Catabolic Wasting - Cachexia and Sarcopenia

Catabolic Wasting - Cachexia and Sarcopenia

1 Overview

Summary and Quick Facts

  • The term catabolic wasting encompasses both cachexia and sarcopenia. In both cachexia and sarcopenia, muscle loss can lead to frailty and declining quality of life, as well as increased risk of death, infection, falls, slower wound healing and reduced exercise capacity.
  • This protocol will describe catabolic wasting conditions and report on some common interventions to prevent and treat lean tissue loss. Research on novel and emerging strategies for the prevention of muscle wasting will be reviewed, as well.
  • A number of nutritional, lifestyle and innovative pharmacological interventions may be useful to prevent and treat catabolic wasting. Many interventions can often produce dramatic improvements in muscle mass/strength and overall health of people with muscle wasting.

Loss of muscle and fat tissue due to illness is called cachexia. The general loss of muscle mass that occurs with advancing age is called sarcopenia. In both cachexia and sarcopenia, muscle loss can lead to frailty and declining quality of life, as well as increased risk of death, infection, and falls; slower wound healing; and reduced exercise capacity. The term “catabolic wasting” encompasses both cachexia and sarcopenia.

A number of nutritional interventions may be useful to prevent and treat catabolic wasting, including whey protein, creatine, and the amino acids glutamine, arginine, and HMB (hydroxy-methylbutyrate) (a leucine derivative).

Symptoms and Diagnosis

  • Weakness, fatigue, and difficulties in daily living
  • May be difficult to distinguish between cachexia and sarcopenia; aging individuals may experience both simultaneously.
  • Moderate-to-severe cachexia or sarcopenia can be diagnosed by observing loss of muscle mass, strength, and tone.

Some researchers have proposed that cachexia and sarcopenia should be diagnosed by calculating lean and fat body mass by imaging techniques such as MRI (magnetic resonance imaging).

Risk Factors

Cachexia

  • Chronic diseases, such as cancer, AIDS, heart failure, chronic lung disease, and inflammatory bowel disease

Sarcopenia

  • Aging
  • Malnutrition
  • Physical inactivity
  • Heart and/or kidney failure
  • Type 2 diabetes

Conventional Treatment

  • Encourage food and fluid intake and drug treatment, including DHEA, growth hormone, and cannabinoids.
  • It is important to receive proper treatment for the underlying cause of the cachexia.
  • A number of studies have reported that testosterone treatment has been useful in promoting lean weight gain for people with AIDS- or COPD-related cachexia, and can improve protein synthesis and muscle mass in men and women.

Note: Aging individuals who notice their muscle mass begin to decline should have their hormones tested at least once a year. More information is available in the Male and Female Hormone Restoration protocols.

Novel and Emerging Treatments

  • A double-blind study in healthy postmenopausal women reported that a single dose of an experimental drug that inhibits myostatin activity (a protein that limits muscle growth) produced a 5.1% increase in thigh muscle volume compared with a 0.2% reduction with placebo.
  • Beta-adrenergic drugs like formoterol, selective androgen receptors modulators (SARMs) like the investigational drug enobosarm, and the investigational anti-cancer drug selumetinib also increase lean muscle mass.
  • A number of human studies have reported that treatment with ghrelin, a hormone produced in the gut that functions in the central nervous system, is associated with increased appetite, muscle and fat mass, and functional status in people with sarcopenia, cancer, COPD, and end stage renal disease.

Dietary and Lifestyle Considerations

  • Exercise, especially resistance training (eg, lifting weights), is critical for maintaining muscle mass in those with cachexia and sarcopenia, and is most effective when coupled with proper nutrition.
  • Consume adequate protein and amino acids.
  • Avoid smoking.

Integrative Interventions

  • Whey protein: Whey provides has an excellent amino acid profile; it is a rich source of many amino acids vital for muscle building, including the branched chain amino acids leucine, isoleucine, and valine.
  • Creatine: Daily supplementation with creatine has been shown to increase muscle strength and endurance in the elderly while performing daily activities.
  • Amino acids: Leucine’s derivative HMB, along with the amino acids glutamine and arginine, play key roles in treating muscle wasting.
  • L-carnitine: Several published studies have reported that many patients with cancer-related cachexia are often low in carnitine, and daily supplementation is associated with reduced fatigue and increased lean body mass.
  • Omega-3 fatty acids: A British study of older adults reported that consuming higher levels of fatty fish was associated with greater handgrip strength, which is a marker of muscle function.

2 Introduction

Loss of muscle and fat tissue due to chronic illness is called cachexia. The general loss of weight and muscle mass that occurs with advancing age is called sarcopenia. In both cachexia and sarcopenia, muscle loss can lead to frailty and adversely affect a variety of clinical outcomes (Rolland 2011; Fearon 2013; Muscaritoli 2013).

Individuals with cachexia and/or sarcopenia have an increased risk of death, infection, and falls; slower wound healing; significantly lower exercise and breathing capacity; and overall diminished quality of life (Sirola 2011; Paddon-Jones 2009; Janssen 2004; Zacker 2006; Thomas 2007; Cosqueric 2006; Cawthon 2007).

Cachexia and sarcopenia share some pathological mechanisms, including excess levels of systemic inflammation, oxidative damage, and reduced levels of anabolic hormones like testosterone, and may occur simultaneously (Rolland 2011; Fearon 2013; Muscaritoli 2013). The term “catabolic wasting” encompasses both sarcopenia and cachexia. (“Catabolic” refers to the breakdown of tissue; it is the opposite of “anabolic,” which means tissue-building.)

Cachexia usually causes more rapid and pronounced weight reduction than sarcopenia and is generally characterized as loss of muscle and fat tissue totaling more than 5% of body weight, but losses of more than 20% of body weight are common (Rolland 2011; Nicolini 2013; Siddiqui 2006; Muscaritoli 2013; Gordon 2004; Gullett 2011). In many cases, a person with cachexia continues losing weight even if they are getting enough calories (Siddiqui 2006; Muscaritoli 2013).

Severe, chronic illnesses such as cancer, AIDS, and chronic obstructive pulmonary disease (COPD) are known causes of cachexia (Sididqui 2006; Fearon 2013). Between 50% and 80% of all cancer patients experience cachexia, and it is estimated that cachexia is the main cause of over 20% of all cancer-related deaths (Nicolini 2013; von Haehling 2010; Suzuki 2013). Cachexia in HIV/AIDS patients is common and occurred almost universally before the advent of antiviral HIV drugs (Guillory 2013).

Sarcopenia (from the Greek meaning "poverty of flesh") generally refers to age-related loss of muscle mass and function (Iannuzzi-Sucich 2002). Approximately 50% of people over age 80 experience sarcopenia (Baumgartner 1998; Janssen 2004).

Sarcopenia can also occur as a result of physical inactivity, poor nutrition, or illness. Some researchers refer to age-related muscle loss not associated with an underlying cause as “primary sarcopenia,” and that which occurs as a consequence of one or more other causes as “secondary sarcopenia” (Rolland 2011; Muscaritoli 2013). Also, sarcopenia can sometimes occur in a person who still has significant fat stores, a condition known as “sarcopenic obesity” (Zamboni 2008). Sarcopenia is associated with increased risk of insulin resistance and type 2 diabetes in non-obese adults over age 60 years (Moon 2013).

The conventional medical establishment often fails to provide early, aggressive intervention for cachexia, resulting in poor clinical outcomes, including premature death and disability. Standard medical treatments for cachexia include encouraging consumption of liquids and food and use of certain drugs. However, many standard medical therapies to treat sarcopenia and cachexia present the risk of adverse effects such as nausea, edema, and fatigue, and some of them have not been adequately tested in clinical trials (Gullett 2010; Fox 2009; Fearon 2013). Early recognition and treatment of cachexia is even more important, considering that losing as little as 5% of body weight in cancer patients may increase the risk of adverse effects from chemotherapy drugs (Brotto 2012; Fearon 2013).

