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Models of Sarcopenia

Alfred L. Fisher

Sarcopenia refers to the loss of muscle mass during normal aging. The medical importance of sarcopenia lies in the significant loss of muscle strength that accompanies the loss of muscle mass. Clinical studies have linked the loss of strength to decreases in mobility and functioning seen in older people, and have suggested that the extent ofstrength loss could serve as a risk factor for mortality. Sarcopenia has been observed in multiple mammalian species besides humans and even in simple non-vertebrate animals, like the nematode Caenorhabditis elegans. This observation suggests that the development of sarcopenia may be an unfortunate but normal part of the aging of the neuromuscular system. Although the exact cause of sarcopenia is currently unknown, there is evidence from studies in people and experimental animals to support a number of theories, such as loss of motor neurons, declines in specific catabolic hormones, increases in inflammatory cytokines, and inadequate protein intake. Given the medical importance of sarcopenia, there is a pressing need to understand this condition further with the hope of developing effective treatments. This chapter will provide an introduction to sarcopenia and the current methods used to study sarcopenia both in people and experimental systems.

Introduction

The term sarcopenia describes the loss of muscle mass and muscle strength that occurs with normal aging (see Figure 81.1).

Sarcopenia is not a uniquely human condition as comparable changes have been seen in people, mice, rats, dogs, and even lower animals such as the nematode worm Caenorhabiditis elegans, and hence sarcopenia may represent the aging of the neuromuscular system in animals (Fisher, 2004).

The medical importance of sarcopenia lies in the reductions of strength that accompany the loss of muscle mass (see Figure 81.2).

Muscle strength reaches a peak in the late 20s to early 30s before beginning a slow, continuous decline. For much of adulthood the declines in muscle strength are of little consequence except for elite athletes and those involved in intense physical labor. However, starting in the late 50s, the loss of muscle mass and strength appears to accelerate (Lexell, 1995; Vandervoort, 2002). However, the loss of strength varies between individuals resulting in significant differences between individuals of the same age. Consequently, by the 60s the loss of muscle strength begins to impact individuals to varying degrees. The declines in strength have been linked to impairments in mobility and functioning seen in older people. The decline in strength also appears to act as a risk factor for mortality (Fisher, 2004).

At a simple level, the loss of muscle strength impairs the ability to lift and carry objects, such as groceries or laundry. For example, data from the Framingham cohort indicate that 45% of women aged 65 to 74 years and 65% of women aged 75 to 84 years are unable to lift 4.5 kg. (Fisher, 2004). The loss of strength also has a significant impact on lower extremity strength and on lower extremity function as measured by gait speed, rising from a chair, or climbing stairs (Evans, 1997; Greenlund and Nair, 2003). Besides the direct impact of impaired lower extremity function on mobility in daily life, poor lower extremity function is strongly associated with both falls and need for nursing home placement (Guralnik et al., 1995; Rantanen, 2003). Besides the impairment in functioning, the loss of strength also serves as a risk factor for future mortality as multiple studies have demonstrated weaker individuals to have higher mortality than stronger individuals even after correction for comorbid illnesses (Metter et al., 2002; Rantanen, 2003; Rantanen, et al., 2003). The reason for this association between strength and mortality is not known, but could involve sarcopenia and the loss of strength serving as a marker for the aging of the entire body, with individuals with worse sarcopenia being biologically older than the individuals with more preserved muscles (Fisher, 2004).

The cause of sarcopenia is unknown, but there is evidence from human and experimental animals for multiple theories, including loss of motor neurons, oxidative stress, declines in catabolic hormones, increases in inflammatory cytokines, and inadequate nutrition.

Electromyography and anatomic studies have demonstrated a loss of up to 50% in the numbers of motor neurons in the spinal cord with resulting reduction in the numbers of functioning motor units (Lexell, 1995; Vandervoort, 2002). As some of the changes seen in aging

Handbook of Models for Human Aging

Copyright © 2006 by Academic Press All rights of reproduction in any form reserved.

muscle are reminiscent of changes seen following denervation, this suggests that the chronic denervation and reinnervation occurring due to the loss of motor neurons may be a cause of sarcopenia during aging (Lexell, 1995; Vandervoort, 2002).

During aging, metabolically active tissues such as muscle are at risk of damage from reactive oxidative species either from atmospheric oxygen or internally generated radicals from mitochondrial metabolism (Carmeli et al., 2002). The oxygen radicals are highly reactive and can damage DNA, proteins, and lipids in the muscle cell, eventually leading to cell death or dysfunction. Studies in aging muscle have shown increases in markers of oxidative damage to proteins and lipids with age. Additionally, lower levels of oxidative damage have been seen in animals treated with caloric restriction, which

Figure 81.1 Sarcopenia is a loss of muscle mass during aging. A. CT scan of the mid-thigh of a young active person shows subcutaneous fat (dark gray) and skeletal muscle (light gray). B. A CT scan of the mid-thigh of an older person demonstrates the dramatic loss of skeletal muscle mass and the accompanying increase in subcutaneous fat. Reproduced from Roubenoff (2003b) with permission of the publisher.

Figure 81.1 Sarcopenia is a loss of muscle mass during aging. A. CT scan of the mid-thigh of a young active person shows subcutaneous fat (dark gray) and skeletal muscle (light gray). B. A CT scan of the mid-thigh of an older person demonstrates the dramatic loss of skeletal muscle mass and the accompanying increase in subcutaneous fat. Reproduced from Roubenoff (2003b) with permission of the publisher.

is an intervention that slows organismal aging (Carmeli et al., 2002).

The levels of muscle catabolic hormones, such as growth hormone and testosterone, decline significantly during aging. For growth hormone, during aging there is an approximately 14% per decade decline in secretion (Horani and Morley, 2004). This decline is due to reductions in both the frequency and amplitude of pulses of secreted growth hormone from the pituitary. Associated with the decrease in growth hormone production is an accompanying decrease in IGF-1 (insulin-like growth factor) production, which is made by the liver in response to growth hormone. IGF-1 acts on several tissues including muscle, where IGF-1 simultaneously promotes muscle hypertrophy and inhibits muscle atrophy (McKinnell and Rudnicki, 2004). In men, testosterone declines at a rate of approximately 100 ng/dL per decade during adulthood (Horani and Morley, 2004). Testosterone has anabolic actions on muscle and also appears to increase the production of muscle stem cells. Unfortunately, human studies investigating the effects of testosterone or growth hormone replacement on sarcope-nia have produced at best modest results, though none of the studies were long-term (Blackman et al., 2002; Horani and Morley, 2004).

Aging is associated with increasing levels of inflammatory cytokines, such as TNFa (tumor necrosis factor) and IL-6 (interleukin) (Ferrucci et al., 2002; Roubenoff, 2003a; Roubenoff et al., 2003). The reason for the observed increases and the sites of cytokine production are not known. However, clinical studies have demonstrated an association between higher levels of

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