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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:M511-M518 (2002)
© 2002 The Gerontological Society of America

Molecular-Based Therapeutic Approaches in Treatment of Anorexia of Aging and Cancer Cachexia

David Hamermana

a Resnick Gerontology Center, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

David Hamerman, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467 E-mail: Hamermandj{at}aol.com.


   Abstract
Top
 Abstract
Anorexia of Aging
 Caloric Restriction
 Cancer Cachexia
 Conclusion
 References
 
Loss of appetite, or anorexia, has profound implications for older persons, altering social interactions, reducing quality of life, and leading to weight loss with grave health consequences. Two conditions associated with anorexia considered in this article are the multidetermined anorexia of aging and the wasting syndrome termed cachexia induced by cancer. Nutritional interventions may have some benefit in the former, but are of limited value in the latter. Emerging studies at the molecular level relating to appetite regulation and energy balance may offer new approaches to arrest progressive weight loss in the anorexia of aging and cancer cachexia.

"There is immense anguish with the loss of appetite" (1).

THIS article was initially derived from a chapter on cancer cachexia I wrote more than a year ago as part of the third edition of a text on comprehensive geriatric oncology (in preparation). A number of dysregulated metabolic pathways are understood in cancer cachexia, and it seemed to me that an emerging understanding of these pathways at the molecular level might offer opportunities for therapeutic interventions to arrest the cachexia despite cancer persistence. After submission of the article to the Journal of Gerontology: Medical Sciences, editorial review suggested expanding the article to include comparison with what is known concerning the anorexia of aging.

The editorial request for this modification posed a significant challenge for me. In the first place, the anorexia of aging (2)(3)(4)(5)(6), with the sense of progression to unintentional weight loss (7), reflected a myriad of predisposing conditions—diseases and psychological, physiological, social, and environmental factors (8)(9). A second concern arose from a broader context relating to "wasting and cachexia" (10)(11) in aging and geriatric syndromes (12)(13), but also in a more unrelenting form with cancer, the "ultimate insult to the natural order" ((14), p. 68). Therapeutic interventions for the anorexia of aging with weight loss can potentially address many of the predisposing conditions, and possibly halt or even reverse the process (e.g., treatment of basic contributory factors and appropriate nutritional supplementation) (8)(9)(15)(16)(17). However, nutritional intervention (18) and supplementation appear to be without benefit in relieving the cachexia of persistent cancer (19)(20)(21)(22). Nevertheless, it seemed possible to compare and consider therapies for both syndromes based on a discussion of underlying causes of appetite diminution and weight loss.


   Anorexia of Aging
Top
 Abstract
 Anorexia of Aging
Caloric Restriction
 Cancer Cachexia
 Conclusion
 References
 
Whether anorexia of aging progresses to a profound state of weight loss, malnutrition (23), and the visible appearance of cachexia depends, of course, on the duration of loss of appetite and weight, on contributing conditions, and on the outcome of interventions. Even weight loss of 5% in older persons reflects poor health, hospitalization, and a higher rate of mortality, so clinical assessment of anorexia of aging must be taken seriously (24). Profound weight loss (i.e., more than 10% of body weight within a period of 6 to 12 months) may be encountered in up to 13% of elderly outpatients and in much higher frequency (up to 50–65%) in nursing home residents (7)(25). Weight loss without apparent underlying cause(s) implies that one has not been found either because there has been a choice not to explore possible causes, as may be the case in some frail individuals (26) who have taken to bed (27), or because comprehensive studies have failed to turn up a contributory cause (7).

The basis for a "physiologic" diminution of appetite and subsequent weight loss in older persons is complex and arises from multiple determinants. Perhaps at the outset, the spectrum of palatability—or the hedonic (pleasurable) qualities of food—may be diminished (4). Changes in perceptions of taste and smell lead to dietary deficiencies. Anorexia associated with deficiencies in zinc or magnesium may prevail in a number of clinical conditions (28)(29). Satiety signals (Fig. 1), principally cholecystokinin, released when food enters the stomach and duodenum, may be enhanced with aging and delay gastric emptying (30). Aging may impair production of nitric oxide synthase, and, with diminished nitric oxide formation, gastric emptying may be delayed (4)(5). So-called adiposity signals—leptin arising from peripheral adipose tissues, and insulin from ß cells of the pancreas—induce multiple hypothalamic responses involving systems of appetite suppression (anorexigens) or stimulation (orexigens) (Fig. 1). While leptin has multiple physiological roles (31), it is one of the prime regulators of food intake and other metabolic responses (32)(33)(34)(35)(36). Morley has linked decline in testosterone in aging males with an increase in leptin levels (37)(38), thus promoting hypothalamic anorexigens. Indeed, low testosterone levels in hypogonadal men were associated with elevated leptin (39). However, over the long term of an energy-restricted diet and loss of adiposity with weight reduction, leptin levels are likely to be lower (40).