A number of nutritional, lifestyle, and innovative pharmacological interventions may be useful to prevent and treat catabolic wasting. Whey protein, creatine, and the amino acids glutamine, arginine, leucine, and hydoxy-methylbutyrate or HMB (a leucine derivative) are especially important for building and maintaining lean muscle mass (Thomas 2007; Casperson 2012; Katsanos 2008; Kim 2010; Clark 2000; Hayes 2008; Kim 2010). Omega-3 fatty acids, conjugated linoleic acid, and vitamin D also fight lean tissue loss (Siddiqui 2006; Rahman 2009; Drey 2011; Kim 2011).

Many interventions can often produce dramatic improvements in muscle mass/strength and overall health of people with muscle wasting. This protocol will describe catabolic wasting conditions and report on some common interventions to prevent and treat lean tissue loss. Research on novel and emerging strategies for the prevention of muscle wasting will be reviewed as well.

3 Background

A number of factors often converge to cause catabolic wasting. Malnutrition due to reduced food consumption or impaired nutrient absorption occurs frequently in later stages of chronic disease and can cause marked loss of muscle and fat tissue. Even though cachexia is typically accompanied by loss of appetite, it rarely responds to increased food intake alone (Siddiqui 2006; Solheim 2013). Dehydration is another important contributor, as loss of fluid results in reduced weight (Morley 2006).

Inflammation also plays a major role in deterioration of body mass among individuals with cachexia (Morley 2006). Both acute and chronic illness can cause marked increases in the production of inflammatory cell-signaling molecules called cytokines. These inflammatory mediators alter numerous metabolic processes, resulting in reduced muscle protein synthesis and increased muscle protein breakdown. Several specific cytokines have been linked to cachexia including interleukin-1, interleukin-2, interleukin-6, interferon-γ, and tumor necrosis factor-alpha (TNF-α). Inflammatory cytokines activate a major metabolic regulator called nuclear factor kappa B (NF-κB), which in turn drives several physiological changes that promote tissue deterioration. Inflammatory cytokines also stimulate the release of the adrenal hormone cortisol and neurotransmitter hormones called catecholamines; both cortisol and catecholamines can exacerbate catabolic wasting by disrupting muscle cell metabolism and altering the basal metabolic rate (Siddiqui 2006; Morley 2006).

Reductions in levels of testosterone and insulin-like growth factor-1 (IGF-1) are thought to play an important role in catabolic wasting as well. Both testosterone and IGF-1 exert anabolic actions in muscle tissue, so declining levels of these hormones can lead to reduced muscle mass (Morley 2006).

Sarcopenia involves multiple factors including increased inflammation, insulin resistance, oxidative damage, and protein breakdown; reduced protein synthesis; changes in hormone levels (such as lower levels of growth hormone and testosterone); dysfunction of blood vessels and nerves; and damage to mitochondria (organelles that produce cellular energy) (Semba 2007; Thomas 2007; Zacker 2006; Kim 2011; Moon 2013; Marzetti 2009; Marzetti 2013).

4 Risk Factors

Risk factors for cachexia include cancer, HIV/AIDS, or other conditions such as heart failure, chronic lung disease, and inflammatory bowel disease (Siddiqui 2006). Cancer-related cachexia is somewhat more common in men than women (Merck 2013).

Major risk factors for sarcopenia include aging, malnutrition, physical inactivity, and serious health problems such as heart and/or kidney failure (Marzetti 2009; Rolland 2011). Type 2 diabetes in older men has also been associated with an accelerated loss of muscle mass compared to men with normal blood sugar levels (Leeanders 2013).

5 Symptoms and Diagnosis

Most people with cachexia or sarcopenia experience weakness, fatigue, and difficulties in daily living. There is not yet a consensus as to how to determine when catabolic wasting reaches the point of cachexia or sarcopenia. In 2008, cachexia was defined as “a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass” (Evans 2008). In 2010, a proposed definition of sarcopenia was based on age-related loss of muscle mass, handgrip strength, and walking speed (Cruz-Jentoft 2010).

There is large overlap between cachexia and sarcopenia, and it may be difficult to clinically distinguish between the two (Rolland 2011; Fearon 2013; Muscaritoli 2013). Many aging individuals may experience both cachexia and sarcopenia simultaneously (Rolland 2011; Fearon 2013; Muscaritoli 2013).

While it may be difficult to define a precise point where significant muscle wasting begins, moderate to severe cachexia and/or sarcopenia can be diagnosed by observing loss of muscle mass, strength, and tone in the person. Recently, some researchers have proposed that cachexia and sarcopenia should be diagnosed by calculating lean and fat body mass by imaging techniques such as MRI (magnetic resonance imaging) (Fearon 2013).

Pre-cachexia and the Importance of Early Recognition of Catabolic Wasting

Loss of body mass and muscle strength often occur gradually among individuals with slowly progressing, chronic diseases as well as aging populations typically considered otherwise healthy. This often precludes recognition of the early stages of wasting and results in missed opportunities for preemptive intervention that may help patients maintain better functional capacity and quality of life in the long term (Norman 2008; Muscaritoli 2010).

Estimates suggest as many as 50% of hospitalized individuals are malnourished (Norman 2008). More concerning still, nutritional status very often worsens during hospitalization, owing to the under-recognition and under-treatment of early signs of wasting by physicians and hospital staff (Norman 2008). Malnourished patients typically require longer hospital stays and have worse prognoses for both acute and chronic illnesses (Norman 2008).

The harsh reality is that medical care providers often fail to address early signs of wasting until it has reached advanced stages, at which point the efficacy of interventions aimed at improving body composition is considerably impaired (Norman 2008; Muscaritoli 2010).

Fortunately, recent collaborative research efforts have focused on the critical need to recognize and address wasting and cachexia in earlier stages. In 2010, specific guidelines on the recognition and classification of “pre-cachexia” were developed. These guidelines established the following requisites for the diagnosis of pre-cachexia (Muscaritoli 2010):

  1. underlying chronic disease;
  2. unintentional weight loss ≤5% of usual body weight during the preceding 6 months;
  3. chronic or recurrent systemic inflammatory response;
  4. anorexia or anorexia-related symptoms.

The hope is that these guidelines will usher better management of nutritional status among individuals with early stage wasting and help avert the decline in health linked to advanced stages of wasting and cachexia. Patients, their families, and their health care providers should all remain cognizant of the pivotal role that maintaining adequate nutritional status plays in aiding recovery from illness and prolongation of health span. Even small changes in body composition or eating habits among aging and chronically ill individuals should not be overlooked, as early nutritional intervention may stave off subsequent declines in quality of life and improve patient outcomes (Muscaritoli 2010; Norman 2008).

​​

6 Conventional Treatment

Conventional medicine generally does not treat muscle wasting until it has reached a moderate to advanced state involving unintentional loss of at least 5% of body weight within 12 months (Muscaritoli 2013; Evans 2008). The usual therapies include encouraging food and fluid intake and drug treatment. A number of interventions may be used in the treatment of people with catabolic wasting, including testosterone, dehydroepiandrosterone (DHEA), progestins, growth hormone, cannabinoids, and thalidomide (Gordon 2004; Khan 2003; Dunn 2009; Fearon 2013; Zacker 2006; Siddiqui 2006; Nicolini 2013). It is also important to utilize proper conventional treatment for the underlying cause of cachexia/sarcopenia such as cancer, HIV/AIDS, or respiratory or kidney failure. If cancer is successfully treated, the underlying cachexia is often resolved (Merck 2013).

Testosterone and DHEA

Testosterone plays a critical role in muscle building, and many muscle-wasted patients (men and women) are deficient in testosterone. One study reported that testosterone was deficient in over 70% of men with cancer cachexia. Total testosterone levels were lower in patients who had cancer with cachexia compared to patients who presented with cancer without cachexia (Burney 2012). A number of studies have reported that testosterone treatment has been useful in promoting lean weight gain for people with HIV/AIDS- or COPD-related cachexia (Gullett 2010; Kong 2002).

