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

AGING, May 2011, Vol. 3. No 5 www.impactaging.com Review Branched‐chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective Alessandra Valerio1, Giuseppe D’Antona2, and Enzo Nisoli3 1 Pharmacology Unit, Department of Biomedical Sciences and Biotechnologies, Brescia University, Brescia 25123, Italy 2 Department of Physiology, Human Physiology Unit and Interuniversity Institute of Myology, Pavia University, Pavia 27100, Italy 3 Center for Study and Research on Obesity, Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, Milan University, Milan 20129, Italy Key words: branched‐chain amino acids; calorie restriction; aging; lifespan; nitric oxide; mitochondrial biogenesis; mammalian target of rapamycin Received: 4/21/11; Accepted: 4/29/11; Published: 4/30/11 Corresponding author: Enzo Nisoli, MD/PhD; E‐mail: Δ Copyright: © Valerio et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Abstract: 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. INTRODUCTION palatable energy-dense foods increases fat accumulation and vulnerability to a range of age-related diseases, including type 2 diabetes, cardiovascular disorders, and cancer. A substantial number of older people in westernized countries are overweight. Although the increase in the relative risk for death that is associated with being obese is not as great in older subjects as it is in young adults, functional capacity, mobility and quality of life are significantly reduced in the obese elderly [3]. On the other side, undernutrition is a common feature among aged individuals, due to multiple reasons that include reduced appetite and food intake – the physiologic ‘‘anorexia of aging’’ – and numerous nonphysiologic factors, i.e., impaired nutrient At an age when proper nutrition is a fundamental health requirement, almost half the elderly people in developed countries are not adequately nourished. By the widely used Mini Nutritional Assessment, the reported prevalence of nutritional risk in older subjects is approximately 45% in the community, with higher values in domiciliary care settings or hospitals and 84% to 100% in residential care facilities [1]. Malnutrition is defined as a state in which a deficiency, excess or imbalance of energy, protein and other nutrients causes adverse effects on body form, function and clinical outcome [2]. Excess caloric intake or consumption of www.impactaging.com 464 AGING, May 2011, Vol.3 No.5 absorption and other age-related medical, psychological and social changes [1, 2]. Inadequate nutritional intake may conduct to a global functional decline referred to as frailty, a newly recognized geriatric syndrome due to excess demand imposed upon reduced capacity [4]. Particularly, potein-energy undernutrition is associated with reduced strength, decreased bone mass, immune dysfunction, anemia, impaired cognitive function, poor wound healing, delayed recovering from surgery and higher hospitalization rate and is a strong independent predictor of mortality in elderly people [3]. Model organisms Saccharomyces cerevisiae The budding yeast, Saccharomyces cerevisiae, has been widely used for the identification of genes and cellular and biochemical pathways that affect the aging process. In unicellular yeast, aging mechanisms can be investigated by measuring replicative lifespan (RLS, the number of daughters produced by each dividing mother cell), or chronological lifespan (CLS, the capacity of stationary G0 cultures to maintain viability over time) [13]. CR, that is known to lengthen the mean and maximum lifespan of many species [7], extends both RLS and CLS [14-16]. The NAD+-dependent histone deacetylase, Sir2, a well-characterized RLS factor [17], is required for yeast RLS extension by CR [14]. Both yeast RLS and CLS are also affected by genetic interventions on lifespan effectors related to nutrient signaling, i.e., deletion of the yeast Sch9 gene [which is homologous to the mammalian Akt/PKB implicated in the insulin-like growth factor (IGF) signaling] and mutations in the target of rapamycin (TOR) signaling pathway [18-20]. Saccharomyces cerevisiae is a facultative anaerobe that, under standard laboratory growth conditions (2% glucose), generates ATP largely by fermentation. Interestingly, deletion of the TOR1 gene and CR cause a shift in glucose metabolism from fermentation – based on anaerobic glycolysis – toward respiration – based on oxidative metabolism involving the electron transport chain (ETC) – in both lifespan models [15, 20, 21], revealing a strong link between prolongevity effects and mitochondrial function. Geriatric nutrition research aims to decipher the molecular mechanisms involved in the effects of dietary nutrients and to clarify their efficacy in the attainment of healthy aging. Several studies focused in particular on the effects of varying nutrient supply on animal and human longevity, with responses strongly dependent on genotype, age, nutrients, and regulation of nutrientsensing pathways [5, 6]. Calorie restriction (CR), a low-calorie dietary regimen without malnutrition, decreases the incidence of several age-associated disorders and is considered the goldstandard, non-genetic approach for lifespan extension [7]. A body of evidence in several organisms demonstrates that an increase in mitochondrial activity, together with activation of the reactive oxigen species (ROS) defense system, is associated with the salutary effects of the CR regimen, [7, 8]. Although it has beneficial effects in humans [9], long-term CR requires a major commitment of will power (...truncated)