Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective

Malnutrition is common among older persons, with important consequences increasing frailty and morbidity and reducing health expectancy. On the contrary, calorie restriction (CR, a low-calorie dietary regimen with adequate nutrition) slows the progression of age-related diseases and extends the lifespan of many species. Identification of strategies mimicking key CR mechanisms – increased mitochondrial respiration and reduced production of oxygen radicals – is a hot topic in gerontology. Dietary supplementation with essential and/or branched chain amino acids (BCAAs) exerts a variety of beneficial effects in experimental animals and humans and has been recently demonstrated to support cardiac and skeletal muscle mitochondrial biogenesis, prevent oxidative damage, and enhance physical endurance in middle-aged mice, resulting in prolonged survival. Here we review recent studies addressing the possible role of BCAAs in energy metabolism and in the longevity of species ranging from unicellular organisms to mammals. We also summarize observations from human studies supporting the exciting hypothesis that dietary BCAA enriched mixture supplementation might be a health-promoting strategy in aged patients at risk

Efficacy and tolerability of a specific blend of amino acids in patients with anorexia nervosa treated in a hospital setting: study protocol for a randomized controlled trial

BackgroundSpecific blends of essential amino acids (EAA) containing a high percentage of branched-chain amino acids preserves mitochondrial metabolism and higher physical resistance in elderly mice, increasing their survival and improving physical performance and cognitive functions in malnourished elderly patients. However, no study has been yet done on patients with anorexia nervosa (AN) who regain weight with specialized intensive treatment. The present study aims to evaluate the efficacy of supplementation with EAA on the change in lean body mass (LBM) and other physical and psychological outcomes in patients with AN who are undergoing specialist treatment for eating disorders.MethodsThis is a 13-week randomized, double-blind, placebo-controlled study. Patients will be randomized to either a mixture of a complex blend of EAA and intermediates of the tricarboxylic acid (TCA) cycle (citrate, malate, succinate) supplementation (or placebo) upon admission at the intensive residential and day-hospital treatment for eating disorders. Ninety-two participants with AN aged 16-50 years will be recruited from a specialized intensive treatment of eating disorders. Double-blind assessment will be conducted at baseline (T0) and the end of the 13 weeks of treatment (T1). The study's primary aim is to evaluate the efficacy of supplementation with EAA and TCA intermediates on the change in lean body mass (LBM) with weight restoration in patients with AN who are undergoing specialist treatment for eating disorders. The secondary aims of the study are to assess the effect of dietary supplementation on physical fitness, weight restoration, modification of AN and general psychopathology, and psychosocial impairment.DiscussionThe study's results will inform researchers and clinicians on whether supplementing a mixture of EAA and TCA cycle intermediates will improve the increase of LBM and other important physical and psychological outcomes in patients with AN who regain weight with specialized intensive treatment

Erratum to: From simplicity towards complexity: the Italian multidimensional approach to obesity

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A peculiar formula of essential amino acids prevents rosuvastatin myopathy in mice

Aims: Myopathy, characterized by mitochondrial oxidative stress, occurs in ∼10% of statin-treated patients, and a major risk exists with potent statins such as rosuvastatin (Rvs). We sought to determine whether a peculiar branched-chain amino acid-enriched mixture (BCAAem), found to improve mitochondrial function and reduce oxidative stress in muscle of middle-aged mice, was able to prevent Rvs myopathy. Results: Dietary supplementation of BCAAem was able to prevent the structural and functional alterations of muscle induced by Rvs in young mice. Rvs-increased plasma 3-methylhistidine (a marker of muscular protein degradation) was prevented by BCAAem. This was obtained without changes of Rvs ability to reduce cholesterol and triglyceride levels in blood. Rather, BCAAem promotes de novo protein synthesis and reduces proteolysis in cultured myotubes. Morphological alterations of C2C12 cells induced by statin were counteracted by amino acids, as were the Rvs-increased atrogin-1 mRNA and protein levels. Moreover, BCAAem maintained mitochondrial mass and density and citrate synthase activity in skeletal muscle of Rvs-treated mice beside oxygen consumption and ATP levels in C2C12 cells exposed to statin. Notably, BCAAem assisted Rvs to reduce oxidative stress and to increase the anti-reactive oxygen species (ROS) defense system in skeletal muscle. Innovation and Conclusions: The complex interplay between proteostasis and antioxidant properties may underlie the mechanism by which a specific amino acid formula preserves mitochondrial efficiency and muscle health in Rvs-treated mice. Strategies aimed at promoting protein balance and controlling mitochondrial ROS level may be used as therapeutics for the treatment of muscular diseases involving mitochondrial dysfunction, such as statin myopathy

Role of Portion Size in the Context of a Healthy, Balanced Diet: A Case Study of European Countries

Over the past decades, a generalised increase in food portion sizes has probably contributed to the growing global obesity epidemic. Increasing awareness of appropriate portion sizes could contribute to reversing this trend through better control of calorie intake. In this study, a comparison of standard portion sizes in European countries for various food categories shows a wide variability of their importance for food, nutrient, and energy consumption according to government and institutional websites. On the other hand, the overall averages appear to be largely in line with the values indicated by the Italian Society of Human Nutrition, which is the most comprehensive and detailed document among those evaluated. The exceptions are milk and yoghurt, for which the reference portions in Europe are generally higher, and vegetables and legumes, for which portions are smaller than those reported in the Italian document. Moreover, the portion sizes of staple foods (e.g., pasta and potatoes) vary according to different food traditions. It is reasonable to consider that the creation of harmonised standard reference portions common to the European countries, based on international guidelines and scientific evidence, would significantly contribute to consumers' nutritional education and ability to make informed choices for a healthy diet