Injected testosterone (eg, Andro LA 200®, Delatestryl®, Depandro 100® and Depo-Testosterone®) and related oral compounds (eg, oxandrolone [Oxadrin®]) are often useful for individuals with catabolic wasting and low testosterone levels. Testosterone can also be applied in gel form (eg, AndroGel®, Testim®, Axiron®) or as skin patches (Androderm® and Testoderm®). A review of published studies of people with HIV/AIDS-related wasting reported that both testosterone injections and patches led to lean weight gain (Kong 2002). A Texas study treated healthy men aged 60 to 85 years who had low testosterone (<500 ng/dL) with testosterone or placebo. After 5 months, men treated with testosterone injections gained an average of 6.9 pounds of lean mass and lost an average of 2.7 pounds of fat, while men given placebo lost an average of 2.4 pounds of lean mass and gained an average of 2.6 pounds of fat (Sheffield-Moore 2011). Studies have also reported that testosterone can improve protein synthesis and muscle mass in older women (Sheffield-Moore 2006; Smith 2014).

The oral testosterone derivative oxandrolone has been used for decades as a therapeutic intervention against unintentional weight loss associated with such causes as HIV/AIDS-related muscle wasting, severe burns, infections, and major surgery. It has demonstrated efficacy in a variety of studies and has a favorable side effect and safety profile compared to some other oral anabolic agents (Orr 2004). Importantly, oxandrolone has less of a tendency to promote virilization (expression of male characteristics) in females, making it a reasonable option for the treatment of wasting conditions in women (Gullett 2010). In a double-blind, randomized study carried out across multiple centers, oxandrolone at doses of either 5 mg or 15 mg daily improved body weight and well-being more so than placebo in 63 HIV-positive men who had experienced weight loss of more than 10% of initial body weight (Berger 1996). In another trial published in the Journal of the American Medical Association, 24 HIV-positive men exhibiting an average 9% weight loss were randomized to receive 20 mg oxandrolone or placebo daily. All the subjects were also participating in a progressive resistance training program during the study and received supraphysiologic doses of intramuscularly-injected testosterone (100 mg per week). Twenty-two men completed the 8-week study (11 men in each group). Both the placebo group and the oxandrolone group exhibited improvements in body mass and measures of muscle anabolism. However, the improvements were significantly greater among the men who received oxandrolone. The researchers concluded “A moderately supraphysiologic androgen regimen that included an anabolic steroid, oxandrolone, substantially increased the lean tissue accrual and strength gains from [progressive resistance exercise], compared with … testosterone replacement alone, in … men with HIV-associated weight loss” (Strawford 1999). In a larger double-blind, placebo-controlled trial, 262 HIV-infected men who either had a body mass index (BMI) ≤20 or had experienced 10-20% weight loss were assigned to receive 20, 40, or 80 mg of oxandrolone or a placebo daily. After 12 weeks, men receiving 40 or 80 mg oxandrolone exhibited greater body mass gains than those who took a placebo, prompting the study investigators to remark “Oxandrolone administration is effective in promoting dose-dependent gains in body weight … in HIV-infected men with weight loss” (Grunfeld 2006). Oxandrolone can cause some side effects such as potentially significant increases in liver enzymes, increases in LDL cholesterol, and decreases in HDL cholesterol, but these generally are outweighed by the benefits for those experiencing significant wasting (Grunfeld 2006).

More information about testosterone replacement can be found in the Male Hormone Restoration and Female Hormone Restoration protocols.

DHEA is a hormone and precursor to many other important hormones including testosterone and estrogen (Samaras 2013). Low DHEA levels are common in older adults and are associated with lower muscular mass and strength, higher risk of osteoporosis and bone fractures, depression, cardiovascular disease, and sexual dysfunction (Samaras 2013; Hwang 2013). A number of published studies have reported that DHEA administration (typically 25-50 mg daily) is associated with higher bone densities in osteoporosis patients, with beneficial effects sometimes greater in women than men (Samaras 2013; Weiss 2009). DHEA supplementation may also have beneficial effects on mental abilities (cognition), mood, cardiovascular disease, and sexual function. More information about DHEA is available in the DHEA Restoration Therapy protocol.

Maintaining Optimal Hormone Levels to Prevent Sarcopenia

Levels of growth hormone, testosterone, DHEA, and other hormones important for maintaining muscle mass usually decline with age (Liefke 2000; Jones 2009). By age 70, about 70% of men have low levels of testosterone and may benefit from testosterone replacement therapy (Baer 2012). A double-blind study treated frail elderly men (>65 years) who had low testosterone (below 345 ng/dL) with either 50 mg daily of testosterone gel (130 men) or placebo gel (132 men). After 6 months of treatment, lean muscle mass increased significantly by an average of 2.2 pounds in the testosterone group but stayed the same in the placebo group. In addition, knee extension strength and reported sexual function improved significantly in the testosterone group but not in the control group (Srinivas 2010).

Testosterone levels usually also fall with age in women (Hwang 2013). Testosterone replacement has been used with some success in older women with a number of medical conditions including age-related muscle loss, mood problems, sexual dysfunction, and bone loss (Maclaran 2012; Sheffield 2006).

Any person with suspected muscle wasting should have their hormones tested at least once a year. If necessary, persons with muscle wasting should be treated with bioidentical hormones by a physician trained in hormone replacement therapy. 

Growth Hormone

Growth hormone (brand names Genotropin®, Humatrope®, Norditropin®, Nutropin®, Saizen®, Serostim®) has been approved by the Food and Drug Administration (FDA) for treating HIV/AIDS-related wasting and is sometimes used “off label” to treat other catabolic wasting conditions. Growth hormone is produced by the pituitary gland and its natural production usually declines significantly with age or during severe, chronic illness like AIDS or cancer (Gullet 2010).

Several studies have reported that growth hormone treatment can increase lean weight in people with COPD- or HIV/AIDS-related cachexia (Gullett 2010). A 12-week study of people with HIV/AIDS-related wasting treated 90 subjects with growth hormone (0.1 g/kg body weight per day) and 88 subjects with placebo. After 12 weeks, the growth hormone group had an average gain of 6.6 pounds of lean weight while the placebo group lost an average of 0.2 pounds of lean weight. In addition, subjects given growth hormone had a significantly greater gain in treadmill exercise capacity compared to those receiving placebo. Adverse effects observed more commonly in growth hormone treatment patients than controls included fluid retention (edema), joint pain, and diarrhea (Schambelan 1996). Growth hormone has also been used in older adults with age-related sarcopenia. An analysis of studies which included a total of 220 older adults reported that use of growth hormone for 2 weeks or more was associated with an average 4.6-pound lean weight gain and no significant change in bone density. However, growth hormone treated elders experienced health problems at significantly higher rates (compared to controls) including fluid retention (edema), joint pain, and carpel tunnel syndrome, and were somewhat more likely to experience the onset of type 2 diabetes (Liu 2007).

