The Journal of Nutrition Vol. 129 No. 1 January 1999, pp. 256S-259S

The Pathophysiology of Wasting in the Elderly^1,2

Ronenn Roubenoff³

Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts and Tupper Research Institute and Division of Clinical Nutrition, Department of Medicine, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts

	ABSTRACT

Abstract Introduction References

Aging is associated with changes in body composition and energy and protein metabolism that are due both to the direct effects of aging and to the effect of age-related diseases. We have recently differentiated these changes under three categories: wasting, cachexia, and sarcopenia. We have defined wasting as unintentional loss of weight, including both fat and fat-free compartments. Experience in the HIV epidemic suggests that wasting is driven largely by inadequate dietary intake. Cachexia, on the other hand, refers to loss of fat-free mass, and especially body cell mass, but with little or no weight loss. The metabolic hallmarks of cachexia are hypermetabolism and hypercatabolism, driven by inflammatory cytokine-mediated acute phase responses. Finally, sarcopenia refers to loss of muscle mass specifically, and seems to be an intrinsic age-related condition. In the elderly, wasting as defined here is at the extreme end of the spectrum, but generally develops in the setting of pre-existing sarcopenia and cachexia. The challenges before us now are to better define these conditions, establish guidelines for their recognition, and develop better methods for intervening when appropriate.

	INTRODUCTION

Abstract Introduction References

The changes in body composition that occur with aging and disease have important implications for functional status and survival (reviewed in Roubenoff and Kehayias 1991). Loss of lean body mass and body cell mass (BCM)⁴ is associated with loss of strength, immune function, pulmonary function, and with increased disability and mortality (Arora and Rochester 1982, Castaneda et al. 1995, Launer et al. 1994, Watkins et al. 1992). We have recently proposed that the terms wasting, cachexia, and sarcopenia should be considered as three distinctly defined entities (Roubenoff et al. 1997). We suggested that the term wasting be reserved for involuntary weight loss, generally driven by inadequate dietary intake. In contrast, we proposed the term cachexia be used for involuntary loss of body cell mass or fat-free mass when this compartment is reduced with little or no weight loss. Such cachexia generally occurs in the setting of hypermetabolism (elevated resting metabolic rate by >10% above predicted) and hypercatabolism (increased protein degradation). Finally, we agreed with current definitions of sarcopenia as a term indicating specifically involuntary loss of muscle mass (Holloszy 1995). Unlike wasting and cachexia, sarcopenia may well be an intrinsic feature of aging, rather than an effect of an age-associated disease.

	BODY COMPOSITION

Body weight can be divided, at the simplest level, into fat mass and fat-free mass. Fat-free mass consists, in turn, of BCM, extracellular fluid, and the extracellular solids such as collagen and bone mineral. BCM can be further subcompartmented into the fat-free portion of cells within muscle, viscera, and the immune system. Although the available direct evidence is limited, most researchers in body composition agree that BCM is the functionally important compartment in determining energy expenditure, protein needs, and the metabolic response to physiologic stress (the acute phase response). Further functional consequences are implicit in the BCM subcompartments: muscle BCM directly predicts strength and thus functional status (Frontera et al. 1991); visceral and muscle BCM is the major determinant of energy needs (Moore 1980); and immune function depends on an adequately constituted immunocompetent cell system. A key observation made by Krieger (1921), and later more comprehensively and tragically by the Warsaw Ghetto investigators (Winick 1979), as well as by modern studies of patients with AIDS (Kotler et al. 1989), is that humans do not survive once their BCM declines below approximately 60% of normal levels for young adults. Furthermore, BCM declines steadily with age even in healthy, successfully aging people (Cohn et al., 1980; Flynn et al., 1989).

However, it is important to realize that BCM can erode without a parallel loss of body weight. In fact, BCM can be lost in the face of increasing weight if there is an increase in the mass of another compartment at the same time. Such compartmental shift is common: Early in the course of congestive heart failure, cirrhosis, or renal failure, an increase in extracellular fluid often masks the BCM loss, resulting in an increase in weight (Caregaro et al. 1996, Dinarello and Roubenoff 1996, Freeman and Roubenoff 1994, King et al. 1997, Nielsen et al. 1993). Similarly, in aging and in rheumatoid arthritis (Roubenoff et al. 1992, Roubenoff et al. 1994), there is an increase in fat mass that often exceeds in absolute terms the loss of BCM. In these conditions, dietary energy intake is generally normal while weight is stable or rising; weight loss and wasting occur later.