Therapeutic Induction of Energy Metabolism Reduces Neural Tissue Damage and Increases Microglia Activation in Severe Spinal Cord Injury

: Neural tissue has high metabolic requirements. Following spinal cord injury (SCI), the damaged, tissue suffers from a severe metabolic impairment, which aggravates axonal degeneration and, neuronal loss. Impaired cellular energetic, tricarboxylic acid (TCA) cycle and oxidative, phosphorylation metabolism in neuronal cells has been demonstrated to be a major cause of neural tissue death and regeneration failure following SCI. Therefore, rewiring the spinal cord cell metabolism may be an innovative therapeutic strategy for the treatment of SCI. In this study, we evaluated the therapeutic effect of the recovery of oxidative metabolism in a mouse model of severe contusive SCI. Oral administration of TCA cycle intermediates, co-factors, essential amino acids, and branched-chain amino acids was started 3 days post-injury and continued until the end of the experimental procedures. Metabolomic, immunohistological, and biochemical analyses were performed on the injured spinal cord sections. Administration of metabolic precursors enhanced spinal cord oxidative metabolism. In line with this metabolic shift, we observed the activation of the mTORC1 anabolic pathway, the increase in mitochondrial mass, and ROS defense which effectively prevented the injury-induced neural cell apoptosis in treated animals. Consistently, we found more choline acetyltransferase (ChAT)-expressing motor neurons and increased neurofilament positive corticospinal axons in the spinal cord parenchyma of the treated mice. Interestingly, oral administration of the metabolic precursors increased the number of activated microglia expressing the CD206 marker suggestive of a, pro-resolutive, M2-like phenotype. These molecular and histological modifications observed in treated animals ultimately led to a significant, although partial, improvement of the motor functions. Our data demonstrate that rewiring the cellular metabolism can represent an effective strategy to treat SCI

Dietary essential amino acids for the treatment of heart failure with reduced ejection fraction

Aims: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of mortality worldwide, requiring novel therapeutic and lifestyle interventions. Metabolic alterations and energy production deficit are hallmarks and thereby promising therapeutic targets for this complex clinical syndrome. We aim to study the molecular mechanisms and effects on cardiac function in rodents with HFrEF of a designer diet in which free essential amino acids - in specifically designed percentages - substituted for protein. Methods and results: Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricle (LV) pressure overload or sham surgery. Whole body glucose homeostasis was studied with glucose tolerance test, while myocardial dysfunction and fibrosis were measured with echocardiogram and histological analysis. Mitochondrial bioenergetics and morphology were investigated with oxygen consumption rate measurement and electron microscopy evaluation. Circulating and cardiac non-targeted metabolite profiles were analyzed by ultrahigh performance liquid chromatography-tandem mass spectroscopy, while RNA sequencing was used to identify signalling pathways mainly affected. The amino acid-substituted diet shows remarkable preventive and therapeutic effects. This dietary approach corrects the whole-body glucose metabolism and restores the unbalanced metabolic substrate usage - by improving mitochondrial fuel oxidation - in the failing heart. In particular, biochemical, molecular, and genetic approaches suggest that renormalization of branched-chain amino acid oxidation in cardiac tissue, which is suppressed in HFrEF, plays a relevant role. Beyond the changes of systemic metabolism, cell-autonomous processes may explain at least in part the diet's cardioprotective impact. Conclusion: Collectively, these results suggest that manipulation of dietary amino acids, and especially essential amino acids, is a potential adjuvant therapeutic strategy to treat systolic dysfunction and HFrEF in humans

In vivo Study of the Layered Structure on the Abdomen by Broadband Time-Domain Diffuse Optical Spectroscopy

We investigate the effect of depth heterogeneity in the abdomen by multidistance time-domain diffuse optical spectroscopy on 4 volunteers finding a higher water content in shallower regions, possibly due to fat heterogeneity and/or dermis contributions

CB1 Signaling in Forebrain and Sympathetic Neurons Is a Key Determinant of Endocannabinoid Actions on Energy Balance

SummaryThe endocannabinoid system (ECS) plays a critical role in obesity development. The pharmacological blockade of cannabinoid receptor type 1 (CB1) has been shown to reduce body weight and to alleviate obesity-related metabolic disorders. An unsolved question is at which anatomical level CB1 modulates energy balance and the mechanisms involved in its action. Here, we demonstrate that CB1 receptors expressed in forebrain and sympathetic neurons play a key role in the pathophysiological development of diet-induced obesity. Conditional mutant mice lacking CB1 expression in neurons known to control energy balance, but not in nonneuronal peripheral organs, displayed a lean phenotype and resistance to diet-induced obesity. This phenotype results from an increase in lipid oxidation and thermogenesis as a consequence of an enhanced sympathetic tone and a decrease in energy absorption. In conclusion, CB1 signaling in the forebrain and sympathetic neurons is a key determinant of the ECS control of energy balance