflammation and steatosis with compromised mitochondrial respiratory chain activity. Dietary supplementation with naringin (approximately 100 mg/kg/day) improved glucose intolerance and liver mitochondrial dysfunction, lowered plasma lipid concentrations and improved the structure and function of the heart and liver without decreasing total body weight. Naringin normalised systolic blood pressure and improved vascular dysfunction and ventricular diastolic dysfunction in high carbohydrate, high fat-fed rats. These beneficial effects of naringin may be mediated by reduced inflammatory cell infiltration, reduced oxidative stress, lowered plasma lipid concentrations and improved liver mitochondrial function in rats.     

Hypercorticism and manganese metabolism in brown adipose tissue of the obese mouse

In ob/ob mice, we showed previously that brown adipose tissue (BAT) has an abnormally low manganese (Mn) content associated with low Mn-superoxide dismutase (MnSOD) and succinate dehydrogenase (SDH) activities. These anomalies can be corrected partially by supplementing the diet with Mn. The present work was designed to find out whether the hypercorticism of the obese mouse plays a role in this anomalous Mn metabolism in BAT. Mn content and MnSOD and SDH activities were determined in BAT from control and adrenalectomized (ADX) obese mice and from control and corticosterone-supplemented lean mice. Adrenalectomy of the obese mouse restored BAT Mn content, SDH activity and lipid peroxidative activity to normal but had little effect on MnSOD activity. Corticosteroid supplementation in the lean mouse did not reproduce the anomalies of Mn metabolism found in the untreated obese mouse. These results show that hypercorticism alone is not responsible for the anomalies of Mn metabolism. It is possible that the hyperinsulinemia of the obese mouse is involved in this process since adrenalectomy corrected hyperinsulinemia in the obese mouse, but corticosteroid supplementation of the lean mouse did not reproduce the high plasma insulin levels or the anomalies in body composition typical of the untreated obese mouse.     

The effect of severe zinc deficiency on serum levels of albumin, transferrin, and prealbumin in man

Concentrations of three serum transport proteins, albumin, transferrin, and prealbumin, were determined in seven patients with severe zinc deficiency. Zinc deficiency was manifested not only by depressed serum zinc concentrations, but also by skin lesions typical of zinc deficiency that corrected with zinc supplementation only. Concentrations of all three serum proteins were significantly depressed in zinc-deficient patients compared to healthy controls, and levels of all three proteins improved or corrected with a short period of zinc supplementation as the sole form of therapeutic intervention. Prealbumin levels dropped and corrected most rapidly, probably due in part to its short half-life of 2 days. This study demonstrates that zinc plays an important role in protein metabolism in man and is necessary for the maintenance of normal levels of certain transport proteins. These results support the possibility that zinc deficiency may alter tissue availability of other nutrients such as vitamin A or iron through its effect on transport proteins.     

Relative contribution of cysteine and methionine to glutathione content and thyroid hormone levels in the rat

1. For a period of 24 d rats were given diets containing either casein or pea (Pisum sativum) protein at two different concentrations (180 and 120 g/kg) without or with cysteine or cysteine + methionine supplementation. 2. The effects of these diets on levels of blood and liver reduced glutathione (GSH) and serum thyroid hormones were studied. 3. When compared with the 180 g casein/kg diet, the 120 g casein/kg diet decreased liver GSH and serum thyroid hormone concentrations. These changes were related to dietary cysteine supply since supplementation induced an increase in these variables. 4. When compared with 180 g pea protein/kg diet, the 120 g pea protein/kg diet decreased liver GSH and serum thyroid hormone concentrations. These changes could not be corrected by cysteine or cysteine + methionine supplementation.     

Long-term intake of fish oil increases oxidative stress and decreases lifespan in senescence-accelerated mice

Objective

The effects of fish oil including ω-3 polyunsaturated fatty acids on aging and lifespan are not well understood. In this study, the influence of long-term ingestion of fish oil on lifespan was examined in senescence-accelerated (SAMP8) mice.

Methods

We investigated the effects of dietary fish oil on lifespan and on lipid composition and oxidative stress in plasma and liver in SAMP8 mice. Male mice were fed a fish oil diet (5% fish oil and 5% safflower oil) or a safflower oil diet (10% safflower oil) from 12 wk of age.

Results

The SAMP8 mice fed fish oil did not have a longer maximum lifespan and had a shorter average lifespan than mice fed safflower oil. To examine the mechanism underlying these results, the effects on oxidative stress of long-term ingestion of fish oil were also examined. SAMP8 mice fed fish oil for 28 wk showed strong oxidative stress that caused hyperoxidation of membrane phospholipids and a diminished antioxidant defense system due to a decrease in tocopherol compared with mice fed safflower oil.

Conclusion

These findings suggest that intake of fish oil increases oxidative stress, decreases cellular function, and causes organ dysfunction in SAMP8 mice, thereby promoting aging and shortening the lifespan of the mice.     