	CHANGE IN BODY COMPOSITION WITH AGESARCOPENIA VS. WASTING

As defined by Rosenberg (1989) and recently expanded at an NIH-sponsored workshop (Holloszy 1995), sarcopenia refers specifically to involuntary loss of skeletal muscle mass and consequently of strength. Sarcopenia is commonly seen with advanced age, but may also occur in other situations in which skeletal muscle loss is the predominant problem, such as high-dose corticosteroid therapy, disuse, and weightlessness. Sarcopenia is distinct from the muscle atrophy that occurs due to focal pathologic conditions such as peripheral nerve damage or stroke, in which some muscles waste while others remain normal or even hypertrophy in response to physical therapy. It should be pointed out that although the etiology of sarcopenia is currently unknown, that does not imply that it is normative in aging, as it may occur at least in part because of reduced physical activity in our society. There are many candidate mechanisms leading to sarcopenia (Holloszy 1995), including loss of alpha motor neurons in the spinal column, loss of endogenous growth hormone production, inadequate protein intake, dysregulation of catabolic cytokines (especially interleukin-6), loss of estrogen and androgen production, and reduced physical activity (Roubenoff et al. 1997). It is clear that in the elderly there is a reduction in the number and size of type II muscle fibers, although type I fibers are spared (Lexell 1995). In aging, it is muscle cell mass that declines to the greatest extent of the subcompartments of BCM (Cohn et al. 1980, Holloszy 1995).

It should be emphasized that sarcopenia develops even in successfully aging adults, and seems to be a universal phenomenon. Should we consider sarcopenia a disease? In an analogous fashion to osteopenia leading to fractures and loss of function, sarcopenia is postulated to lead to weakness and loss of function. Unfortunately, the current state of the art is such that there are no normative data for sarcopenia as there are for osteopenia, nor is it clear what the best way to measure sarcopenia is. Although both are `normal` changes in that they seem to occur in the absence of a single disease, they may well be responsible for much of the disability and morbidity associated with aging. If the disease paradigm helps us develop effective means of preventing or reversing these changes, then by all means let us call them diseases.

In contrast to sarcopenia, both wasting and cachexia may occur in the elderly as a result of age-associated diseases or psychosocial problems, but probably not as an intrinsic result of aging. Wasting in the elderly, like in any other population, requires a negative whole-body energy balance. Based on experience in the HIV epidemic, it appears that inadequate intake is the key event in the development of wasting (Macallan et al. 1995). Similarly, elderly nursing home residents who lose weight also have evidence of inadequate dietary energy (and protein) intake (Abbasi and Rudman 1994, Fischer and Johnson 1990).

	THE ROLE OF CACHEXIA IN THE ELDERLY

The elderly are at increased risk for diseases that cause cachexia, such as chronic urinary tract and other infections, decubitus ulcers, and malignancies. As a result, they often develop elevated resting metabolic rates, and accelerated loss of BCM. If untreated, this cachexia can progress to anorexia, decreased intake, and overt wasting as loss of mass from all body compartments develops.

We have examined body composition by bioelectrical impedance (BIA) in 164 nursing home residents (113 women, 53 men, mean ages 81 and 71, respectively), compared to 863 ambulatory participants in the Framingham Heart Study (541 women and 322 men, mean ages 79 and 78) (Roubenoff et al. 1996). Nursing home residents were selected for study by nursing home staff members because of concern about their nutritional status. BIA equations validated in the comparison population were applied. Compared to the ambulatory elderly subjects, nursing home subjects weighed less (Women: BMI 21.6 vs. 26.7 kg/m²; Men: 20.9 vs. 26.9 kg/m², both p < 0.0001), and had substantially lower LBM (Women: 33.9 vs. 38 kg; Men: 44.3 vs. 54.7 kg, both p < 0.0001). Total body water was also substantially lower in the nursing home group (Women: 20.6 vs. 24.2 L; Men: 28.8 vs. 36.4 L, both p < 0.0001).

