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 corresponding accumulation of body fat (24). Muscle atrophy results from a gradual and selective loss of muscle fibers. The number of fibers in the vastus lateralis muscle from cadavers of older men is 23% lower than in young men (26). There is a preferential atrophy of fast-twitch, type II fibers (24), in part because of their reduced reinnervation capacity than type I fibers (26). There is an increase in intramuscular fat and connective tissue (27). These changes reduce the contractile tissue volume available for locomotive and metabolic functions and the increased amount of connective tissue presumably acts as a friction brake to slow contractile velocity (24, 28). Most studies of muscle mass and body composition have relied on cross-sectional data. Many of these studies have not taken into account individual variation due to the level of physical activity, nutritional status, and disease. There is also a paucity of data on ethnic differences in body composition. Sarcopenia has been identified as a contributor to disability in old age (29, 30). Walking, stair climbing, rising from a chair, and load carrying represent functional activities that deteriorate with sarcopenia. Loss of muscle mass, particularly the preferential loss of type II fibers (24), results in diminished strength and power-generating capacity (31). There is a significant correlation between strength and leg power and maximal walking speed and stair-climbing height (31–34). Rantanen and Avela (34) have described critical ranges of leg power for different walking speeds, suggesting that below the critical range the probability of walking at a particular speed is low. Falls are a serious consequence of the loss of muscle strength and power. Leg weakness and decreased peak torque and power are associated with impaired gait characteristics, such as small steps and slow speeds (35) and a history of falling (36, 37). Because strength is fundamental to the neuromuscular function that supports mobility (37), loss of strength below a critical threshold may be associated with an increased risk of falls. Therefore, interventions that increase muscle mass, strength, and power in the lower extremity may reduce the risk of falling. The maximal oxygen uptake rate (VO2max) defines the capacity for endurance exercise (22). Both decreased muscle mass (23) and decreased oxidative capacity of skeletal muscle (38) with aging contribute to the 1% annual decline in maximal aerobic capacity. Resistance training can increase VO2max in the elderly (39); this suggests that increasing muscle mass can increase maximal aerobic power. Sarcopenia contributes to the decline of aerobic capacity, thus limiting the extent to which older individuals may participate in a variety of activities and retain their independence. Therefore, interventions that augment muscle mass can help older men maintain or regain their ability to perform daily functional activities and live independently. Approximately 20% of muscle weight is protein; therefore, changes in muscle mass will likely be associated with alterations in muscle protein turnover (which includes muscle protein synthesis and break down) (14, 24). Whole body protein synthesis declines from birth to old age (40). However, when protein turnover rates are normalized to FFM, there is no difference between young and old subjects (41, 42). Because older people lose FFM but not weight, it is possible that the difference observed in whole body protein synthesis in the elderly is due to their increased fat mass (14). Also, the muscle contributes<30% to whole body protein turnover; therefore, small changes in muscle protein synthesis or breakdown are difficult to detect with measurements of whole body protein turnover. Indeed, the fractional synthesis rates of mixed or myofibrillar protein are lower from muscle biopsy samples in old people as compared with young people (42–44). Standardized exercise programs, testosterone, and amino acids can stimulate the synthetic rates of total muscle protein (44), as well as myofibrillar proteins (45). In contrast, high-protein meals do not enhance the stimulation of myofibrillar synthesis induced by resistance exercise (45). Because amino acids alone can stimulate muscle protein anabolism in young and older subjects (46), it is unlikely that alterations of muscle protein metabolism in the elderly are due to a defect in amino acid transport. There are alterations in the synthesis rates of individual muscle proteins in older individuals. Compared with younger subjects, the middle-aged and older men and women have significantly lower synthetic rates of myosin heavy chain, an important contractile protein (47). The fractional myofibrillar protein synthesis rate (the rate of synthesis per gram of myofibrillar protein already present) is 28% slower in older subjects (42). The reduced myofibrillar protein synthesis in the elderly is not due to a reduction in the availability of mRNAs encoding actin and myosin (48) and may be the result of posttranslational events. Protein turnover is important for maintaining the mass of structural and contractile proteins and enzyme function (24). There is a 40% decrease in mitochondrial protein synthesis rates in middle-aged subjects, but no further decrease in older subjects (49). The changes in mitochondrial function may contribute to alterations in muscular endurance and fatigability and contractility (24). Although it is now possible to measure synthesis and breakdown rates of specific muscle proteins and to study their regulation (14, 47, 49, 50), these methods are invasive and are not clinically applicable to older individuals with sarcopenia. We have little information about the genetic regulation of skeletal muscle protein turnover in humans. 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