Megestrol Acetate

Megestrol acetate (Megace®) is a synthetic derivative of the hormone progesterone that increases appetite and is used for that purpose in AIDS and cancer patients with weight loss. Some studies have reported that megestrol acetate significantly increases body mass; however, this is largely attributable to gains in fat mass (Gullett 2010; Fox 2009). A 12-week study of frail elders (≥65 years old) in a low-resistance exercise program reported that subjects given 800 mg of megestrol acetate daily gained an average of 20.9 pounds of fat and lost an average of 8.6 pounds of lean tissue, while subjects given placebo gained an average of 1.7 pounds of fat and lost an average of 0.2 pounds of lean tissue. Researchers also noted that the addition of megestrol acetate blunts the beneficial effects of muscle strength training (Sullivan 2007). A 20-week study of 9 elderly men with kidney dialysis-associated cachexia reported that an exercise program coupled with 800 mg of megestrol acetate daily was associated with an average fat gain of 6.2 pounds and an average lean tissue gain of 5 pounds. Subjects on the exercise program with placebo experienced an average loss of 0.4 pounds of fat and 1.2 pounds of lean tissue (Yeh 2010). In a small 12-week study of patients with HIV/AIDS-associated weight loss, subjects were treated with either megestrol acetate (400 mg daily) or nandrolone (ie, an anabolic steroid sometimes used by bodybuilders to increase muscle mass; 100 mg bi-weekly). The megestrol acetate group experienced an average fat weight gain of 17 pounds and an average lean weight gain of 6.1 pounds. The nandrolone group lost an average of 1.4 pounds of fat and gained an average of 7.8 pounds of lean weight (Batterham 2001).

Possible side effects of megestrol acetate include diarrhea, nausea, rash, insomnia, confusion, headache, dizziness, short-term adrenal insufficiency, and edema (water-based swelling of feet, hands, and other areas) (Gullett 2010; Fox 2009). Megestrol acetate treatment may be useful for people with significant loss of both muscle and fat, but it is probably not a good choice for those with significant muscle loss and presence of major fat stores (sarcopenic obesity). Some data suggest that megestrol acetate may increase tumor risk (Tassinari 2003; First Consult 2014). Moreover, although megestrol acetate is often used to promote weight gain in wasting conditions, evidence suggests it may not provide superior benefits compared to other common drugs used in this setting. Given the frequency of potentially serious side effects such as edema, blood clots, and death associated with megestrol acetate and its lack of superiority to other drugs used to treat wasting, it may not be the ideal choice for all individuals. Individuals prescribed megestrol acetate should talk with their health care providers about other drug options that may offer similar benefits and potentially reduced side effects (Ruiz Garcia 2013).

Cannabinoids and Thalidomide

Cannabinoids are compounds derived from the marijuana plant or synthetically produced analogue drugs such as dronabinol (Marinol®). Cannabinoids may be useful for increasing appetite in persons with catabolic wasting. Various studies have found cannabinoids to be very helpful in promoting gain of muscle mass in people with HIV/AIDS-related cachexia but are less useful for people with cancer-related cachexia (Beal 1997; Fearon 2013). Another study of HIV-positive marijuana smokers reported that oral dronabinol (5 or 10 mg four times daily) or 4 marijuana cigarettes smoked daily were associated with a significant increase in daily calorie consumption (Haney 2007). Mild to moderate neurological side effects such as anxiety, confusion, dizziness, and sleepiness are common with the use of cannabinoids (Beal 1997).

As of the time of this writing, 21 U.S. states and the District of Columbia allow for physician-recommended or prescribed marijuana use (NORML 2013). Most of these state laws specifically include HIV/AIDS- and cancer-related cachexia or wasting as approved conditions for allowed marijuana use. However, marijuana smoke contains large amounts of toxic chemicals such as carbon monoxide, particulates, and cancer-causing polycyclic aromatic hydrocarbons (Earleywine 2007; Abrams 2007). Another method for marijuana delivery involves using “vaporization” machines that heat the marijuana up to between 356o F and 392o F to vaporize some of the active compounds without burning (Abrams 2007). Several studies have reported that use of marijuana vaporizers is associated with significantly lower exposure to carbon monoxide and significantly fewer respiratory symptoms (such as coughing) compared to conventional marijuana smoking (Earleywine 2007; Abrams 2007).

Thalidomide (Thalomid®) is a drug that may be helpful to people with cancer-related cachexia and weight loss. Two studies have reported that thalidomide use has been associated with significant gain of total and lean weight in cachectic patients with esophageal or pancreatic cancer (Khan 2003; Gordon 2005). Thalidomide treatment may improve anorexia and nausea, and it inhibits production of the highly inflammatory cytokine TNF-α. Thalidomide treatment has many common adverse side effects including fatigue, peripheral neuropathy, blood clots, respiratory problems, and severe birth defects (Fearon 2013).

Feeding Tubes and Total Parenteral Nutrition (TPN)

Ensuring adequate nutrition is critical for combatting catabolic wasting in severely ill individuals with cachexia. One challenge, however, is that sometimes it is difficult for these people to consume food by mouth. Such barriers as nausea or lack of appetite due to chemotherapy among cancer patients with cachexia, or mechanical difficulties with chewing or swallowing can perturb consumption of adequate nutrition.

A common and effective solution is administration of nutrition via a feeding tube or parenteral nutrition (Arends 2006; Anker 2006).

With a feeding tube, nutrients are delivered through a tube that enters directly into the stomach (“G-tube”) or the segment of the small intestine called the jejunum (“J-tube”); this is called enteral nutrition. This allows semi-solid nutritional solution containing fats, carbohydrates, and proteins, as well as vitamins, minerals, and other micronutrients to be delivered into the patient’s digestive tract while bypassing active eating. Parenteral nutrition involves delivering standardized formulations of liquid nutrients directly into the patient’s bloodstream. Parenteral nutrition can be used to supplement other forms of nutrition consumption, or in cases in which the patient cannot receive any nutrition via their digestive tract, all nutrition may be delivered intravenously – this is called total parenteral nutrition (TPN). Whenever possible, enteral nutrition (as opposed to parenteral nutrition) is preferred, as it more closely mimics natural eating and typically provides better outcomes (Mercadante 1998). Enteral nutrition typically provides 20 – 35 calories per kg (roughly 2.2 pounds) of body weight per day (Nitenberg 2000; Jiménez Jiménez 2011a).

Maintenance of adequate protein and amino acid intake is critical to avert muscle wasting in individuals with cachexia who are receiving enteral nutrition. An enteral and parenteral nutrition research organization based in Spain developed guidelines for enteral feeding of critically-ill cardiac patients indicating that protein intake should be 1.2 – 1.5 g/kg of body weight per day. The formulation should also contain sufficient concentrations of the amino acid glutamine, as it is of critical importance for muscle cell and immune function. In addition, omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) may be added to the enteral formula as well; these Spanish guidelines suggest 1 g per day (Jiménez Jiménez 2011a; Nitenberg 2000).

Although enteral nutrition is not suitable for all patients with wasting or cachexia, guidelines suggest it should be considered if undernutrition is already clinically evident or if food intake is reduced significantly for 7 – 10 days (Arends 2006).

​​

7 Novel and Emerging Treatments

Myostatin Inhibitors

Myostatin is a naturally-produced protein that limits muscle growth and is often found in relatively high levels in patients with cachexia, sarcopenia, and osteoporosis (Buehring 2013; Elliot 2012). Myostatin is also significantly higher in smokers versus non-smokers, probably due to the complex mixture of toxins in cigarette smoke (Rom 2012; Petersen 2007).

Research is currently underway to develop therapies that could increase muscle and bone mass by reducing myostatin activity in the body (Buehring 2013; Elliot 2012; Attie 2013). A double-blind study in 48 healthy postmenopausal women reported that a single dose of the experimental drug ACE-031 (which inhibits myostatin activity) produced a 5.1% increase in thigh muscle volume compared to a 0.2% reduction in women given placebo (Attie 2013).

Beta-Adrenergic Drugs

There is ongoing research investigating the possible use of beta-adrenergic drugs like formoterol (Foradil®) to prevent or reverse the muscle wasting and weakness associated with cachexia and sarcopenia. Beta-adrenergic drugs are believed to help build and maintain muscle by a number of pathways that reduce protein breakdown and increase protein synthesis. However, they do have a number of possible side effects, including heart problems and insomnia (Koopman 2009; Lee 2013).

