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American Journal of Clinical Nutrition, Vol. 70, No. 2, 183-197, August 1999
© 1999 American Society for Clinical Nutrition

Review Article

Geriatric cachexia: the role of cytokines1,2

Shing-Shing Yeh and Michael W Schuster

1 From the Geriatric Division, Department of Medicine, VA Medical Center Northport, NY; The Weill Medical College of Cornell University, New York; and the New York Presbyterian Hospital, Division of Hematology/Oncology, New York.

2 Address reprint requests to S-S Yeh, Geriatric Division, Department of Medicine, VA Medical Center Northport, 79 Middleville Road, Northport, NY 11768-2290. E-mail: Yeh.Shing_Shing{at}Northport.VA.gov.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 WEIGHT LOSS AND MORBIDITY...
 TREATMENT OF CACHEXIA
 CONCLUSION
 REFERENCES
 
Weight loss in elderly patients is a common clinical problem. Wasting and cachexia are associated with severe physiologic, psychologic, and immunologic consequences, regardless of the underlying causes. Cachexia has been associated with infections, decubitus ulcers, and even death. Multivariate analyses of risk and prognostic factors in community-acquired pneumonia in the elderly have found that age by itself is not a significant factor related to prognosis. Among the significant risk factors, only nutritional status is amenable to medical intervention. Cachexia in the elderly may have profound consequences: medical, cognitive, and psychiatric disorders may diminish self-reliance in activities of daily living, thus reducing quality of life and increasing the frequency of secondary procedures, hospitalizations, and the need for skilled care. Cachexia is associated with higher-than-normal concentrations of tumor necrosis factor {alpha} (TNF-{alpha}), interleukin (IL) 1, IL-6, serotonin, and interferon {gamma}. The role of these proinflammatory cytokines has been established in the cachexia seen in cancer and AIDS patients. Reduction in the concentrations of these cytokines is associated with weight gain. Drugs that promote appetite stimulation and weight gain, such as progestational agents, cyproheptadines, pentoxifylline, and thalidomide may work by down-regulating these proinflammatory cytokines. An understanding of the relation between cachexia and negative regulatory cytokines may point to effective treatment of geriatric cachexia as well.

Key Words: Weight loss • geriatric cachexia • cytokines • metabolism • cytokine inhibitor • appetite stimulants • weight gain • the elderly • interleukins • tumor necrosis factor {alpha} • interferon {gamma}


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
WEIGHT LOSS AND MORBIDITY...
 TREATMENT OF CACHEXIA
 CONCLUSION
 REFERENCES
 
Weight loss in geriatric patients is not unusual. Of nursing home residents, 30–50% have substandard body weight and midarm muscle circumferences, and low serum albumin concentrations (1). Morley and Kraenzle (2) found that 15–21% of 156 nursing home residents had lost >=5 lb (2.3 kg) over 3–6 mo. Wasting and cachexia (3–5) are associated with severe physiologic, psychologic, and immunologic consequences, regardless of the underlying causes. Cachexia has been associated with increased numbers of infections, decubitus ulcers, and even deaths (6–8). Wallace et al (9) reported that involuntary weight loss exceeded 13% in a group of 247 community-residing male veterans >=65 y of age. They also found involuntary weight loss of >4% of body weight to be an important independent predictor of increased mortality (9). Goodwin et al (10), Braun et al (11), and Morley and Silver (12) found that malnutrition may also cause or exacerbate cognitive and mood disorders. Marton et al (13) and Rabinovitz et al (14) found that weight loss and cachexia are even predictive of morbidity and mortality. In the elderly, medical, cognitive, and psychiatric disorders may diminish self-reliance in activities of daily living, thus reducing quality of life and increasing the frequency of secondary procedures, hospitalizations, and the need for skilled nursing care. Adequate weight and nutrition, therefore, are necessary for a good quality of life and for optimal health in nursing home settings.


   WEIGHT LOSS AND MORBIDITY IN THE GERIATRIC POPULATION
TOP
 ABSTRACT
 INTRODUCTION
 WEIGHT LOSS AND MORBIDITY...
TREATMENT OF CACHEXIA
 CONCLUSION
 REFERENCES
 
There is a direct relation between the loss of body weight and morbidity and mortality. Pamuk et al (15) found that weight loss was associated with an increased risk of death in a cohort of US adults. They also found that preexisting illness may influence the association between weight loss and death from noncardiovascular diseases (15). Studies of patients with tuberculosis and a report on starvation in the Warsaw ghetto during World War II showed that there is a critical level beyond which further loss of lean body mass leads to death. Kotler et al (16) found that death is imminent when AIDS patients drop to 66% of their ideal body weight. Graham et al (17). in the Multicenter AIDS Cohort Study, found that the clinical features of HIV infection appear to be closely related to weight loss.