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  		Figure 1. Summary of adiposity and satiety signals that regulate appetite through CNS effectors (see text for discussion). In a state of increasing adiposity, higher levels of insulin (secreted from the endocrine pancreas in proportion to fat mass) and leptin (from adipocytes) constitute adiposity signals that turn on the catabolic effector systems, reduce appetite, increase energy expenditure, and turn off the anabolic systems. The converse occurs in a state of diminishing adiposity: the levels of the signals fall, the anabolic pathways are turned on, appetite increases, energy expenditure diminishes, and the catabolic systems are turned off. The hypothalamus is the major site for these systems. Satiety signals arise from food in the gastrointestinal tract by way of CCK and GLP, which convey messages to the nucleus of the solitary tract. AgRP = agouti-related protein; CART = cocaine and amphetamine-regulated transcript; CCK = cholecystokinin; CNS = central nervous system; GLP = glucagon-like peptide; MC = melanocortin; MCH = melanin concentrating hormone; {alpha}MSH = {alpha}-melanocyte stimulating hormone; NPY = neuropeptide Y; ORX = orexin. Adapted from Woods SC, Seeley RJ. Adiposity signals and the control of energy homeostasis. Nutrition. 2000;16:894–902. Reprinted with the permission of Balducci L, ed. Comprehensive Geriatric Oncology, 3rd ed., in preparation.

 
In community-dwelling older persons without discernable disease, increases in serum levels of the cytokine interleukin-6 (IL-6) were associated with functional decline (41). The concept of cytokines as contributory to anorexia (10)(42), especially IL-6 and tumor necrosis factor {alpha} (TNF-{alpha}), assumes great importance, for not only do these cytokines modulate appetite loss, they are also interactive with and may suppress hypothalamic orexigens (43). For example, ciliary neutrophic factor (CNTF)—a member of the IL-6 superfamily—reduces the appetite enhancer hypothalamic neuropeptide Y (NPY) (44)(45).

The anorexia of aging imposes an acceleration of two key, inevitable processes of structural loss that occur with advancing age in muscle and bone, termed sarcopenia and osteopenia, respectively (46)(47)(48)(49)(50)(51). Multiple conditions predispose to loss of muscle and bone mineral: dietary deficiencies with malnutrition, diminished anabolic stimuli to muscle and bone as a result of "hormonal aging" (3)(52) and andropause in men (53), and enhanced catabolic cytokine pathways (49)(50). Interesting differences in sex hormones between men and women contribute to muscle weakness and decline in activities of daily living (49)(54)(55), and in postmenopausal women, sarcopenia with reduced physical activity diminishes bone mineral density (47). Indeed, the central place of exercise as a nonpharmacologic means to reverse aging changes in muscle and bone deserves emphasis (48)(54)(56).


   Caloric Restriction
Top
 Abstract
 Anorexia of Aging
 Caloric Restriction
Cancer Cachexia
 Conclusion
 References
 
The status of experimental caloric restriction (CR) must be considered in the spectrum of physiologically driven anorexia of aging and cancer cachexia. CR is primarily a laboratory-based phenomenon, yet it is of great current interest because weight loss under controlled dietary conditions with restriction of energy intake and expenditure produces metabolic adaptation and stability (34). Unlike anorexia of aging or cancer cachexia, CR has long-term beneficial effects on the rodent and nonhuman primate populations studied in the laboratory (57)(58)(59)(60)(61). Indeed, among various intervention strategies, CR has been the most powerful modulator of the "vicious spiral" ((62), p. 1606) of aging processes (57)(60)(63)(64)(65)(66).