Selective Androgen Receptor Modulators

Selective androgen receptors modulators (SARMs) like the investigational drug enobosarm (Ostarine® or GTx-024) have tissue-specific anabolic effects in the muscles and bones while at the same time lacking other androgenic effects, such as hair growth in women and adverse effects on the prostate in men. Enobosarm was found to significantly increase lean muscle mass and muscle function in a group of 120 older adults (Dalton 2011).

Selumetinib

The investigational anti-cancer drug selumetinib may be useful for cachectic cancer patients by reducing production of IL-6, which causes inflammation and may reduce muscle mass. In a placebo-controlled study of bile duct cancer patients treated with selumetinib for 100 days, muscle mass increased an average of 5.1 pounds in the treatment group and decreased an average of 2.6 pounds in the placebo group (Prado 2012).

Ghrelin

Ghrelin treatment has also been observed to increase appetite in people with muscle wasting. Ghrelin is a hunger-stimulating peptide (small protein) primarily produced by the stomach and small intestines. Ghrelin also plays a role in stimulating gastrointestinal motility, reducing inflammation, and stimulating growth hormone release by the pituitary gland. A number of human studies have reported that intravenous or subcutaneous treatment with ghrelin or ghrelin mimetics is associated with increased appetite, muscle and fat mass, and functional status in people with sarcopenia, cancer, COPD, and end stage renal disease (Guillory 2013). Currently, a number of clinical trials are underway to examine the possible effects of ghrelin and related compounds on improving appetite in muscle-wasted individuals.

8 Dietary and Lifestyle Considerations

Exercise

Exercise is critical for maintaining muscle mass in those with cachexia and sarcopenia and is most effective when coupled with proper nutrition (Churchward 2013; Solheim 2012; Penna 2011; Schols 2002). A review of 49 published studies of resistance training programs of ≥ 8 weeks in adults ≥ 50 years reported an average lean weight gain of 2.4 pounds (Peterson 2011). Some studies have reported that weight training is effective even in very old people. A study of 10 frail, aging adults (average age 90 years) reported that an 8-week weight resistance training program was associated with an average 174% gain in muscle strength and an average 9% increase in the mid-thigh muscle area (Fiatarone 1990).

Exercise is also useful for patients with muscle wasting due to HIV/AIDS, cancer, or other severe illnesses. A review of 9 published studies of HIV-positive subjects reported that resistance exercise was associated with an average weight gain of 11 pounds (Fillipas 2010). Another study of HIV-positive patients >60 years old reported that a weight training program (2 times weekly for a year) was associated with average strength gains of 52-133% and significantly faster walking speeds (de Souza 2011).

Researchers reviewed 16 published studies on the effects of exercise on muscle strength/mass in cancer patients. Most of these studies involved patients with cancers of the breast, prostate, or blood (such as leukemia); most patients had low to moderate stage cancers. The studies demonstrated that compared to usual care, resistance exercise improves upper and lower body muscle strength (Stene 2013).

Multiple studies have reported that many types of resistance and aerobic exercises are useful for maintaining muscle mass in the elderly (Montero 2013). However, there is little information comparing muscle building effects of various forms of exercise in elderly individuals (eg, land-based versus water exercises). Research is currently underway to develop optimal exercise strategies for people with muscle wasting (de Souza 2013).

While exercise is best, research has also been undertaken to determine whether electrical stimulation can be useful in maintaining muscle mass in the elderly. Electromyostimulation is often useful for bedridden persons or those with limited mobility who have difficulty walking or doing standard exercise. Electromyostimulation or electrical muscle stimulation involves stimulating muscle contraction with low level electrical impulses applied to the muscles by electrodes. One study used electromyostimulation 3 times bi-weekly for 54 weeks on a group of 76 aging women (average age 75 years). After 54 weeks, the electromyostimulation-treated women gained an average of 0.8% of lean mass while control women lost an average of 0.8% (Kemmler 2013). 

Another method to increase muscle mass and strength in people who find traditional exercise difficult is whole-body vibration (WBV) training. In WBV, oscillations are transmitted vertically from the feet to the rest of the body by using vibrating platforms. This recently-established training method was shown to stimulate muscle strength and power in healthy individuals and to improve gait and balance in older people (Chanou 2012). A study of 13 older women (average age 79 years) reported that WBV training for 10 weeks (3-5 times weekly for 7 to 22 minutes) significantly increased thigh muscle cross-sectional area and strength compared to 13 matched control women (Machado 2010). 

For very ill people, regular exercise may be impossible. However, they should be encouraged to move if possible; even if only to sit up and walk a short distance to the bathroom. Total bed rest impairs protein synthesis in older adults (Drummond 2012).

Avoiding Smoking

Avoiding smoking and secondhand tobacco smoke is important in preventing and treating catabolic wasting. A number of studies have reported that smoking significantly increases the risk of sarcopenia. Smoking and exposure to toxins associated with smoking increase the risk for muscle wasting in at least 4 ways: 1) reducing appetite, 2) inhibiting protein synthesis, 3) increasing protein breakdown, and 4) increasing the body’s levels of myostatin (ie, a natural protein that inhibits muscle growth) (Petersen 2007; Rom 2012).

Consume Adequate Protein and Amino Acids

Older adults may need more protein than current government guidelines indicate. The recommended dietary allowance (RDA) of protein for adults 19 years and older is 0.8 g/kg (1 kg = 2.2 pounds) of body weight daily (Mithal 2013). A number of studies have reported that consuming less than the 0.8 g/kg is associated with significantly lower lean mass in older adults (Scott 2010; Houston 2008). It is now generally recommended that older adults consume from 1.0 to 1.2 g/kg body weight of protein daily (Mithal 2013; Wolfe 2008). This corresponds to 70-84 g protein for a 70 kg (154 pound) person. However, there are some concerns that a higher protein intake may be harmful to those with kidney disease (Martin 2005). People with depressed kidney function should consult with a physician before consuming supplements with protein and amino acids.

Moderate consumption of lean meat and fish may also be useful for people with muscle wasting. A study of 19 elderly men enrolled in a weight training program reported that consuming a “mixed” diet containing meat and fish and an average of 91 g of protein daily for 12 weeks was associated with larger gains in muscle strength and mass compared to a group eating a lacto-ovo vegetarian diet containing milk and eggs but no meat or fish (average 71 g of protein daily) (Campbell 1999).

Individuals with sarcopenia may need higher levels of protein and amino acids in their diet to overcome “anabolic resistance” (ie, a condition in which the body becomes less efficient in converting dietary protein into body protein). Anabolic resistance is common in older individuals with sarcopenia or people with HIV/AIDS- or cancer-related cachexia. Higher levels of dietary or supplemental protein and amino acids are needed to overcome anabolic resistance. The branched-chain amino acid leucine plays a critical role in stimulating protein synthesis in sarcopenic people (Dardevet 2012). Leucine is found in greatest concentrations in animal proteins, especially whey from milk (Hayes 2008; Phillips 2009). Leucine is also readily available as a dietary supplement.

Other Nutrition-Related Factors

Ensuring cachectic patients consume adequate calories each day is of paramount importance. Caloric needs vary with body size, and individuals with similar degrees of weight loss as a result of different diseases may have different caloric needs. Generally, evidence suggests that caloric needs of most cachectic patients can be satisfied by consuming between 25 and 35 calories per kg (2.2 pounds) of ideal body weight per day (Bonet Saris 2011; Jiménez Jiménez 2011b; Nicolini 2013; Diaz 2004).

Difficulties chewing and swallowing can also negatively impact nutrition in people with catabolic wasting. Dental implants have been very helpful, and dentures supported by mandibular implants have been associated with increased nutritional intakes compared to standard dentures (de Oliveira 2004; Hutton 2002). Speech and swallowing therapy has been useful in many people with swallowing difficulties. Many individuals who cannot eat food by mouth and must be tube fed have been able to resume normal eating after speech and swallowing therapy (Logemann 2007).