Roberts et al (18) investigated the effects of aging on body energy regulation to determine the causes of unexplained weight loss in older individuals. They found that aging may be associated with impairment in the ability to control food intake after overeating or undereating. Overeating and undereating are part of the normal evolutionary pattern of energy regulation and occur routinely in adaptation to a changing food supply. In the Framingham substudy of the National Health and Nutrition Examination Survey (NHANES; 19), declining energy intake with increasing age was documented, with 16–18% of people >60 y of age consuming <1000 kcal/d (4148 kJ). The Framingham Heart Study (19) found that the relative risk of death is 2 times higher for those >65 y of age and who are at the lower extreme of body mass index. Wallace et al (9) found that for those who had involuntary weight loss of > 4% of body weight (in an outpatient population), 2-y survival rates were <72% and 3-y survival rates were <65%. We also found that the rate of rehospitalizations in our Veterans Administration Medical Center nursing home is high because of weight-loss-related complications (20).

Immunity aspects of cachexia
Recently, interest has focused on the role that the immune system plays in the development of cachexia. Hunger and satiety are regulated by a variety of psychologic, gastrointestinal, metabolic, and nutritional factors, as well as by neuronal and endocrine mechanisms (21). Changes in one or more of these components can result in anorexia. Involuntary weight loss in the elderly is difficult to treat. Many studies have attempted to find the underlying etiology of weight loss by ruling out infection, malignancy, depression, and digestive problems. In the geriatric population, anorexia and cachexia, which lead to diminished host defenses, are often unexplained (22).

Although it is obvious that reduced oral food intake due to anorexia or gastrointestinal obstruction plays an important role in the development of cachexia, progressive weight loss is also a prominent feature of both neoplastic disorders and chronic infections. The diverse nature of these illnesses suggests that the development of cachexia is not dependent on the specific type of infection or a particular neoplasm, but is rather a function of an endogenous mediator responsive to a variety of stimuli. Specifically, Brennan (23) found that cachectic patients often had accelerated mobilization and oxidation of energy substrates and loss of body proteins, which are different from simple starvation without medical complications (Table 1Go). Because patients with clinically well-controlled rheumatoid arthritis do not typically have malabsorption or hepatic or renal disease, it is easy to study nutritional and metabolic variables in them. Roubenoff et al (24) found that body cell mass was 13% lower and that resting energy expenditure was 12% higher in subjects with rheumatoid arthritis than in normal control subjects. Rheumatoid arthritis patients produced more tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin 1ß (IL-1ß), in a manner directly associated with resting energy expenditure, than did normal control subjects even though energy and protein intakes were similar in the 2 groups. Aging is characterized by progressively increasing concentrations of glucocorticoids and catecholamines and decreasing production of growth and sex hormones, a pattern reminiscent of that seen in patients with chronic stress (25).


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  		TABLE 1. Metabolic characteristics of cachexia and wasting compared with simple starvation1
 
Anorexia is a common clinical manifestation of many disease states (26). Investigators hypothesize that chronic production of negative regulatory cytokines can explain the nonspecific responses resulting in cachexia in cancer (27), AIDS, and rheumatoid arthritis (24) patients. Recently, cytokine immunotherapy with genetically engineered substances for viral diseases, cancer, and autoimmune diseases has also provided confirmation of the involvement of cytokines in anorexia. Cytokines are cell-associated proteins produced and secreted by inflammatory cells that have the capacity to act at low concentrations on other cells both locally and systematically via specific cell receptors (28). Cytokines act principally in a paracrine fashion and their concentrations in tissues are often several times higher than those found in the peripheral circulation.

Cytokines involved in cachexia
IL-1, IL-6, TNF-{alpha} (also called cachectin), interferon {gamma} (IFN-{gamma}), leukemia inhibitory factor (D-factor), and prostaglandin E2 (PGE2) have all been implicated in cancer-induced cachexia (29, 30) (Tables 2 and 3GoGo). The possible transfer of these endogenous mediators (cytokines) via the circulation was shown by Norton et al (57). They found that non-tumor-bearing rats developed cachexia after they had operations attaching their blood supply to sarcoma-bearing cachectic rats.


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  		TABLE 2. Cytokines and compounds involved in cachexia1
 

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  		TABLE 3. Gross metabolic effects of cytokines1
 
Cytokines may inhibit feeding by causing not only nausea and vomiting but also by decreasing gastric motility and gastric emptying, intestinal motility, or by modifying gastric acid secretion (Figure 1Go). Appetite regulators in the central feeding and peripheral satiation systems and their interactions are discussed extensively in Morley's review (58). Corticotropin releasing hormone (CRH) is a potent anorexigenic agent that attenuates feeding induced by norepinephrine, dynorphin, and insulin. Serotonin and oxytocin are also anorexigenic agents involved in the central feeding drive (58). Neuropeptide Y and peptide YY are both orexigenic pancreatic polypeptides (59, 60); Levine and Morley (61) and Morley et al (62) found that rats increased their consumption of a high-carbohydrate diet after the administration of either neuropeptide Y or peptide YY. Other gastrointestinal and pancreatic hormones that can produce satiation include bombesin (63), gastrin-related peptide (64), somatostatin (65), amylin (66), and glucagon (67). Cholecystokinin can inhibit food intake via stimulation of the vagus nerve (68) and inhibition of gastric emptying (69). Dynorphin is one of the opioid feeding agents that enhances feeding (70). Nitric oxide is another potent stimulator of food intake that increases the feeding drive centrally and relaxes the smooth muscles in the fundus of the stomach peripherally to accommodate larger quantities of food (71, 72). Uehara et al (73) and Daun and McCarthy (74) found that IL-1–induced anorexia may involve changes in the concentrations of CRH, cholecystokinin, glucagon, and insulin that suppress feeding.