Abstracts of Recent Articles on Energy Utilization,Obesity, and Weight Reduction

The essentiality of zinc was recognized 46 years ago. Zinc deficiency resulting in growth retardation, hypogonadism, immune dysfunction and cognitive impairment affects nearly 2 billion subjects in the developing world. High phytate content of the cereal proteins consumed in the developing world, results in decreased availability of zinc for absorption. Zinc therapy has been very successful and life saving measure in patients with acrodermatitis enteropathica and Wilson's disease. Beneficial therapeutic responses of zinc supplementation have been ovserved in acute diarrhea in children, chronic hepatitis C, shigellosis, leprosy, leishmaniasis, and common cold. Zinc supplementation was effective in decreasing incidences of infection in elderly and patients with sickle cell disease. Zinc supplementation was effective in preventing blindness in 25% of the elderly with dry type of age related macular degeneration. Zinc supplementation in the elderly decreased oxidative stress and decreased generation of inflammatory cytokines.

Zinc is an intracellular signaling molecule in monocytes, dendritic cells and macrophages and it plays an important role in cell-mediated immune functions and oxidative stress. Zinc is also an anti-inflammatory agent. These unique properties of zinc may have significant therapeutic benefits in several diseases in humans. In many diseases concurrent zinc deficiency may complicate the clinical features, affect adversely immunological status, increase oxidative stress and increase generation of inflammatory cytokines. Oxidative stress and chronic inflammation may play important causative roles in many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, and auto-immune diseases. It is therefore, important that status of zinc is assessed and zinc deficiency corrected in these chronic diseases. A controlled clinical trial of zinc supplementation in these disorders in order to document the preventive and therapeutic effects of zinc is warranted.     

Quercetin Attenuates Chronic Ethanol-Induced Hepatic Mitochondrial Damage through Enhanced Mitophagy

Emerging evidence suggested mitophagy activation mitigates ethanol-induced liver injury. However, the effect of ethanol on mitophagy is inconsistent. Importantly, the understanding of mitophagy status after chronic ethanol consumption is limited. This study evaluated the effect of quercetin, a naturally-occurring flavonoid, on chronic ethanol-induced mitochondrial damage focused on mitophagy. An ethanol regime to mice for 15 weeks (accounting for 30% of total calories) led to significant mitochondrial damage as evidenced by changes of the mitochondrial ultrastructure, loss of mitochondrial membrane potential and remodeling of membrane lipid composition, which was greatly attenuated by quercetin (100 mg/kg.bw). Moreover, quercetin blocked chronic ethanol-induced mitophagy suppression as denoted by mitophagosomes-lysosome fusion and mitophagy-related regulator elements, including LC3II, Parkin, p62 and voltage-dependent anion channel 1 (VDAC1), paralleling with increased FoxO3a nuclear translocation. AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase 2 (ERK2), instead of AKT and Sirtuin 1, were involved in quercetin-mediated mitophagy activation. Quercetin alleviated ethanol-elicited mitochondrial damage through enhancing mitophagy, highlighting a promising preventive strategy for alcoholic liver disease.     

微量元素锌铜铁对大鼠血清和心肌超氧化物歧化酶活性的影响

目的 观察锌铜铁缺乏和强化补充后对初断乳大鼠血清、心肌线粒体超氧化物歧化酶活性的影响。方法 通过耗竭方式造成初断乳大鼠Zn、Cu、Fe单独和联合缺乏模型后强化补充相应营养素。造模成功及干预结束后,测定血清和线粒体总超氧化物歧化酶T-SOD活性。结果 Zn、Cu、Fe缺乏和补充对大鼠血清T-SOD活性无明显影响（P〉0．05）,Zn、Cu、Fe缺乏和3种营养素联合缺乏可导致心肌线粒体T-SOD活性明显降低（P〈O．001）,单独补充Zn、Cu、Fe和3种营养素联合补充可使大鼠心肌T-SOD活性显著增加（P〈0．001）。结论 Zn、Cu、Fe缺乏对初断乳大鼠心肌线粒体T-SOD活性有明显影响,提示重视婴幼儿期Zn、Cu、Fe联合微量元素营养补充具有重要意义。     

REducing Deaths due to OXidative Stress (The REDOXS Study): Rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients

Critically-ill patients experience an extent of hyperinflammation, cellular immune dysfunction, oxidative stress and mitochondrial dysfunction. Supplementation with key nutrients, such as glutamine and antioxidants, is most likely to have a favourable effect on these physiological derangements, leading to an improvement in clinical outcomes. The results of two meta-analyses suggest that glutamine and antioxidants may be associated with improved survival. The purpose of the present paper is to report the background rationale and study protocol for the evaluation of the effect of high-dose glutamine and antioxidant supplementation on mortality in a large-scale randomized trial in 1200 mechanically-ventilated, critically-ill patients. Patients admitted to an intensive care unit (ICU) with clinical evidence of severe organ dysfunction will be randomized to one of four treatments in a 2 x 2 factorial design: (1) glutamine; (2) antioxidant therapy; (3) glutamine and antioxidant therapy; (4) placebo. The primary outcome for this study is 28 d mortality. The secondary outcomes are duration of stay in ICU, adjudicated diagnosis of infection, multiple organ dysfunction, duration of mechanical ventilation, length of stay in hospital and health-related quality of life at 3 and 6 months. A novel design feature is the combined use of parenteral and enteral study nutrients dissociated from the nutrition support. The therapeutic strategies tested in the randomized trial may lead to less morbidity and improved survival in critically-ill patients. The trial will be conducted in approximately twenty tertiary-care ICU in Canada and the first results are expected in 2009.