Social support and eating meals with others can significantly increase nutrient consumption in frail, muscle-wasted elderly individuals (Wright 2006). Good mealtime ambiance (eg, good china/tableware, flowers, background music) has also been associated with better food intake in elderly individuals (Mathey 2001). Sufficient water should be consumed to avoid dehydration (Morley 2006).

​​

9 Integrative Interventions

Amino Acids and Protein Supplements

Supplementing with several amino acids seems more effective than with a single amino acid. Leucine and its derivative HMB (hydoxy-methylbutyrate) along with the amino acids glutamine and arginine play key roles in preventing and treating muscle wasting. An amino acid supplement mixture used in several published studies of people with muscle wasting consists of 3 g HMB, 14 g L-glutamine, and 14 g L-arginine per day given in two divided doses. In a study of people with HIV/AIDS-related muscle wasting, 8 weeks of supplementation with this HMB/glutamine/arginine mixture was associated with an average fat free (lean) weight gain of 5.6 pounds compared to a loss of 1.5 pounds of lean weight in patients given placebo (Clark 2000). In cachectic cancer subjects, 12 weeks of supplementation with an HMB/glutamine/arginine mixture was associated with an average lean weight gain of 4.4 pounds compared to a loss of approximately 0.3 pounds of lean weight in patients given placebo (May 2002). Another study of adults ≥65 years reported that daily supplementation with 2-3 g HMB, 5-7.5 g arginine, and 1.5-2.25 g lysine was associated with significant gains in lean mass compared to subjects receiving a mixture of non-essential amino acids (Baier 2009).

Whey protein. Protein/amino acids in food and supplements are more useful if given in doses of at least 20-30 g per meal with at least 3 or more meals daily compared to one or two large protein meals daily (Paddon-Jones 2009). Muscle protein synthesis is reduced when less than about 20 g of protein per meal is consumed by an average sized older adult. However, consuming huge amounts of protein in one meal does not seem to increase protein synthesis. A study of both young and older healthy adults reported that muscle protein synthesis was not increased in individuals eating a meal with ¾ pound of lean beef (90 g protein) compared to ¼ pound of lean beef (30 g protein) (Paddon-Jones 2009).

Whey protein (from the liquid or non-curd portion of milk) has been used in several studies to prevent or reverse muscle loss. Whey is believed to have one of the best amino acid profiles of any natural protein; it is a rich source of many amino acids vital for muscle building, including the branched chain amino acids leucine, isoleucine, and valine (Hayes 2008; Phillips 2009). A number of studies have reported that supplemental whey protein significantly increases protein synthesis, and the increases in protein synthesis are greater than those obtained from supplemental casein (milk curd) or soy protein (Pennings 2011; Phillips 2009; Katsanos 2008; Gryson 2013). Studies often have subjects participate in an exercise program while receiving nutritional treatment or placebo. Several studies with young adults have reported that supplementation with whey has been associated with significant gains in muscle mass (Hayes 2008; Philips 2009).

Supplementation with soy protein has also been reported to significantly increase muscle protein synthesis in adults, although the increases have generally been smaller than those seen with whey or milk protein supplementation (Phillips 2009). Most of this soy supplementation research has been with young, healthy adults. Studies with soy protein supplementation in older adults have yielded mixed results. One study reported that consumption of 40 g of supplemental soy protein was associated with a small but significant increase in hip lean mass, while a second study of postmenopausal women reported that 25 g of supplemental soy protein did not increase lean weight (Moeller 2003; Maesta 2007). Cooked eggs and powdered whole egg supplements have an excellent amino acid balance and are a good choice for frail elderly individuals. Supplementation with 5-20 g protein from a powdered whole egg drink (taken after exercise) was associated with significantly increased muscle protein synthesis in young men (Moore 2009). Soy- or egg-based protein supplements are a reasonable choice for people with muscle wasting who are allergic to milk or whey.

L-carnitine. L-carnitine, an amino acid derivative found in meat, can be synthesized in small amounts in the body. Carnitine plays a critical role in energy production in 2 ways: 1) carnitine compounds transport fats across the mitochondrial membrane where they can be burned for energy and 2) carnitine upregulates several energy-producing reactions. Fatigue is a frequent manifestation in cancer patients, and significant fatigue is present in 60-96% of patients who receive chemotherapy or radiotherapy (Silverio 2011). Several published studies have reported that many patients with cancer-related cachexia are often low in carnitine and supplementation with 2-6 g of carnitine daily is associated with reduced fatigue and increased lean body mass (Silverio 2011). A study of 12 patients with advanced cancer reported that 4 weeks of treatment with 2 g L-carnitine three times daily (6 grams per day) was associated with a significant average lean weight gain of 4.4 pounds, significantly less fatigue, and significantly higher quality of life scores (Gramignano 2006). Another study treated 50 cancer patients who had low free carnitine levels (<30 µmol/L) with 2 g L-carnitine twice daily for 7 days. After 7 days of treatment, free carnitine levels exceeded 30 µmol/L in all 50 patients and fatigue significantly improved in 45 (90%) of the patients (Graziano 2002). A large study of 376 cancer patients reported that treatment with 2 g L-carnitine daily for 4 weeks was not associated with a significant improvement in fatigue compared to patients given placebo. However, in a subset of patients with low free blood carnitine levels (baseline levels <25 µmol/L for women and <35 µmol/L for men), carnitine supplementation for 4 weeks was associated with a significant improvement in fatigue (Cruciani 2012).

Creatine

Creatine, an amino acid-like compound used commonly by bodybuilders, may also be useful in treating muscle wasting. Creatine is found in meats and fish, and about 1-2 g of creatine is produced each day by the body from the amino acids glycine, arginine, and methionine. Many studies have reported that muscle creatine levels are lower in older adults than younger adults; however, daily supplementation with 5-20 g creatine can significantly increase muscle creatinine levels in the elderly. In a 2011 review, 4 out of 7 (57%) published studies reported that between 5 and approximately 20 g daily (usually given in 3 equal doses during the day) of creatine supplementation significantly increased strength in older adults undergoing a weight training program (Rawson 2011). One study of 35 older men in a 10-week weight training program reported that average muscle thickness increased 10.4% in a group given low dose (0.1 g/kg daily) creatine compared to a 5.5% muscle thickness gain in the placebo group (Candow 2008).

Omega-3 Fatty Acids

Consuming sufficient amounts of omega-3 fatty acids—found in high concentrations in certain fatty fish and fish oil, as well as in some seeds and nuts including walnuts, flaxseed, and chia seed—helps prevent and treat catabolic wasting. In one trial, 20 healthy young women were given 5 grams per day of omega-3 fatty acids, or a control oil, beginning four weeks before one of their legs was immobilized for two weeks. The women who received the omega-3 supplement lost less muscle volume compared with controls, and there was greater muscle protein synthesis in the omega-3 group (McGlory 2019). In a study of 16 healthy older adults, 4 grams daily of an omega-3 supplement (containing 1.86 grams EPA and 1.5 grams DHA) for eight weeks was associated with significantly greater protein synthesis rates than in control participants given 4 grams of corn oil daily (Smith 2011). A British study of 2,983 older adults reported that consuming higher levels of fatty fish was associated with greater handgrip strength (Robinson 2008). In a study of 18 cachectic pancreatic cancer patients receiving approximately 12 grams fish oil (containing 18% EPA and 12% DHA) daily, researchers reported an average weight gain of 0.7 pounds per month. Prior to supplementation, patients were severely cachectic and lost an average of 6.4 pounds per month (Wigmore 1996).