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  		FIGURE 1. Neurotransmitters and hormones involved in appetite regulation. CCK, cholecystokinin; CNTF, ciliary neurotrophic factor; DHEA, dehydroepiandrosterone; E2, estradiol; GRP, gastrin-releasing peptide; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; NOS, nitric oxide synthase; NPY, neuropeptide Y; TNF, tumor necrosis factor.

 
The effects of cytokines may result from direct action on the gastrointestinal system or indirect effects mediated by cytokines (IL-1ß, IL-2, IFN-{gamma}, and TNF) on the central nervous system (75–82) (Figure 2Go). Cytokines can also interact with prostaglandins and CRH to inhibit gastric emptying (78, 79). Cytokine interaction with neuropeptides may induce anorexia. Chance et al (83) found that the hypothalamic concentration and release of neuropeptide Y is reduced in anorectic, tumor-bearing rats. Intracerebroventricular administration of neuropeptide Y, which stimulates eating behavior, can block the anorectic effect induced by IL-1ß in rats (84). This interaction between IL-1ß and neuropeptide Y may have significant clinical implications.



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  		FIGURE 2. Interactions of the appetite regulators with the hypothalamic-pituitary-adrenal axis and cytokines. ACTH, adrenocorticotropin hormone; AVP, arginine vasopressin; CRH, corticotropin releasing hormone; E2, estradiol; GH, growth hormone; IFN, interferon; IL, interleukin; LIF, leukemia inhibitory factor; LPS, lipopolysaccharide; NPY, neuropeptide Y; TNF, tumor necrosis factor; TSH, thyroid-stimulating hormone; C, complement.

 
Cytokines can also modify serotonin and catecholamine pathways in both the central and peripheral nervous systems. Shintani et al (85) found that IL-1ß stimulates the release of serotonin, norepinephrine, and dopamine and their metabolites in plasma which, in turn, suppress food intake. Cytokines may affect the hypothalamic-pituitary-adrenal (HPA) axis (81). Numerous publications have discussed the relations between the appetite regulators, cytokines, and the HPA axis. For example, IL-1 can stimulate the release and production of central CRH under the stimulation of endotoxins. Stress and chronic inflammation can stimulate the release of cortisol and catecholamines, which then stimulate the release of IL-6 and TNF-{alpha} (Figure 2Go). IL-6 and TNF-{alpha} then inhibit gastric emptying (86–97). However, the exact mechanisms are still not well understood.

Cytokines and aging
Aging is characterized by progressively increasing concentrations of glucocorticoids and catecholamines and decreasing production of growth and sex hormones (25). This results in elevated concentrations of proinflammatory cytokines. The cytokines themselves have profound metabolic effects (Tables 4 and 5GoGo).


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  		TABLE 4. Metabolic effects of cytokines1
 

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  		TABLE 5. Cytokine effects on protein, carbohydrate, and lipid metabolism1
 
Tumor necrosis factor {alpha}
TNF-{alpha} was first identified in studies of the weight loss and tissue wasting that accompany chronic disease. Rouzer and Cerami (99) found that when they injected rabbits with the parasite Trypanosoma brucei, the animals developed severe cachexia and lost >=50% of lean body mass within weeks; TNF-{alpha}, a potent anorexigenic agent, was identified as a mediator of cachexia in the study (100). Its effects are mediated both centrally and in the gastrointestinal tract. TNF-{alpha} infusions directly reduce gastric emptying and peristalsis (101). TNF-{alpha} can induce lipolysis and inhibit lipid synthesis (102–106), increase proteolysis in peripheral muscle both in vivo and in vitro (107–112), and can induce the production of IL-1 and IL-6 (113).

Oliff et al (114) devised an animal model using a TNF-producing tumor cell line that constantly produced low concentrations of TNF. When this cell line was transplanted into nude mice, they found that 80% of the animals developed severe, progressive weight loss and ultimately died with the pathologic and histologic characteristics of cancer-induced cachexia. Sherry et al (115) passively immunized C57B1/6 mice (bearing a methylcholanthrene-induced sarcoma that produced TNF) with anti-TNF antibody and were able to significantly reduce weight loss, protein loss, and fat loss. Anker et al (31) found that TNF-{alpha} and norepinephrine concentrations are elevated in cardiac cachexia patients. Cachexia is more closely associated with cytokines and hormonal changes in congestive heart failure than it is with conventional measures of the severity of the congestive heart failure itself. Ikeda et al (32) also found that plasma concentrations of TNF-{alpha} were elevated in patients with congestive heart failure complicated by cachexia, infection, or both but were not elevated in patients with congestive heart failure not complicated by cachexia or infection.

Interleukin 6
To study the role of IL-6 in mediating cancer-induced cachexia, Tisdale (116) used an experimental murine colon adenocarcinoma that induces cachexia with a small tumor burden and without causing hypophagia. He isolated one lipid-metabolizing factor (which turned out to be IL-6) from the tumor. IL-6 has been shown to be involved in muscle protein degradation (41). Strassmann et al (106) reversed the cachectic effect of IL-6 with anti-mouse IL-6 antibody in the same tumor-bearing mice used by Tisdale.