Evolutionary considerations have linked CR to a shift from physiologically costly energy processes, such as reproduction and body growth, to those processes essential for survival and endurance in response to food shortage—a diversion whereby underlying molecular mechanisms extend the life span (34)(67)(68). It is also important to note that this longevity is attained with reduction in manifestations of aging-related pathologies (66). Among the "antiaging" and/or "antidisease" effects are lower plasma glucose and insulin levels with greater insulin sensitivity; lower body temperature; reduced cholesterol and triglycerides and elevated high-density lipoprotein levels; lower blood pressure; and reduced spontaneous growth of tumors (57)(69). The substantial decrease in fat mass—especially decline in visceral obesity (35)(70)—may explain sustained effects related to decrease in fat-derived proinflammatory mediators, including plasma levels of peptides, cytokines, and complement factors (33)(65); lower leptin levels contribute to a shift to enzymes for fatty acid utilization via activation of peroxisome proliferator-activated receptor (PPAR{alpha}) (34). CR in monkeys may also reduce aging-related transcripts involved in inflammation and oxidative stress, upregulate cytoskeletal protein-encoding genes, and decrease expression of genes involved in mitochondrial bioenergetics (61)(64). Thus, the themes running through the laboratory phenomena of reduced caloric intake and loss of body weight are an environmental adaptation with longer life; reductions in disease, stress (61)(63), and immunosenescence (66); and improved "metabolic efficiency" (63) related to adjustments of proteolytic and mitochondrial systems (61)(64)(71).

It might be of interest to ask why the physiologic anorexia of aging in humans does not reproduce the apparent health benefits of CR. There may be a number of reasons. First, older human subjects have not engaged in CR in the earlier decades, and when the anorexia of aging occurs, it is engrafted on accumulated, adverse metabolic conditions and organ-related impairments. Second, CR in the laboratory imposes a balanced nutrient intake while anorexia of aging in humans is almost certain to be deficient in essential nutrients, as noted above. And third, those with late-life anorexia of aging often contend with contributory social, emotional, and economic burdens that modify quality of life and do not pertain in caloric-restricted laboratory animals. It is certainly not clear what the appropriate CR model should be in humans (61)(72). Nevertheless, the human application of CR as therapy may be considered in two examples of short-term, controlled studies. In one, persons with type 2 diabetes given a very low-calorie diet lost weight and achieved better glycemic control and normalization of hemoglobin A1c (73). In another study, diet-restricted obese women in a 40-week program lost weight (74). There are certainly many more examples of human application of diet restriction for therapeutic purposes (61)(75)(76). But as Roth and colleagues point out in considering more widespread approaches to the clinical practice of CR, "it is unlikely that most humans would be willing to maintain a 30% reduced diet for the bulk of their adult lives" ((57), p. 305). Agents that mimic CR, called "CR mimetics" (61), might elicit the same beneficial effects of CR without the necessity of dieting; one study focused on 2-deoxyglucose, a sugar analog with a limited metabolism that actually reduces glucose/energy flux without decreasing food intake in rats (57). This may be an instance of having your cake and eating it, too! Others have considered "candidate substrates and proteins" that may decrease fat stores (35)(65), wherein a large genetic and endocrine reservoir resides (33)(70)(77)(78)(79), or agents with "hormetic" or stress-reducing properties that promote loss of body weight through a variety of metabolic, genetic, energetic, or pharmacologic means (60)(80).


   Cancer Cachexia
Top
 Abstract
 Anorexia of Aging
 Caloric Restriction
 Cancer Cachexia
Conclusion
 References
 
Cancer cachexia encompasses many of the associations of the anorexia of aging—early satiety, appetite loss, weakness, and the cardinal feature of emaciation (81)(82). The end-stage of profound weight loss in cancer-induced cachexia, however, is likely to be a unique syndrome based on specific causative factors. Certainly, in cancer cachexia, there is a range of operative metabolic responses triggered by the immunologic and inflammatory (83)(84) responses of the host to the tumor, conditions that do not prevail in the same way in the uncomplicated anorexia of aging. The metabolic conditions observed in cancer cachexia include hyperglycemia, insulin resistance, increased basal energy expenditure, decreased lipoprotein lipase, lipidemia, and proteolysis of muscle (20)(22)(85)(86)(87)(88). In addition, there appears to be stress and cytokine-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, with increased circulating glucocorticoids (89)(90).