Conjugated Linoleic Acid (CLA)

Conjugated linoleic acid (CLA) consists of 2 slightly different types of unsaturated fat found in milk, meat, and flax. A number of animal and human studies have reported that consumption of CLA is associated with higher lean body mass and/or less fat mass. A study reported that adding 0.5% CLA to the diet of mice was associated with significantly higher lean muscle mass (Rahman 2009). A 6-month placebo-controlled study treated older human adults with 6 g CLA and 5 g creatine daily. All subjects participated in a twice-weekly weight lifting program. After 6 months, the CLA-creatine supplemented group gained significantly more lean weight (4.6 pounds vs. 2.0 pounds) and lost significantly more fat weight (4.2 pounds vs. 0.9 pounds) than the placebo group (Tarnopolsky 2007).

Vitamin D

Vitamin D is a critical nutrient for maintaining immunity as well as for the growth and maintenance of muscle and bone. Vitamin D deficiency is very common, with one study of 3170 U.S. adults ≥60 years reporting vitamin D levels of <30 ng/mL in approximately 76% of Whites, 96% of Blacks, and 92% of Mexican Americans (Ginde 2009). Vitamin D is known to increase muscle strength, and at doses of 700-1200 IU/day in elderly adults, it significantly decreased the rate of falls (Bischoff-Ferrari 2009; Dawson-Hughes 2008). A study in the Netherlands on 127 elderly people found that low vitamin D levels (<20 ng/mL) were associated with reduced lean mass and impaired physical performance (Tieland 2013). In another study, over 4000 men aged 70–88 were followed for an average of 5.3 years after having their vitamin D levels measured at baseline. Among men whose vitamin D levels were about 21 ng/mL or less, prevalence of frailty at baseline was 96% higher than among men whose vitamin D levels were greater than 32 ng/mL. For those men who were not frail at baseline, the risk of becoming frail over the 5.3-year follow up period was 56% higher among those with low vitamin D levels compared to those with the highest levels (Wong 2013). Life Extension® suggests that most people maintain blood levels of 25-hydroxyvitamin D between 50 and 80 ng/mL for optimal health.

Minerals

Adequate mineral intake is also important in maintaining muscle mass among the elderly. Many elderly individuals have insufficient dietary intakes and/or blood levels of several minerals including calcium, magnesium, selenium, chromium, and zinc (Park 2008; Vaquero 2002).

A study of 1339 Korean adults over age 60 years reported that higher daily calcium intakes were associated with significantly less fat mass, greater muscle mass, and reduced risk of sarcopenia compared to adults who consumed less calcium (Seo 2013). A study of 740 Tasmanian adults over age 50 reported that higher intake of iron, magnesium, phosphorus, potassium, and zinc were associated with significantly higher lean muscle mass in their arms and legs (Scott 2010). Animal studies have reported that deficiencies in zinc can reduce appetite and higher levels of dietary and supplemental zinc can increase appetite (Suzuki 2011). 

Many people with cachexia or sarcopenia also experience loss of bone mass (osteoporosis or osteopenia). Some researchers have pointed out that sarcopenia and postmenopausal osteoporosis co-exist and share very similar risk factors, show similarities in disease development, and interact with one another (Sirola 2011). Osteoporosis greatly increases the risk of bone breaks, with breaks to hip and back bones often occurring with little or no trauma. An analysis of 29 studies of 63 897 adults over age 50 reported that daily supplementation with 800-1500 mg calcium and 400-800 IU vitamin D was associated with a significant 12% reduction in osteoporosis-related bone fractures (Tang 2007).

Phytonutrients

In 2013, the typical U.S. adult consumed an average of only 2.7 one-half cup servings of fruits and vegetables per day, which is far less than the recommended 5 to 9 servings (CDC 2013). Fruits and vegetables contain a wide range of chemicals called “phytochemicals” which may be useful in controlling catabolic wasting.

Carotenoids. Carotenoids are phytochemicals that are found in yellow and green vegetables and fruits. Carotenoids have strong anti-inflammatory activity and some carotenoids such as beta-carotene can be converted by the body into vitamin A. Several studies have reported that lower blood levels of carotenoids are associated with significantly less muscle mass and strength and significantly more walking disability compared to elders with higher blood carotenoid levels (Semba 2007). 

Resveratrol. Resveratrol is an anti-inflammatory phytochemical found in grapes (especially dark-colored grapes), Japanese knotweed, and peanuts. Several laboratory studies have reported that supplemental resveratrol (12.5 or 22 mg/kg daily [equivalent to about 61 or 107 mg daily for a 132 pound adult human]) is associated with significant reductions in muscle loss due to aging or lack of use in elderly mice (Jackson 2010; Baur, Pearson 2006; Reagan-Shaw 2007).

Studies of rodents with cancer-related cachexia have reported conflicting results, with one study reporting that high dose (200-500 mg/kg/day) resveratrol significantly inhibited loss of skeletal and cardiac muscle in cachectic mice (Shadfar 2011), while another study reported that low dose resveratrol (1, 5, and 25 mg/kg/day) did not attenuate muscle loss in cachectic rats and mice (Busquets 2007).

Preclinical studies have reported that resveratrol has anti-inflammatory and anti-cancer effects, improves insulin metabolism, reduces blood pressure, and has life-extending properties (Poulsen 2013). Some human clinical studies have been conducted with resveratrol. One study reported that 150 mg resveratrol daily for 28 days significantly improved insulin metabolism and reduced systolic (pumping) blood pressure in 11 obese but otherwise healthy men (Timmers 2011). Resveratrol supplements appear to be quite safe, with consumption of 5000 mg resveratrol daily for 28 days causing no observable side effects in healthy volunteers apart from some mild gastrointestinal complaints like nausea and gas (Brown 2010).

Probiotics

HIV-positive individuals or people treated with cancer radiation or chemotherapy often experience chronic diarrhea, which can significantly reduce absorption of many nutrients. Several studies have reported that use of probiotic bacteria such as Lactobacillus acidophilus and Bifidobacterium longum can significantly reduce incidence of HIV/AIDS or cancer radiation-related diarrhea (Anukam 2008; Fuccio 2009). One study of women with HIV/AIDS-related moderate diarrhea reported that eating 100 mL (about 3.5 ounces) of yogurt supplemented with Lactobacillus rhamnosus GR1 and Lactobacillus reuteri RC-14 daily for 15 days produced resolution of diarrhea in all 12 women. Diarrhea resolved in only 2 of 12 women (17%) receiving 100 mL ordinary yogurt daily. The yogurt given to both sets of women was initially prepared with low levels of 2 bacteria including Lactobacillus delbruekii var. bulgaricus and Streptococcus thermophilus (Anukam 2008). A large double-blind study was conducted on 490 patients who had received radiation therapy for colorectal or cervical cancer. These patients received either a probiotic supplement containing 450 billion live bacteria (containing a mixture of 8 strains of probiotic bacteria including 4 species of lactobacillus - L. casei, L. plantarum, L. acidophilus, and L. delbruekii var. bulgaricus; 3 species of Bifidobacterium - B. longum, B. breve, and B. infantis; and one strain of Streptococcus salivarius var. thermophilus) or placebo 3 times daily for the length of their radiation treatments. Radiation-induced diarrhea occurred in 77 of 243 patients (31.6%) receiving probiotics, which was significantly less than the 124 of 239 participants (51.8%) receiving placebo (Delia 2007).

Mixtures of probiotic bacteria may be more useful in preventing diarrhea than a single probiotic organism alone. In a review of 16 published studies of the effects of probiotic bacteria on several medical conditions (including gut health, prevention of respiratory infections, atopic dermatitis, and diarrhea), 12 studies found that mixtures of probiotic bacteria were more effective than use of a single probiotic strain (Chapman 2011).