Recently, Papanicolaou (25) moderated a clinical staff conference at the National Institutes of Health that reported on the pathophysiologic roles of IL-6 in human disease. IL-6 is an inflammatory cytokine and is characterized by pleiotropy and redundancy. It is elevated during stress, steroid withdrawal syndrome, severe inflammatory disease (such as rheumatoid arthritis), infections, and traumatic states. Roubenoff et al (41) used elderly Framingham Heart Study participants to determine the association between aging, inflammation, and the cytokines produced by their peripheral blood mononuclear cells. They found that IL-6 concentrations were elevated in their 711 elderly subjects. The elevation in IL-6 concentration correlated well with the concentration of C-reactive protein, a marker of inflammation.

Estrogens and androgens negatively control IL-6. Hager et al (42) and Ershler et al (43) showed that plasma concentrations of IL-6 increase with age, probably as the result of catecholamine hypersecretion and sex-steroid hyposecretion. Cohen et al (44) found that IL-6 concentrations correlated with the functional disability of community-dwelling elderly persons. IL-6 also plays a central role in the pathogenesis of osteoporosis (117–119). Tsigos et al (120) and Papanicolaou et al (121) found that high concentrations of IL-6 can cause fatigue. In fact, exercise-induced exhaustion is highly correlated with the concentration of IL-6. Campbell et al (122) found that marked gliosis occurs in the brains of transgenic animals in which IL-6 is overexpressed in the central nervous system. Perrella et al (40) and Merrill and Chen (123) noted that the concentration of IL-6 in the central nervous systems of their patients correlated with AIDS dementia. Wood et al (124) and Bauer et al (45) found that IL-6 concentrations could be used as indexes of disease severity in patients with Alzheimer disease. Therefore, IL-6 may contribute to the increased morbidity and mortality seen in chronically stressed or physiologically aging persons.

Interferon {gamma}
Matthys et al (125) found that severe cachexia developed rapidly in nude mice inoculated with Chinese hamster ovary tumor cells producing IFN-{gamma}. They also reversed the wasting effect of Lewis lung carcinoma (IFN-{gamma} producing) in mice with a monoclonal anti-IFN-{gamma} antibody (126). IFN-{gamma} can induce IL-1 and IL-2 production but inhibits production of IL-10 and IL-8 by a variety of cells (127). The association between IFN-{gamma} and geriatric cachexia remains unclear, however.

Leukemia inhibitory factor
Mori et al (128) found a cachexia-like syndrome in nude mice bearing melanoma cells that produce leukemia inhibitory factor. It is proposed to be a mediator of cachexia. To date, there have been no studies showing the association of leukemia inhibitory factor with geriatric cachexia.

Interleukin 1
McCarthy et al (129) first observed that IL-1 might be involved in suppression of food intake during infection. Otterness et al (130) and Mrosovsky et al (131) confirmed the cachexia-causing effects of IL-1 when it is administrated to experimental animals. They also found that tolerance to these anorexigenic effects develops after several days of continuous administration of IL-1 in rats. Many of the metabolic disturbances associated with IL-1 are similar to those of TNF. For example, IL-1 stimulates hepatic fatty acid synthesis, triacylglycerol secretion, and lipolysis, and reduces lipoprotein lipase activity (132–134). Liao et al (38) found that IL-1 concentrations were significantly elevated in healthy, ambulatory, elderly subjects with cachexia of unknown etiology. Cederholm et al (39) investigated cachectic, afebrile elderly patients for evidence of cancer and acute infection and found increased production of IL-1ß and IL-6 concentrations without any evidence of acute infection or cancer. Therefore, IL-6 and IL-1ß may play roles in the cachexia of those geriatric patients with nonmalignant chronic diseases.

Other substances that are involved in cachexia
Serotonin
Serotonin has a broad spectrum of biological activities. It plays a role in appetite stimulation as well as in emesis (either chemotherapy induced or non-chemotherapy related). It was also shown to play a role in the immune regulation of T lymphocyte function both in vitro and in vivo. Several experimental findings support a role for serotonin in the regulation of feeding. Leibowitz (135) and Cangiano et al (136) found that the hypothalamus contains a large number of serotonergic fibers and that pharmacologically induced variations in brain serotonin concentrations or serotonergic activity result in the fluctuation of appetite. In fact, 2 common agents used as appetite suppressants for the treatment of obesity modulate pathways mediated by serotonin (D-fenfluramine) or by catecholamine (phenylpropanolamine) (137, 138). Sibutramine (an antiobesity agent) is a norepinephrine and serotonin reuptake inhibitor. It can elevate serotonin concentrations, reduce appetite, and cause weight loss (139). Schechter (140) found that seroto-nergic agents such as lysergic acid diethylamide can be used as dose-responsive appetite suppressants similar to norfenfluramine (another antiobesity medication). Martinez et al (48) found the concentration of the serotonin metabolite hydroxyindole acetic acid in cerebrospinal fluid to be elevated in elderly cachectic and anorexic patients suffering from weight loss.