The suggestion in this section that the progressive wasting syndrome of cancer cachexia might be arrested despite persistence of cancer is based on considerations of therapies arising in principle or practice from newer molecular-based research relating to appetite regulation and metabolic controls. Such potential approaches go beyond current and traditional therapies to enhance nutrition, which has been widely used to treat cachexia in cancer patients, with limited success, as noted above (18)(19)(20)(91). It is important to bear in mind that often the basis for death in cancer cachexia is the profound loss of body weight itself rather than the cancer per se. Body weight at death in wasting states can be extrapolated to be 66% of ideal body weight (11), and weight loss itself in frail older persons is associated with mortality (24), as noted.

The question that arises at the outset, however, is whether even temporary arrest of cachexia can be achieved when the cancer is persistent (92). As Barber and colleagues put it, "the best way to treat cancer cachexia is to cure the cancer" ((93), p. 683). Yet a clue that some long-term amelioration of anorexia and cachexia may occur even with persistence of the cancer caught my attention from the unlikely source of "unconventional" approaches to treat patients with advanced cancer—especially pancreatic cancer. An account in The New Yorker entitled "The Outlaw Doctor" reported the apparent prolongation of life in many patients on a regime developed by Nicholas Gonzales, MD. Therapies consisted of coffee enemas and more than 150 pills a day. Until now, such an approach has had an aura of quackery, but may now be entering the medical mainstream based on controlled trials to see if Dr. Gonzales's claim can be verified, that "many—not all by any means—of my patients are alive when they should be dead" ((94), p. 51). Beyond the chance prolongation of the life of an individual patient with advanced cancer is the potential to intervene in pathways understood at the molecular level to enhance appetite, modify metabolic alterations that contribute to wasting, and downregulate transcription factors or catabolic cytokine-induced events. Each of these approaches, summarized in Table 1 , will be considered in turn for possible therapeutic intervention.


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  		Table 1. Some Proposed Therapeutic Approaches That May Be Clinically Effective to Control Cancer Cachexia

 
Enhance Appetite
The most promising leads for new approaches are derived, paradoxically, from obesity research. The widespread presence of obesity, the opposite of cachexia and a major public health problem in its own right (95)(96), has stimulated wide-ranging studies that have defined signals and neural pathways that regulate appetite and energy expenditure. Goals in the control of obesity are to enhance catabolic pathways that diminish food consumption and increase energy production by "adaptive thermogenesis" (97)(98). Goals in the treatment of cancer cachexia are to enhance anabolic pathways that promote food intake and reduce wasteful energy expenditure, what one Science writer has called the "flip side of obesity research" (99). There is now a rather widespread interest in modifying hypothalamic-derived signals to suppress cachexia in cancer and other wasting syndromes. For example, Inui wrote "although therapeutic intervention using neuropeptide agonists/antagonists is now directed at obesity treatment, it may also have an effect on treating cancer-anorexia-cachexia, especially when combined with other agents that have effects on muscle and protein breakdown" ((100), p. 4493). Schwartz and colleagues noted, "the impressive effects of agouti-related protein on food intake in rodents indicate that it warrants evaluation in the treatment of conditions associated with excessive weight loss, including anorexia nervosa and wasting illness associated with AIDS or cancer" ((36), p. 669). And both Marks and Cone (43) and Lechan and Tatro (101), noting that central melanocortin signaling contributes to animal models of cachexia, propose that melanocortin receptor antagonists be developed for human investigation. On the other hand, a melanocortin receptor agonist, alpha-melanocyte stimulating hormone, decreased intraabdominal fat and enhanced insulin sensitivity, thus promoting potential linkages to diabetes control (102).