Clinical estimates of energy needs are traditionally based on the Harris-Benedict equation (HBE), a regression equation that estimates energy needs from body composition based on a sample of several hundred healthy adults under age 50. However, HBE can overestimate resting energy expenditure (REE) if lean body mass is low; or HBE can under-estimate REE if inflammation is present. REE was measured by indirect calorimetry in the 160 elderly nursing home residents described above. Mean REE was significantly higher than expected (1290 ± 388 kcal/d vs. HBE prediction of 1143 ± 237, p < 0.0001). The correlation between HBE and REE was only fair (r = 0.663). REE was classified as Low (<10% below HBE), Normal (within ± 10% of HBE) or High (>10% above HBE): 20% of subjects were Low, 45% Normal, and 35% were High. In the High group, the mean deviation from HBE was +25%; in the Low group it was 13%. On the basis of this small study in chronic care facility residents, we can conclude that 1) cachexia (reduced lean mass and elevated metabolic rate) is common in residents about whom there is staff concern; 2) that dehydration is common among women residents and is associated with hypermetabolism; 3) BIA is a useful method for estimating body composition in the elderly; 4) both hyper- and hypometabolism are common; 5) HBE is a poor estimator of actual REE.

	THE ROLE OF REDUCED PHYSICAL ACTIVITY

The relationship between sarcopenia and wasting remains to be established, but skeletal muscle mass is most responsive to changes in physical activity, so decreasing activity with age may accelerate or even be the cause of sarcopenia, and thus may be most amenable to an exercise intervention (Fiatarone et al. 1994). However, it may well be that the reduced physical activity seen in the elderly is a response to sarcopenia rather than a cause of it, even if sedentariness acts as a positive feedback that accelerates the muscle loss. Some evidence for this hypothesis comes from observations in AIDS wasting, where an early adaptive response to weight loss is reduction in physical activity (Macallan et al. 1995). Similarly, as people become weaker, the proportion of maximal effort (i.e., percent of VO_2max) required to perform daily tasks increases, so that it becomes progressively uncomfortable to perform these tasks, and they are abandoned. While both cardiopulmonary fitness and muscle strength are important determinants of VO_2max, in frail, elderly persons without heart failure or emphysema, the muscle weakness may be more limiting than the aerobic fitness (Shephard 1987). In general, dyspnea occurs at approximately 80% of VO_2max, and people tend to stop doing things that make them short of breath. In an elderly person whose VO_2max is 20 mL/kg/min, 80% of this level is reached with walking a few blocks, thus setting an upper limit on their physical activity. If this person becomes ill, loses muscle mass, and their VO_2max now falls to 16 mL/kg/min, their 80% threshold is now reduced to 13 mL/kg/min, meaning they can only walk inside on level ground. Thus, reduced physical activity follows loss of muscle mass, and then accelerates it by removing the trophic stimulus of walking. The improved survival and reduced disability of elderly athletes who remain physically active suggest that such a vicious cycle is avoidable under some circumstances (Paffenbarger et al. 1986 and 1993).

	RECOGNITION AND TREATMENT

Wasting, at least as defined here, is at the severe end of a spectrum of undernutrition that affects the elderly. By the time wasting occurs, usually as a result of a disease process that reduced dietary intake, it is superimposed on a background of sarcopenia, cachexia, or both. Thus, timely recognition of wasting in the elderly is crucial if we are to intervene successfully. However, such recognition is not easy in the early stages. It is by no means clear at this time how to best diagnose sarcopenia in the elderly, since we do not yet have normative data on the expected change in successfully aging people. Diagnosis of cachexia is also difficult, as it requires both recognition of what is often a subclinical phenomenonhypermetabolism and loss of lean massas well as a thorough evaluation for potential sources of an acute phase response. All too often, subtle signs and symptoms are ignored or misunderstood, so that diagnosis is postponed until overt wasting occurs. Furthermore, although elevated metabolic rate can be diagnosed readily using indirect calorimetry, such an instrument is rarely available in clinical settings. Finally, by the time wasting develops, treatment may be difficult or impossible, depending in part on the underlying conditions that lead to the wasting. In patients with untreatable dementia or malignancy, the level of invasiveness needed to treat wasting, such as feeding tubes or gastrostomies, may be inappropriate. However, there are many elderly residents in nursing homes whose wasting remains untreated out of a therapeutic nihilism that may be unjustified. Thus, a case by case assessment of who should be treated, and with what means, is crucial to the appropriate care of elderly patients with wasting. As our knowledge improves about the contributions to wasting of normal aging as opposed to disease, a more rational approach to wasting in the elderly should become feasible. This would allow us to extend the quality of life for the elderly as well as its duration.

	FOOTNOTES

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