From the Bench to the Bedside: Branched Amino Acid and Micronutrient Strategies to Improve Mitochondrial Dysfunction Leading to Sarcopenia

Abstract

With extended life expectancy, the older population is constantly increasing, and consequently, so too is the prevalence of age-related disorders. Sarcopenia, the pathological age-related loss of muscle mass and function; and malnutrition, the imbalance in nutrient intake and resultant energy production, are both commonly occurring conditions in old adults. Altered nutrition plays a crucial role in the onset of sarcopenia, and both these disorders are associated with detrimental consequences for patients (e.g., frailty, morbidity, and mortality) and society (e.g., healthcare costs). Importantly, sarcopenia and malnutrition also share critical molecular alterations, such as mitochondrial dysfunction, increased oxidative stress, and a chronic state of low grade and sterile inflammation, defined as inflammageing. Given the connection between malnutrition and sarcopenia, nutritional interventions capable of affecting mitochondrial health and correcting inflammageing are emerging as possible strategies to target sarcopenia. Here, we discuss mitochondrial dysfunction, oxidative stress, and inflammageing as key features leading to sarcopenia. Moreover, we examine the effects of some branched amino acids, omega-3 PUFA, and selected micronutrients on these pathways, and their potential role in modulating sarcopenia, warranting further clinical investigation.

Association between Immunosenescence, Mitochondrial Dysfunction and Frailty Syndrome in Older Adults

“…In our previous work, we demonstrated that mitochondrial function in PBMCs from old malnourished patients can be boosted with targeted nutritional support and that this activity is correlated with improvement in clinical outcomes [30]. Our data suggest that mitochondrial dysfunction may be considered a hallmark of frailty and targeted as a possible therapeutic intervention [19]. Mitochondrial function is correlated with muscular strength, performance and mass, and these are key features of sarcopenia, which is associated with physical frailty [27,56].…”

“…The decrease in naïve T cells during aging may lead to the reduced abilities of older patients to respond to unknown immune stimuli, leading to increased susceptibility to infections and cancer and reduced immune response to vaccines [14][15][16]. The impairment of mitochondrial function associated with aging [17] has been proposed as one of the main contributors to the development of immunosenescence and immune system dysfunction [18][19][20]. Immunosenescence and immune cell mitochondrial dysfunction may be the cause of the increase in sterile inflammation associated with aging named "inflammaging" [21,22].…”

Nutrition therapy in critically ill patients with severe acute pancreatitis

“…57 It is suggested that amino acid infusion might counteract the development of sarcopenia by stimulating protein anabolism. 58 Another potential benefit of amino acid infusion is protecting the kidney, which is one of the most affected organs in SAP. 59 Animal models have demonstrated an increase in renal blood flow in response to a shortterm amino acid infusion, 60 and this was confirmed in the Nephro-Protective Trial showing that amino acid infusion could increase estimated glomerular filtration rate and urine output in critically ill patients.…”

“…Furthermore, branched‐chain amino acids can enhance mitochondrial function and reduce oxidative stress, especially when patients are in a protein catabolic state, such as the early phase of SAP 57 . It is suggested that amino acid infusion might counteract the development of sarcopenia by stimulating protein anabolism 58 …”

The syndromic triad of COVID-19, type 2 diabetes, and malnutrition

“…Diets that accentuate protein and antioxidants may combat sarcopenia by increasing muscle mass and strength via improved protein homeostasis and autophagy (the orderly degradation and recycling of cellular components) as well as reduced oxidative stress ( 120 ). Likewise, branched-chain amino acids, polyunsaturated fatty acids, selenium, vitamin D, and zinc can reduce oxidative stress, support mitochondrial homeostasis, and mitigate low-grade inflammation, thus suggesting their potential roles in the treatment of sarcopenia ( 128 ). To the contrary, however, a Mendelian randomization analysis shows little effect from these nutrients with the exception of a genetically high concentration of serum iron, which increased sarcopenia risk ( 129 ).…”