Again, leptin (103) figures prominently in the anorexia of cancer cachexia. In patients with advanced cancer and cachexia, studies indicated that leptin levels were low (84)(104). This is the appropriate physiological response in view of wasting, low fat stores, and decreased food intake, and should have stimulated anabolic effector systems, in particular the orexigen NPY as shown in Fig. 1. Yet profound anorexia prevailed in these patients, perhaps due to dysregulation of NPY by CNTF (44)(45) as noted. NPY is also suppressed by the hyperinsulinemia and chronic stimulation of corticotrophin releasing hormone (CRH) (105)(106)(107), perhaps accounting for low NPY levels in patients with advanced cancer and anorexia (45). Further, melanin concentrating hormone (MCH) may be necessary for the hyperphagic response to leptin deficiency: targeted deletion of the MCH gene in mice mimics many features of cancer cachexia, such as increased metabolic rate, hypophagia, and leanness (108). In cachectic animals with prostate cancer or with a sarcoma, weight gain and resistance to tumor-induced lean body mass were achieved by intracerebroventricular administration of the melanocortin receptor antagonist (MC3-R/MC4-R) agouti-related protein despite tumor persistence (101)(109). How to approach the therapeutic options of enhancing orexigens—NPY, MCH, agouti-related protein—or to use melanocortin receptor antagonists in human subjects with cancer cachexia to stimulate appetite and downregulate anorexigens as noted above will indeed be a therapeutic challenge. However, as approaches to treat human obesity have shown, no single intervention may suffice.

Modify Metabolic Parameters
An "entry point" for possible metabolic intervention in cancer cachexia might be on the state of insulin resistance. This state may seem surprising in view of the diminished fat stores in cancer cachexia, because adiposity is associated with insulin resistance (110)(111)(112). Yet by virtue of the response to TNF{alpha}, adipocyte secretion in cancer cachexia may be enhanced, with release of free fatty acids and a newly described protein called resistin, which may contribute to insulin resistance in peripheral tissues (113). Yet as attractive as these findings are, an important role for resistin in terms of adipose tissue gene expression in human insulin resistance has recently been questioned (114). There may be a rationale, nevertheless, in treating cancer cachexia with a new class of antidiabetic drugs called thiazolidinediones (TZD), which enhance tissue sensitivity to insulin in vivo (110)(115). These drugs function as high-affinity ligands for PPAR{gamma}, a nuclear receptor in fat cells that may be the biological target of TZDs (110)(115). The adipogenic action of PPAR{gamma} may account, in part, for adipose tissue-related weight gain in type 2 diabetes, which would be an added benefit in cancer cachexia (115). Additional benefits of the TZDs in cancer cachexia may be to suppress hyperinsulinemia, which activates the HPA axis, in turn elevating serum glucocorticoids (90)(106) and diminishing orexigenic signals. Leptin deficiency or unresponsiveness may also be detrimental by virtue of failure to upregulate PPAR{gamma}, leading to fatty acid accumulation and impaired cell function in organs concerned with glucose regulation (i.e., ß cells of the pancreas, or myocytes of muscle) (116).

Downregulate a Transcription Factor
There is much recent interest in the transcription factor nuclear factor-kB (NF-kB) because this regulates genes encoding cytokines, cytokine receptors, and cell adhesion molecules that drive immune and inflammatory responses (117). NF-kB is activated by many stimuli, including cytokines and oxidative stress (118). In cancer cachexia, apparent NF-kB dysregulation may induce detrimental cellular effects in muscle and bone, with ensuing sarcopenia and osteopenia, respectively. These aging-related conditions may be exacerbated in older persons with cancer cachexia and are clinically relevant (119) due to added weakness, potential for falls and fractures, and mortality (120). The basis for muscle wasting and failure of repair in cancer cachexia is coming to be understood at the molecular level (121)(122)(123)(124)(125)(126)(127)(128). The cytokines TNF{alpha} and interferon-{gamma} (IFN-{gamma}) suppress myogenesis by activating NF-kB in muscle cells through a process that involves dissociation of NF-kB from its inhibitory protein IkB (125). A key proteolytic pathway is then activated—the high energy requiring ubiquitin-proteasome system that leads to degradation of IkB and breakdown of myofibrillar proteins (50)(122)(123)(125)(127). Inhibition of NF-kB might stimulate recovery of lost muscle mass in patients with cancer cachexia (126). Suggested current therapies include eicosapentaenoic acid, a polyunsaturated fatty acid, and dehydroepiandrosterone, which can repress the IL-6 gene promoter via inhibition of NF-kB (126)(127)(128). Oral eicosapentaenoic acid may stabilize weight in cachectic patients with pancreatic cancer (1)(129). But as Mitch and Price point out, the biology of muscle loss is complicated because NF-kB upregulation (123) may suppress the ubiquitin-proteasome system (125). Moreover, in studies with laboratory animals that define these complex associations, a wide range of provocative techniques are used—including sepsis, severe injury, and other catabolic conditions besides cancer-associated cachexia (123). Thus, much more needs to be learned before "patients can be identified who would benefit from safe and effective means" to prevent loss of muscle and accelerate recovery (125).