Prostaglandin E2
Prostaglandins, especially PGE2, are involved with many biological activities related to cachexia. Both IL-1 and TNF can stimulate PGE2 production in macrophages, fibroblasts, and endothelial cells (33, 53, 141). Indomethacin (a prostaglandin synthesis inhibitor) can reverse the pyretic effect mediated by IL-1, probably by decreasing the production of PGE2 (142). Callery et al (143) also reported that PGE2 can regulate IL-6 production. n-3 Fatty acids, which interfere with prostaglandin substrate availability, reduce PGE2 production and can reduce the production of IL-1 and TNF and, thus, reverse cachexia. Use of PGE2 analogues in NMRI mice can produce cachexia by hypophagia (141), which is similar to the effect of administering TNF. Indomethacin was found to increase food intake and survival and to preserve body composition in carcinoma-bearing mice without affecting the production of acute phase proteins or the protein content of the liver (144, 145). However, Mahony and Tisdale (53) found that the chronic infusion of TNF-{alpha} enhanced PGE2 production but did not produce cachexia.

Leptin
Leptin is a recently identified obese (ob) gene product that plays a central role in energy regulation, food intake, and maintenance of total body fat mass (146, 147). In Sinha and Caro's (148) review of the clinical aspects of leptin, they point out that although hyperleptinemia is an essential feature of human obesity, only in insulin-sensitive individuals do basal concentrations of insulin and leptin correlate positively. There is great heterogeneity in leptin concentrations in the obese population; {approx}5% of the obese population is relatively leptin deficient. Cerebrospinal fluid leptin concentrations are only modestly elevated in these obese subjects. Peskind et al (149) found that serum leptin concentrations were proportional to body mass index. There may be defective leptin signaling or impaired affector systems in obese, leptin-resistant individuals.

Independent of adiposity, leptin concentrations are higher in woman than in men, and this sexual dimorphism is also present in adolescent children (148). Leptin concentrations decline slightly in older women (50). Concentrations increase under stress, such as hip replacement surgery (51), but are low in malnourished older men (52). Sih et al (150) and Urban et al (151) measured increases in muscle strength and decreases in leptin concentrations after testosterone replacement in elderly men. Schols et al (49) found that the afferent part of the leptin feedback mechanism functions normally and that elevated leptin concentrations are not involved in the development of lung cancer cachexia. Because lower plasma leptin was not associated with an increased appetite and decreased energy expenditure in these lung cancer patients, disturbances in the hypothalamic part of the feedback mechanism or release of proinflammatory cytokines may be the cause of their cachexia. Sarraf et al (152) reported that TNF, IL-1, and leukemia inhibitory factor could produce prompt, dose-dependent increases in serum leptin concentrations and increase the basal metabolic rate, causing anorexia and weight loss in mice. IL-10, IL-4, and IL-2 have no effect on leptin gene expression or concentrations, and thus have no anorexic effect. Cytokine induction of leptin may, therefore, play a role in the cachexia and anorexia of inflammatory diseases.

Lipid-mobilizing factors
Groundwater et al (54) found lipid-mobilizing factors in the sera of cancer patients; the concentration was proportional to the extent of weight loss, and was reduced with chemotherapy (153). Lipid-mobilizing factors act on adipose tissue to release fatty acids and glycerol, as do lipolytic hormones (154). Beck et al (155, 156) and Smith and Tisdale (157) found lipid-mobilizing factors concentrations to be lower or undetectable in normal subjects and in cancer patients without cachexia. The association of lipid-mobilizing factors with geriatric cachexia is not clear.

Protein-mobilizing factors
Todorov et al (55, 56) found protein-mobilizing factors in the sera of humans and animals with cancer-induced cachexia, which are associated with loss of skeletal muscle mass (55, 56, 158). They also found that protein-mobilizing factors could not be detected in those cancer patients without cachexia or in normal subjects (159). The association of protein-mobilizing factors with geriatric cachexia is not clear.

Cytokines and their interactions
Cytokines rarely act alone because they stimulate a variety of cell types to produce and secrete a cascade of other cytokines (49). There are also so-called "counter-proinflammatory cytokines" that dampen the effects of proinflammatory cytokines. These cytokines are produced in response to other secreted cytokines and function synergistically to induce various responses (Figure 3Go). IL-10 and IL-4 are regulatory cytokines that can inhibit the release and function of IL-1, TNF-{alpha}, IL-6, and IL-8 (160–163). Fujiki et al (164) used IL-10 gene transfer in the mouse model of cachexia (animals with an adenocarcinoma) and found that this can increase serum IL-10 concentrations, thereby decreasing IL-6 concentrations and retarding further weight loss and hypophagia. Drazan et al (165) found that IL-10 gene therapy with viral vectors could inhibit TNF-{alpha} and IL-1ß production, thus preventing endotoxemic sepsis in mice.



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  		FIGURE 3. Cytokines and their interactions. IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; PGE2, prostaglandin E2.

