REVIEWLoss of skeletal muscle mass in aging: Examining the relationship of starvation, sarcopenia and cachexia☆
Introduction
Involuntary weight loss is common in older persons and is a harbinger of poor outcome. A body mass index (BMI, weight in kilograms divided by height in meters squared) of less than 22 has been associated with a higher 1-year mortality rate and with poorer functional status among older community-dwelling persons.1 This higher mortality risk begins at a BMI of less than 22 in both men and women older than 65 years. At a BMI of less than 20.5 in men older than 75 years, a 20% higher mortality risk is observed. Similarly, at a BMI of less that 18.5 in women older than 75 years, there is a 40% higher mortality risk.2 In hospitalized patients, the risk of mortality is directly associated with BMI,3 even after controlling for recent weight loss, serum albumin, severity of illness score, and patient demographics.4
Although there is a strong association between BMI and mortality, the key factor in the mortality risk appears to be recent weight loss. A loss of 10% or more of body weight between age 50 and old age is associated with a 60% increase in mortality compared to persons with stable weight.5 In institutionalized nursing home residents, a 10% loss of body weight over a 6-month interval strongly predicted mortality in the ensuing 6 months.6 In residents who lost a least 5% of their body weight, a five- to-ten fold increased risk for death has been reported.7, 8
A low body weight alone is not associated with an increase in mortality in epidemiological studies, when persons who lost 10% or more of their body weight were excluded.9 Most of the large epidemiological studies have found little relationship between BMI and mortality after excluding subjects with weight loss. In persons over age 50 years who reported an unintended loss of 10 pounds or more in the year before evaluation, the age-adjusted death rate was much higher compared to persons who lost weight through diet or exercise or who maintained or gained weight.10 Nearly all of the observational studies have found that any weight loss is associated with increased rather than decreased risk for death.11, 12, 13, 14
The higher mortality rate associated with weight loss may extend even to voluntary weight loss. Paradoxically, a higher 2-year mortality was found in community living subjects who lost weight by dieting (36%) compared to those who had skeletal muscle loss (28%).15 This data suggests that even voluntary weight loss by dieting may place older persons at risk.
The importance of weight loss lies not only in increased mortality but also in the fact that it is associated with a decline in functional status.16 Weight loss of more than 5% in community-dwelling women 60–74 years old is associated with a two-fold increase in risk of disability over time, compared to women who did not lose weight, after adjustment for age, smoking, education, study duration, and health conditions.17
A large component of involuntary weight loss in older persons is a loss in fat-free mass. The fact that muscle mass decreases with age has been known for some time. Earlier work demonstrated that the excretion of urinary creatinine, a measure of muscle creatine content and total muscle mass, decreases by nearly 50% between the ages of 20 and 90 years.18 The age-related loss of muscle mass appears to be fairly consistent, at a rate of approximately 1–2% per year past the age of 50 years.19 This decline in muscle mass occurs in both sedentary and active aging adults. In contrast, in healthy young adults, no net change occurs in skeletal muscle mass under equilibrium conditions, due to balance in skeletal muscle protein synthesis and degradation.
This age-related reduction in muscle mass and strength is also accompanied by a reduction in motor unit number20, 21 and by atrophy of muscle fibers, especially the type IIa fibers.22 An associated decline in protein synthesis, particularly in the synthesis of myosin heavy chains, has been observed.23
The loss of muscle mass with aging is clinically important because it leads to diminished strength and exercise capacity.24 Both dynamic, static, and isokinetic muscle strength decreases with age.25 Maximal oxygen consumption declines with age at a rate of 3–8% per decade beginning at age 30.26 However, after correction for muscle mass, there is no important decline in VO2Max with aging, indicating that a change in muscle mass is the significant factor.27 The result of age-related muscle mass loss produces a decline in function. Up to 65% of older men and women report that they cannot lift ten pounds using their arms.28
Section snippets
Causes of skeletal muscle loss
The regulation of body composition is dynamic over time. Minute-to-minute composition is regulated by a person's metabolic state. Day-to-day regulation depends of insulin and glucagon. Month-to-month, hormones such as estrogens and androgens, growth hormone, prolactin, thyroid hormones, catecholamines, and corticosteroids regulate body composition. Immune mediators, such as interleukin-1 (IL-1), tumor necrosis factor, and interleukin-2 (IL-2), also can affect body composition through modulation
Sarcopenia
Sarcopenia is characterized subnormal amounts of skeletal muscle. The ability to easily measure body composition by dual-emission X-ray spectrometry, or bioelectrial impedence has led to intensive research on skeletal muscle mass in aging.32, 33
Sarcopenia is operationally defined as an appendicular skeletal muscle mass divided by height in meters of more than two standard deviations below the young normal mean. Using this definition, Baumgartner found that 14%, 20%, 27%, and 53% of men aged
Cachexia
Although there is no widely accepted definition, cachexia is best viewed as the cytokine-associated wasting of protein and energy stores due to the effects of disease.57 Systemic inflammation mediated through cell injury or activation of the immune system triggers an acute inflammatory response. Persons with cachexia lose roughly equal amounts of fat and fat-free mass, while maintaining extracellular water and intracellular potassium. The loss of fat-free mass is mainly from the skeletal muscle.
Differentiating sarcopenia from cachexia
A decline in muscle mass, muscle strength, and muscle quality is common in older adults. Epidemiological data demonstrates that sarcopenia is the most frequent cause (Fig. 1). Cachexia is the next most common cause of loss of muscle mass, occurring in a number of disease states. In the extreme, starvation can lead to cachexia but is usually not as common, at least in developed countries where access to food is not a factor. Although starvation, cachexia, and sarcopenia can be defined as
Interventions for sarcopenia
For persons with sarcopenia, the primary intervention should include resistance exercise interventions. Progressive resistance exercise training increases muscle protein mass and strength in men and women. The increase in muscle protein mass is attributable to an acute and chronic increase in muscle protein turnover resulting in the rate of muscle protein synthesis exceeding muscle proteolysis. Coincident with the increase in muscle protein are increases in maximum voluntary muscle strength and
Interventions for cachexia
In contrast to starvation, cachexia is remarkably resistant to hypercaloric feeding. Trials of both enteral and parenteral feeding in cancer cachexia have consistently failed to show any benefit in terms of weight gain, nutritional status, quality of life, or survival.77 Pharmacological treatment of anorexia with agents that modulate cytokine production may produce weight gain in cachexia states.105 Steroids and hormonal agents such as megesterol acetate are currently widely used in the
Conclusion
A therapeutic approach to the loss of skeletal muscle mass and strength in older persons depends on correct classification. The term sarcopenia should be reserved for age-related decline in muscle mass not attributable to the presence of proinflammatory cytokines. Cachexia may be a better term for a decline in muscle mass associated with known inflammatory disease states. While starvation due to protein energy undernutrition is widely regarded as the primary cause of loss of fat and fat-free
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- ☆
This paper is based on the presentation given at the III Cachexia Conference (Rome, 8–10 December 2005). During the conference, experts in wasting disease, both basis scientists and clinical researchers, discussed relevant topics in the anorexia-cachexia field, including pathogenic mechanisms, diagnostic tools, current therapeutic strategies and future options. More details can be found at http://www.cachexia.org.