Anabolic Interventions for Aging-Associated Sarcopenia

AGING in humans is associated with a progressive decrease in skeletal muscle mass and strength (sarcopenia) that contributes to frailty and falls. The age-associated changes in body composition result from lower levels of anabolic hormones, neuromuscular alterations, and a general decline in muscle protein turnover (1–3). The frailty of old age has emerged as an important public health problem because it impairs mobility and quality of life and increases the risk of falls and the use of health care resources (4–6). Therefore, recent years have witnessed a growing interest in the use of anabolic interventions for augmenting muscle mass and function in older men. The term sarcopenia, originally coined by Rosenberg (4) and recently reviewed by the National Institutes of Aging (5), refers to the involuntary loss of skeletal muscle mass and strength. This is in contrast to wasting, the involuntary loss of weight driven largely by inadequate nutrition, and cachexia, the involuntary loss of fat-free mass (FFM), especially body cell mass, generally resulting from a state of hypermetabolism and hypercatabolism (6). The etiology of sarcopenia is currently unknown. Holloszy (5) identified several possible mechanisms leading to sarcopenia, including loss of α motor neurons in the spinal column, impairment of endogenous growth hormone, androgen and estrogen production, inadequate protein intake, dysregulation of catabolic cytokines, and reduced physical activity. Mortality in the elderly is primarily associated with atherosclerosis, cancer, and dementia. In an increasing number of the elderly men and women, however, loss of muscle mass and strength is an important determinant of the individual’s ability to live an independent life (7). There is no consensus on whether sarcopenia should be viewed as a disease or process of normative aging (4). It has been argued that, because loss of muscle mass occurs even during the course of successful aging, sarcopenia should be considered a disease only when it induces disability (4). There is also no consensus on what threshold of muscle loss should be used to define sarcopenia. The magnitude of the public health problem posed by sarcopenia is not known (8). Baumgartner et al. (9) examined the prevalence of sarcopenia in Hispanic and non-Hispanic white elderly men and women in New Mexico. Sarcopenia was defined as the relative muscle mass that was two sds below the sex-specific means of the Rosetta Study reference data (10) for young adults, aged 18–40 yr. The study (9) demonstrated that the prevalence of sarcopenia increased from 13% to 24% in persons under 70 years of age. Nearly half of all persons over 80 years of age met this definition of sarcopenia. The study also demonstrated that sarcopenia was associated with a 3- to 4-fold increased likelihood of disability in elderly people, independently of age, sex, obesity, ethnicity, socioeconomic status, chronic morbidity, and health behaviors (9). Another cross-sectional survey performed by Melton (11) in Olmsted County in Minnesota used slightly different thresholds for defining sarcopenia and reported lower prevalence rates. Based on an age-stratified, random sample of the population of Rochester, Minnesota, this survey verified the findings of Baumgartner et al. (9) that lean body mass decreases progressively after the second decade of life in both men and women. Age-related losses in fat-free mass, appendicular muscle mass, and total muscle mass are all linear in both men and women, and there was no significant difference in the slope of the regression line before 50 and after 50 years of age. The prevalence of sarcopenia in individuals over 20 years of age was 2–3% and in those over 65 years of age, approximately 10% (11). Taken together, these two epidemiological studies provide evidence that sarcopenia is an important public health problem. In the two-compartment model of body composition, body weight is the combination of fat mass and fat-free mass. Fat-free mass, in turn, is the combination of body cell mass, extracellular fluid, and the extracellular solids such as collagen and bone mineral. Body cell mass can be further divided into the fat-free portion of cells within muscle, viscera, and the immune system. Muscle cell mass is an important determinant of muscle strength, whereas the sum of visceral and muscle body cell mass predicts energy requirements (6). Thus, changes in body composition with aging, especially in the FFM component, have important implications for functional status and survival (6, 13). Weight gain in adults is associated with an increase in absolute and percent fat mass (14). In women, body weight increases between the ages of 40 and 50 yr and remains stable thereafter; percent body fat is also stable until 40 yr of age and increases from 28% to 35% between 40 and 50 yr of age (15). In another cross-sectional study (16) of men and women 18–85 yr of age who used total body potassium, percent fat increased from 18% to 36% and 33% to 44% in men and women, respectively. In addition to an overall increase in adiposity, aging is associated with a more central distribution of fat (14). The composition of lean tissues also changes with advancing age. Men experience a more rapid muscle loss between the ages of 41 and 60 yr, whereas women experience the rapid loss after the age of 60 (17). Total body nitrogen, calcium, water, and bone mineral content also decline with age (18–21). More recent epidemiological surveys suggest that age-associated decrease in skeletal muscle mass starts after the second decade of life in both men and women and is slowly progressive thereafter. The principal component of the decrease in fat-free mass is the loss of muscle mass; there is little change in nonmuscle lean mass (18, 19). Between 20 and 80 yr of age, the cumulative decline in skeletal muscle mass amounts to 35–40% (22, 23). The depletion of muscle mass does not result in weight loss because of the co