 
PGE2 can augment secretion of IL-6 and IL-10, but it cannot induce IL-6 and IL-10 secretion alone. IL-10 can, in turn, down-regulate production of IL-6 and PGE2 (166). IL-1 and TNF have been shown to interfere with tryptophan and serotonin turnover (85). IL-1 may then participate in serotonin-induced anorexia. The exact relations and feedback mechanisms among all of these cytokines, serotonin, leptin, and PGE2, however, remain unclear.

Chyczewska and Mroz (167) pointed out that IFN-{gamma} can work in cooperation with TNF-{alpha} and IL-1 to inhibit proliferation of tumor cells. IFN-{gamma} can work synergistically with IL-2 to induce cytotoxicity of natural killer cells. IFN-{gamma}, TNF-{alpha}, and IL-1 can activate mononuclear phagocytes and through B lymphocyte stimulation augment lysis of cancer cells. IL-1 stimulates the necrotizing activity of TNF-{alpha} and augments cachexia by catabolism of lipids. IL-2, IL-6, and IL-12 induce natural killer cell and lymphocyte-activated killer cell cytotoxicity. IL-12 inhibits metastasis formation. IL-10, by inhibiting synthesis of cytokines, may lead to tumor development.

All of these interactions point to the complex roles of cytokines in causing cachexia. A pool of anti-cytokine antibodies or more globally acting cytokine inhibitors might, therefore, be used as a potential intervention strategy for the treatment of cachexia. But this approach may induce immunosuppression and increase the risk of infection or tumor development.


   TREATMENT OF CACHEXIA
TOP
 ABSTRACT
 INTRODUCTION
 WEIGHT LOSS AND MORBIDITY...
 TREATMENT OF CACHEXIA
CONCLUSION
 REFERENCES
 
Treating malnutrition and weight loss can help to ameliorate many medical conditions. Rehabilitation time after hip fractures has been shown to decrease with nutritional supplementation (168). In hospitalized geriatric patients, nutritional supplementation resulted in improved serum proteins, improved nutritional status, and reduced mortality (169). In a subset of geriatric inpatients, low serum albumin concentrations with weight loss predicts those patients at highest risk of death during the subsequent 2 y (170). Riquelme et al (171) performed a multivariate analysis of risk and prognostic factors in community-acquired pneumonia in the elderly and found that age by itself was not a significant factor related to prognosis. Among the significant risk factors, only nutritional status is amenable to medical intervention. Understanding the pathophysiology of geriatric cachexia will help guide the use of safe and effective nutritional interventions. However, nonselective nutritional support with total parenteral nutrition or percutaneous endoscopic gastrostomy tube insertion with associated complications has failed to provide a benefit. Most malnourished geriatric patients undergo tube feeding, which has a high rate of complications and questionable efficacy.

The effects of nutritional support on the prevention and treatment of cancer and AIDS cachexia have been investigated extensively (72, 172). An understanding of the role of cytokines in mediating cachexia in those diseases may also provide a possible new mode of nutritional therapy and pharmacotherapy for the treatment of geriatric cachexia.

TNF-{alpha} is elevated in patients with advanced HIV infection or those with opportunistic infections, and there is a correlation with the development of wasting (34–37). Pharmacologic manipulation of TNF-{alpha} regulation has been proposed as a means of stabilizing or reversing the wasting process (Table 6Go).


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  		TABLE 6. Treatment agents for geriatric cachexia
 
Pentoxifylline
Pentoxifylline decreases TNF-{alpha} production by suppressing TNF-{alpha} messenger RNA transcription (173). Landman et al (174) treated 5 wasting, HIV-infected patients with pentoxifylline and found no evidence of weight gain after 6 wk of treatment. The treatment may have even had an adverse effect on the natural history of the patients' opportunistic infections. Sathe et al (175) found that pentoxifylline treatment impaired TNF-{alpha} secretion and thereby increased the mycobacterial load in macrophages from AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection. The drug has not been used in a geriatric population.

Thalidomide
Thalidomide decreases TNF-{alpha} production by increasing degradation of TNF-{alpha} messenger RNA (176). Reyes-Teran et al (177) performed a double-blind, placebo-controlled study with thalidomide in 23 HIV-infected patients with wasting and found a significant weight gain and improved Karnovsky scores in the treatment group; there was no significant change in viral load or absolute CD4+ cell counts. Twenty-nine percent of the treatment group developed a rash. Other well-known side effects are peripheral neuropathy and teratogenicity. Vivid memories of thalidomide babies born several decades ago make it very difficult to revive this medication. Nonetheless, further studies with HIV-infected patients are ongoing. This drug has not been used yet in a geriatric population.

Megestrol acetate
Megestrol acetate is a synthetic derivative of a naturally occurring progestational agent that is similar to progesterone. Megestrol acetate treatment of patients with cancer increases appetite and nonfluid weight gain in a dose-dependent manner and is well tolerated in patients with advanced malignant diseases (178–189). Oster et al (190) and Von Roenn et al (191) found that treating patients with megestrol acetate for AIDS-related anorexia and cachexia not only increased weight but also improved body image, sense of well-being, and pleasure from eating. The Food and Drug Administration has approved the use of megestrol acetate for the treatment of anorexia, cachexia, and unexplained, significant weight loss in patients with AIDS.

