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Review
. 2011 May;3(5):464-78.
doi: 10.18632/aging.100322.

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

Alessandra Valerio  1 , Giuseppe D'Antona, Enzo Nisoli
Affiliations
Review

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

Alessandra Valerio et al. Aging (Albany NY). 2011 May.

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.

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Conflict of interest statement

The authors of this manuscript have no conflict of interests to declare.

Figures

Figure 1.
Figure 1.
Amino acids are degraded to compounds that can be metabolized to CO2 and H2O, or used in gluconeogenesis. Indeed the oxidative degradation of amino acids produces 10 – 15% of total metabolic energy in animals. The standard amino acids are degraded to one among the seven metabolic intermediates (pyruvate, α-ketoglutarate, succinyl-CoA, fumarate, oxaloacetate, acetyl-CoA or acetoacetate). Thus, amino acids may be divided into two groups, on the basis of their catabolic pathways: 1) gluconeogenic amino acids, which are catabolized to pyruvate, α-ketoglutarate, succinyl-CoA, fumarate or oxaloacetate, and are glucose precursors; 2) ketogenic amino acids, which are catabolized to acetyl-CoA or acetoacetate, and, thus, may be transformed into fatty acids or ketone bodies. Some amino acids are precursors both of carbohydrates and ketone bodies. Because mammals have no metabolic pathway which allows a net transformation of acetyl-CoA or acetoacetate to gluconeogenic precursors, no net synthesis of carbohydrates is possible from lysine and leucine, exclusively ketogenic amino acids. BCAAs, branched-chain amino acids.
Figure 2.
Figure 2.
Catabolism of branched-chain amino acids. Starvation and exercise stimulate protein breakdown, thereby increasing the concentrations of branched-chain amino acids (BCAAs) in adipose and muscle cells. The BCAAs are transaminated in muscle mitochondria by branched-chain aminotransferase (BCAT), and branched-chain α-keto acids (BCKAs, especially α-keto acid from leucine) inhibit branched-chain α-keto acid dehydrogenase kinase, resulting in elevation of the active state of the rate limiting enzyme branched-chain α-keto acid dehydrogenase complex (BCKDH). Recent results indicate a novel mechanism for regulation of BCAA oxidation in adipose tissue, i.e. changes in the expression of BCAA enzymes, in contrast to altered BCKDH phosphorylation, which is the major mechanism regulating BCAA oxidation in muscle and liver [121]. Ala, alanine; α-KG, α-ketoglutarate; Glu, glutamate; Gln, glutamine; IB-CoA, isobutyryl-coenzyme A; IV-CoA, isovaleryl-coenzyme A; MB-CoA, α-methylbutyryl-coenzyme A; R-CoA, acyl-coenzyme A; TCA, tricarboxylic acid.
Figure 3.
Figure 3.
Possible health effects of amino acid mixtures in humans. Accurate clinical trials enrolling larger number of patients are necessary to confirm the safety and efficacy of BCAA/amino acid supplementation in geriatric patients. COPD, chronic obstructive pulmonary disease
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