TNF{alpha} is among the most potent of the osteoclastogenic cytokines (130)(131). The apparent elevation of TNF{alpha} in cancer cachexia may act synergistically with the ligand for receptor activator of NF-kB (RANK L) expressed by marrow stromal cells and osteoblasts to activate osteoclast RANK and promote osteopenia (130). RANK L action, in turn, may be countered by the osteoblast-secreted decoy receptor, osteoprotegerin (OPG). Thus, OPG can block RANK ligand–RANK interaction that enhances osteoclastogenesis (119). OPG has come into clinical trials to relieve pain and osteoclastic bone resorption associated with tumor cell metastases to bone, and could constitute adjunctive therapy to improve quality of life in cancer patients with painful bone metastases (132)(133). Whether OPG would also be beneficial to limit sarcopenia in cancer cachexia is not known, although there are also a number of therapeutic strategies aimed at blocking NF-kB activity in inflammatory diseases (134).

Induce Cytokine Blockade
Lack of success with pentoxifylline, a cytokine inhibitor, to limit cancer cachexia (85)(135), has raised questions about whether "dysregulated" cytokines contribute to the metabolic disturbances in cancer cachexia (136). However, detecting circulating cytokines may be difficult, and consideration must also be given to the appearance of "downstream" cytokine constituents that may still be active, such as neopterin for IFN-{gamma} or STNFR-4 for TNF (88)(137). Moreover, thalidomide, thought to be an inhibitor of TNF-{alpha}, has had promising results in treating HIV-associated wasting or cancer cachexia (18)(92)(138)(139)(140). The improved clinical status of patients with rheumatoid arthritis treated with agents that inhibit TNF or block the TNF receptor (141) has prompted trials of such agents in cancer cachexia (142)(143)(144). Again, such therapies may be additive with others, such as TZDs to counter insulin resistance and improve food intake (145).


   Conclusion
Top
 Abstract
 Anorexia of Aging
 Caloric Restriction
 Cancer Cachexia
 Conclusion
References
 
Emerging molecular insights in our understanding of cancer cachexia provide a rationale for possible therapeutic intervention to limit loss of appetite and lean body mass despite tumor persistence. These approaches may improve quality of life, response to chemotherapy, and gain time (1)(146). In revising this article, it seemed to me that research on cancer and the related metabolic alterations have led to insights not yet forthcoming in the syndrome of anorexia and weight loss associated with aging. Perhaps in this sense, research on disease "trumps" research on aging itself (147)(148). The approaches discussed in this review on possible therapeutic interventions in cancer cachexia may be applicable to advanced, unintentional weight loss in aging. However, in this latter condition, the considerations are more complex for they require of the geriatrician and the patient a decision to explore an etiologic basis that neither side may wish to do when the choice may be a more palliative approach and to address the pervasive psychosocial accompaniments. While the use of appetite enhancers or protein-caloric supplements have very limited effects in cancer cachexia, they may ameliorate or slow aging-related anorexia and unintentional weight loss, and more studies are needed here. The inexorable progression of cancer cachexia does not, as a rule, leave an option "not to treat" in most patients, where quality of life is so profoundly affected due to loss of the cultural pleasures associated with eating and social interactions (1)(149)(150). Clearly, the conditions for intervention are very different in the anorexia of aging compared to cancer cachexia, but it is my hope that this article may stimulate new thoughts and studies related to the potential to ameliorate both conditions.


   Acknowledgments
 
I am grateful to Stephen C. Woods, MD, Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio, for advice concerning Fig. 1. Dawn Bowen-Jenkins provided expert assistance in the preparation of this paper.

Received January 2, 2002

Accepted March 19, 2002


   References
Top
 Abstract
 Anorexia of Aging
 Caloric Restriction
 Cancer Cachexia
 Conclusion
 References
 

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