Although the mechanism by which megestrol acetate promotes weight gain is unknown, Hamburger et al (192) suggested that it either blocks TNF or reverses TNF effects by affecting adipocyte differentiation. Reitmeier and Hartenstein (193) found that megestrol acetate increases body weight by increasing fat mass and body cell mass rather than by increasing fluid retention. Beck and Tisdale (194) reported that the weight gain associated with megestrol acetate could be blocked by cotreatment with TNF-{alpha} in NMRI mice.

Castle et al (46) reported results from a pilot trial (4 patients), in which an oral suspension of megestrol acetate was used to treat geriatric cachexia and anorexia. Although the study size was small, 2 of the patients gained weight. Those with the highest IL-6 concentrations showed the greatest weight gain in response to the treatment; a result similar to that seen in cachectic HIV-infected patients (17).

It makes sense that progesterone plays an important role in nutritional status. Lapp et al (195) found, for example, that higher progesterone concentrations are common in late pregnancy, resulting in IL-6 concentrations that are 40–50% of those of control subjects.

McMillan et al (196) treated cachectic advanced gastrointestinal cancer patients with megestrol acetate and ibuprofen for 6 wk and found weight gain and reductions in C-reactive protein concentrations. Mantovani et al (197) found that cancer patients' appetite, weight, and sense of well-being improved with meges-trol acetate. They also found that these patients' cytokine concentrations decreased with megestrol acetate treatment but not with chemotherapy alone. Mantovani et al (47) also found that medroxyprogesterone acetate reduces the in vitro production of certain cytokines (IL-1, IL-6, TNF-{alpha}, and serotonin) by peripheral mononuclear cells of cancer patients. All of these cytokines are involved in anorexia, cachexia, and emesis. Because this study looked at only 9 patients and the production of cytokines was only examined in vitro, further work will be needed to confirm the results. McCarthy et al (198) found that megestrol acetate stimulated food and water intake, and that the effect may involve neuropeptide Y. In another animal study, Costa et al (199) showed that megestrol acetate stimulation of appetite might involve the calcium channels in the ventromedial hypothalamus.

Although prolonged use of the drug appears to be safe, there are reports of long-term administration of megestrol acetate that may have induced secondary adrenal suppression and adrenal insufficiency (200). Short-term administration (12 wk) of meges-trol acetate in a preliminary pilot study of geriatric nursing home residents with cachexia (n = 69) revealed the drug to be safe without apparent evidence of adrenal suppression.

Anabolic agents
The use of anabolic drugs such as methyltestosterone, oxandrolone, and stanozolol is currently being explored in clinical trials with cachectic AIDS patients. Chlebowski et al (201) found that nandrolone decanoate can decrease the weight loss of patients suffering from advanced non–small cell lung cancer. The main side effects were masculinization, fluid retention, and hepatic toxicity. However, the efficacy in geriatric patients is unknown. In elderly men, an additional problem associated with the use of testosterone-like drugs might be the exacerbation of prostate cancer, which would limit its use in this population. However, Morley et al (202) were able to give testosterone safely to older men with hypogonadism and noted an increase in their upper-arm strength.

Growth hormone and insulin-like growth factor I
The use of recombinant human growth hormone in elderly patients with a low somatomedin C or insulin-like growth factor (IGF) concentration is still under investigation. Reports from Kaiser et al (203) showed that this very expensive form of therapy led to nitrogen retention and weight gain in malnourished older patients. Preliminary reports from Schambelan et al (204) and Lieberman et al (205) of results in AIDS patients have all been positive as well. Peripheral edema, hyperglycemia, carpal tunnel syndrome, and gynecomastia were the major adverse effects. The effects of growth hormone may be mediated through IGF-I. Results of treatment with IGF-I alone, however, have been uneven (206). The combination of growth hormone and IGF-I did not result in consistent appetite stimulation (206). The Food and Drug Administration recently granted accelerated approval for a form of human growth hormone to treat AIDS wasting. There are small trials under way now in geriatric populations.

Dronabinol
The use of dronabinol (a cannabinoid derivative) in the HIV-infected population was reported anecdotally by Gorter et al (207) to lead to weight gain and appetite stimulation. The side effects were mainly sedation and hallucinations (208). It was recently approved by the Food and Drug Administration as an appetite stimulant and antiemetic in patients with HIV infection. Stelly et al (209) found that dronabinol treatment increased body weight in Alzheimer disease patients. The main side effects were euphoria, somnolence, and fatigue. However, other side effects such as sedation, dizziness, and hallucinations make this drug less than ideally suited for the geriatric population.

n -3 Fatty acids
n-3 Fatty acids, mainly from fish oils, interfere with cyclooxygenase (in PGE2 production) and lipooxygenase metabolic pathways. They also inhibit cytokine synthesis and activity (210). Dinarello et al (211) and Endres et al (212) found that n-3 fatty acids improved food intake in rats with IL-1–induced anorexia. Tisdale and Dhesi (213) also found that n-3 fatty acids can stop weight loss in an experimental cachexia model. The potential role of n-3 fatty acids in the treatment of cachexia is promising and is still under investigation in cancer and HIV-infected patients.

