Sarcopenia—Understanding the Dynamics of Aging Muscle

Sarcopenia is not a disease but rather refers specifically to the universal, involuntary decline in lean body mass that occurs with age, primarily due to the loss of skeletal muscle.¹ Sarcopenia has important consequences. The loss of lean body mass reduces function, and loss of approximately 40% of lean body mass is fatal.^{2 - 5} Sarcopenia is distinct from wasting—involuntary weight loss due to inadequate intake, which is seen in starvation, advanced cancer, or acquired immunodeficiency syndrome. Sarcopenia also differs from cachexia, a cytokine-driven loss of lean body mass that occurs despite maintenance of weight, which is seen in patients with rheumatoid arthritis, congestive heart failure, or renal failure.⁶ However, sarcopenia is the backdrop against which the drama of disease is played out: a body already depleted of protein because of aging is less able to withstand the protein catabolism that comes with acute illness or inadequate protein intake.⁷

Protein stores in humans have at least 2 important functions. First, unlike fat, which is truly stored in the sense that it is in reserve for times of starvation, body proteins are in use as contractile proteins in muscle, antibodies, enzymes, etc. Thus, loss of protein means loss of function. Second, during illness, nitrogen must be mobilized from muscle to provide amino acids to the immune system, liver, and other organs. If adequate nitrogen cannot be provided, either exogenously from diet or endogenously from muscle, the body's capacity to withstand an acute insult declines, and—at about 60% of baseline nitrogen throughput—the body ceases to function.^{2 - 5} Thus, it is likely that some of the explanation for the poorer outcomes observed with nearly all diseases in older persons relates to their lower body protein stores. Muscle is the major source of protein for functions such as antibody production, wound healing, and white blood cell production during illness. If the body's protein reserves are already depleted by sarcopenia, there is less to mobilize for illness.

The determinants of sarcopenia include genetic and environmental factors,⁸ with a complex series of poorly understood interactions. Amino acids and proteins are the primary substrates for skeletal muscle mass maintenance. Therefore, knowledge of amino acid kinetics and the balance between protein synthesis and protein breakdown is pivotal to understand how sarcopenia develops. Until now, most studies have indicated that muscle protein synthesis declines with age, suggesting that sarcopenia is due to failure of muscle protein synthesis.^{9 - 11}

In this issue of THE JOURNAL, Volpi and colleagues¹² report findings from the largest reported study to date to examine basal muscle protein synthesis, as well as the first direct measures of protein breakdown and net muscle protein balance in a group of healthy older men. The three-compartment model developed by this group of investigators uses amino acids labeled with stable isotopes to examine the rates of inward and outward transport of amino acids in muscle and to determine the rates of muscle protein synthesis and breakdown and the size of the intracellular free amino acid pool. Contrary to the notion of reduced protein synthesis with age, muscle protein synthesis was slightly higher in healthy older men compared with healthy young men. Basal net protein catabolism was not statistically different between the groups.

These observations strongly suggest that sarcopenia is not due to inadequate basal (fasting) protein synthesis. More likely, aging muscle fails to respond to stimuli that are anabolic to young muscle—eg, diet and exercise—perhaps because of hormonal or immunological changes that occur with age and no longer favor anabolism.⁸ For example, an earlier study by Volpi et al¹³ suggested that the anabolic response to a mixed glucose-amino acid meal was reduced in older men. Taken together, these 2 studies implicate insulin resistance or immune factors, such as catabolic cytokines or other hormonal or immunological factors, acting primarily in the postprandial state as an important cause of sarcopenia. These observations also suggest that interventions aimed at treating or preventing sarcopenia should maximize the response of muscle to anabolic stimuli, such as diet and exercise, rather than trying to increase basal protein synthesis. Since the latter may be impossible to achieve or require potentially harmful doses of anabolic agents, such as growth hormone, insulin-like growth factor 1, or testosterone, the results of the study by Volpi et al appear to be good news indeed.

However, several limitations of this study should be considered. First, only men were studied, and it is possible that sarcopenia is regulated differently in men and women. Second, these were remarkably lean, healthy older men, and the generalizability of these data to the more typical overweight, sedentary population in many developed countries remains to be determined. For example, if insulin resistance were partly responsible for sarcopenia, then studying lean subjects would tend to bias the results toward the null, as was the case in this study. Third, the major advance of this investigation over earlier studies is the measurement of protein breakdown and synthesis. Yet, this technique is still very new, and it is unknown how sensitive it is to factors such as changes in diet and physical activity. Additional studies would help to clarify whether the increase in basal protein synthetic rate via enhanced entry of amino acids into muscle observed in the older subjects represents the end result rather than the process by which skeletal muscle compensates for the gradual loss of muscle mass.

The study by Volpi et al indicates that sarcopenia cannot be explained by differences in basal rates of muscle protein turnover between young and older men. The authors acknowledge additional work is needed in the older population to determine the individual and combined effects on muscle mass of specific stimuli, such as protein and energy intakes, physical activity, sex hormones, and growth hormone. For the clinician, the most important message is that sarcopenia exists in all older individuals. In the face of acute or chronic illness, maximizing muscle mass and protein stores through adequate nutritional support, aggressive physical therapy, and exercise programs becomes all the more important if muscle function and quality of life are to be preserved in the older population.