Glutamine
Glutamine is the most abundant amino acid in the body. It is important for maintaining healthy immune status, protein metabolism, and gastrointestinal mucosal integrity (214, 215). Tumors can deplete the body of glutamine, thereby reducing immune status and causing cachexia (216). But because glutamine is an essential nutrient for cell growth, exogenous supplements of this substance might be used by rapidly growing tumor cells in patients with cancer. This, in turn, may lead to increased concentrations of proinflammatory cytokines that may cause cachexia (217, 218). The efficacy of glutamine in treating geriatric cachexia is unknown.

Branched-chain amino acids
Other attempts at improving appetite through the use of nutritional substrates such as branched-chain amino acids, which have been used in total parenteral nutrition, are still under investigation. Branched-chain amino acids can compete with tryptophan (the precursor of serotonin in the central nervous system), thus reducing serotonin production and increasing food intake (219). Once again, the efficacy of this substance in the geriatric population is unknown.

Cyproheptadine
Cyproheptadine is an antihistamine and antiserotonergic reagent. Cyproheptadine is effective in treating selected groups of children with anorexia and reportedly affects central appetite centers. However, the results of clinical trials in cancer patients have been disappointing (220). The side effects of sedation and dizziness make this drug less likely to be used in the geriatric population. Its efficacy in the geriatric population is unproved despite its wide use in treating cachexia.

Hydrazine sulfate
Hydrazine sulfate is an inhibitor of gluconeogenesis. Clinical trials in cancer patients, however, have failed to show a benefit in cancer-induced cachexia (221, 222). Its efficacy in the geriatric population has not been studied.

Ornithine oxoglutarine
Brocker et al (223) at 2 centers randomly assigned 194 elderly patients to ornithine oxoglutarine or placebo and noted improved appetite and weight gain with treatment. The drug works by increasing amino acid and insulin concentrations and, therefore, a major side effect could be hypoglycemia.

N-Acetylcysteine
N-Acetylcysteine is effective in replenishing depleted glutathione concentrations and can regulate concentrations of proinflammatory cytokines such as TNF, IL-1, and IL-6 (224). Therefore, it may have potential for clinical use in the treatment of cachexia.

Melatonin
Melatonin down-regulates TNF concentrations. In a randomized trial of 100 patients with metastatic cancer, Lissoni et al (225) showed that melatonin given at a dose of 20 mg orally every evening resulted in a significant decrease in TNF concentrations in treated patients compared with the placebo group (P < 0.05). Of even more interest was the fact that the melatonin-treated patients had significantly less weight loss. Its use in geriatric cachexia has not been studied.

Creatine
Creatine is a physiologically active substance required for muscle contraction. The proper amount of creatine phosphate in the muscle allows high rates of adenosine triphosphate resynthesis. Therefore, it plays a vital role in the performance of high-intensity exercise. Creatine supplementation has been shown to increase performance in situations in which the availability of creatine phosphate is important (226–228). Short-term creatine supplementation appears to increase body mass in young males, although the initial increase is most likely water. Chronic creatine supplementation, in conjunction with physical training involving resistance exercise, may increase lean body mass (229). Its use in geriatric cachexia has not yet been studied.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 WEIGHT LOSS AND MORBIDITY...
 TREATMENT OF CACHEXIA
 CONCLUSION
REFERENCES
 
Weight loss is a major problem in the geriatric population that increases mortality. Feelings of well-being and the pleasure derived from eating positively affect the quality of older individuals' lives. The connection between eating and good health has been understood for hundreds of years and transcends all cultures. Furthermore, it is understood that when elderly people stop eating, their death is imminent. For many years, this problem was largely ignored because of our lack of understanding of its pathophysiology and our inability to treat it. Now that the role of proinflammatory cytokines in mediating cancer and HIV-induced cachexia is better understood, we may have an explanation for the geriatric wasting syndrome as well.

The relation between geriatric cachexia and increased concentrations of negative regulatory cytokines may lead us to an important understanding and a possible treatment for the phenomenon. Several cytokines stimulate the same response when induced. Overlapping physiologic activities make it unlikely that a single substance is the sole cause of cachexia. The potential involvement of IL-6, TNF-{alpha}, IL-1, serotonin, PGE2, and other cytokines (IL-10 and IL-4) in the pathophysiology of aging, chronic diseases, and wasting calls for research on ways to suppress their secretion, dysregulation, or effects.

Cytokine antibodies have been given to try to reverse cancer-induced cachexia in animal models with some success. These studies showed improvement in food intake, but no single antibody alone was able to reverse all the changes seen in the tumor-bearing state. Combination studies such as those that combine a PGE2 inhibitor with cytokine antibody or IL-10 gene transfer and IL-6 antibody have shown augmentation of the anticachectic effect. Further investigation, with specific nutritional manipulations, the administration of specific steroids or progestational agents such as megestrol acetate, and the administration of neuropeptides and peptide hormones, are promising. Further research will be needed to fully evaluate the safety and efficacy of these interventions and to determine what their effect is in the treatment of geriatric cachexia.


   ACKNOWLEDGMENTS
 
We thank Gaylord Hoffert, Marie Higgins, Michelle Dellavecchia, Kathy Kessel, and Rebecca Womble for technical contributions and administrative support.


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