Digestive Enzymes

People with muscle wasting may also benefit by taking oral digestive enzyme supplements. A number of research studies have reported that older people are more likely to have lower levels of pancreatic enzymes (ie, enzymes that digest protein, fat, and carbohydrates) compared to younger adults (Holt 2007). A case series was reported of 3 adults (aged 78 to 80 years with no history of pancreatic disease) who experienced chronic diarrhea or vomiting and severe weight loss. Upon taking digestive enzymes, the diarrhea and vomiting resolved and the patients gained 13 to 30 pounds in 1 to 10 months (Coulson 2004). Another study reported that out of a group of 22 HIV-positive patients who were taking antiviral drugs and had chronic diarrhea, 8 had low levels of pancreatic digestive enzymes. One patient died of HIV/AIDS-related illness during the study. The other 7 experienced significant reductions in diarrhea after being treated with 10 000 to 60 000 units of pancreatic enzymes daily (Price 2005). In another study of 24 HIV/AIDS patients with severe fat malabsorption (ie, fat in stools or steatorrhea), subjects were treated with 1000 units of lipase, 800 units of amylase, and 60 units of protease per gram of fat consumed. After 2 weeks of enzyme treatment, fat malabsorption resolved in 8 patients (33%) and significantly improved in 11 other patients (46%) (Carroccio 2001).

Successful Management of Muscle Wasting Requires Many Nutrients

Successfully managing catabolic wasting requires a treatment plan that incorporates many nutrients. Such a multifaceted program was tested for 4 months on 39 patients with cancer cachexia and loss of appetite. Patients received the following daily interventions: 1) a well-balanced diet rich in fruits and vegetables to provide phytonutrients called polyphenols; 2) two cans daily of a liquid nutrient diet containing a broad range of vitamins and minerals, 16 g protein, 1.1 g EPA, and 0.46 g DHA per can; 3) an amino acid supplement containing 2.7 g of lysine and cysteine; 4) 200 mg daily of the anti-inflammatory drug celecoxib (Celebrex®); 5) 500 mg of medroxyprogesterone; and 6) other nutrients including 300 mg α-lipoic acid, 30 000 IU vitamin A, 500 mg vitamin C, and 400 mg vitamin E (Mantovani 2006). After 4 months, patients gained an average of 3.7 pounds of lean weight, had significantly lower markers of inflammation in the blood (such as IL-6), and had a markedly better quality of life (Mantovani 2006). Life Extension would recommend that natural progesterone cream be used in place of the synthetic progestin (medroxyprogesterone) used in this study. A starting dose for women would be ¼ to ½ teaspoon of natural progesterone cream (2.5%) applied twice a day to different parts of skin that has fat beneath its surface. Men might consider testosterone replacement in addition to a small dose of progesterone. Those with hormone sensitive cancers need close physician supervision when using hormone drugs.

Another study treated head and neck cancer patients who lost over 5% of their initial body weight over the preceding 6 months. Subjects were given 1500 calories per day of either a standard nutrition formula (Isocal) versus 1500 calories per day of a nutritional formula (Ethanwell/Ethanzyme [EE]) enriched with probiotic bacteria, omega-3 fatty acids, glutamine, arginine, selenium, and coenzyme Q10. After 3 months of treatment, subjects receiving the enriched nutritional formula gained an average of 7% of body weight, while the subjects receiving Isocal lost an average of 8% of body weight (Yeh 2013).

Treatment regimens that combine drug therapy and nutritional supplements may also be useful for patients with sarcopenia/cachexia. One study treated 332 cancer cachexia patients with one of 5 regimens:

  1. medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day)
  2. two cartons daily of a nutritional supplement containing 2.2 g EPA, 32 g milk protein, and 28 vitamins and minerals
  3. 4 g daily of L-carnitine
  4. 200 mg daily of thalidomide
  5. a combination of all 4 nutritional/drug treatments

All patients also received a daily supplement containing 300 mg polyphenols (phytonutrients), 300 mg α-lipoic acid, 2.7 g carbocysteine (a mucus-thinning drug), 400 mg vitamin E, 30 000 IU vitamin A, and 500 mg vitamin C.

After 4 months of treatment, the group receiving all 4 interventions (group 5) had significantly higher lean body mass, significantly less fatigue, and significantly lower levels of the inflammatory cytokine IL-6 compared to the single treatment groups (Mantovani 2010).

References

Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL.  Vaporization as a smokeless cannabis delivery system: A pilot study.  Clin Pharmacol Ther 2007;82:572-578.

Anker SD, John M, Pedersen PU, Raguso C, Cicoira M, Dardai E, . . . Vogelmeier C. ESPEN Guidelines on Enteral Nutrition: Cardiology and pulmonology. Clinical nutrition (Edinburgh, Scotland). Apr 2006;25(2):311-318.

Anukam KC, Osazuwa EO, Osadolor HB, Bruce AW, Reid G. Yogurt containing probiotic Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 helps resolve moderate diarrhea and increases CD4 count in HIV/ AIDS patients. J Clin Gastroenterol 2008; 42(3):239-243.

Arends J, Bodoky G, Bozzetti F, Fearon K, Muscaritoli M, Selga G, . . . Zander A. ESPEN Guidelines on Enteral Nutrition: Non-surgical oncology. Clinical nutrition (Edinburgh, Scotland). Apr 2006;25(2):245-259.

Argiles JM, Busquets S, Lopez-Soriano FJ, Costelli P, Penna F. Are there any benefits of exercise training in cancer cachexia? Journal of cachexia, sarcopenia and muscle. Jun 2012;3(2):73-76.

Attie KM, Borgstein NG, Yang Y, et al.  A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers.  Muscle Nerve 2013;47(3):416-423.

Baer JT.  Testosterone replacement therapy to improve health in older males.  Nurse Practitioner 2012;37:39-44.

Baier S, Johannsen D, Abumrad N, Rathmacher JA, Nissen J, Flaholl P. Year-long changes in protein metabolism in elderly men and women supplemented with a nutrition cocktail of β-hydoxy-β-methylbutryate (HMB), L-arginine and L-lysine. J Parenter Enter Nutr 2009;33(1):71-82.

Batterham MJ, Garsia R.  A comparison of megstrol acetate, nandrolone decanote and dietary counseling for HIV associated weight loss.  Int J Andrology 2001;24(4):232-240.

Baumgartner RN., Koehler KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epid 1998;147(8):755-763.

Baur JA, Pearson KJ, Price NL, et al.  Resveratrol improves health and survival of mice on a high-calorie diet.  Nature 2006a:444(7117):337-342.

Baur JA, Sinclair DA.  Therapeutic potential of resveratrol: the in vivo evidence. Nature Rev Drug Discov 2006b;5(6):493-506

Beal JE, Olson R, Lefkowitz L, et al.  Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage  1997;14(1):7-14.

Berger JR, Pall L, Hall CD, Simpson DM, Berry PS, Dudley R. Oxandrolone in AIDS-wasting myopathy. AIDS (London, England). Dec 1996;10(14):1657-1662.

Bischoff-Ferrari A, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. BMJ 2009;339:b3692.

Bocock MA, Keller HH.   Hospital diagnosis of malnutrition: a call for action.   Can J Diet Prac Res 2009;70:37-41.

Bonet Saris A, Marquez Vacaro JA, Seron Arbeloa C. [Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the Spanish Society of Intensive Care Medicine and Coronary Units-Spanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE): macro-and micronutrient requirements]. Medicina intensiva / Sociedad Espanola de Medicina Intensiva y Unidades Coronarias. Nov 2011;35 Suppl 1:17-21.

Brotto M, Abreu EL.  Sarcopenia: Pharmacology for today and tomorrow.  JPET 2012;343:510-512.

Brown VA, Patel KR, Viskaduarki M, et al. Repeat dose study of cancer chemopreventive agent resveratrol in healthy volunteers: Safety, pharmacokinetics and effect on the insulin-like growth factor axis. Cancer Res 2010;70(22):9003-9011.

Buehring R, Binley N.  Myostatin- The Holy Grail for muscle, bone and fat?  Curr Osteoporos Rep. 2013; In Press.

Burney BO, Hayes TG, Smiechowska J, et al.  Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia. J Clin Endocrin Metab 2012;97(5):E700-E709.

Busquets S, Fuster G, Ametller E, et al.  Resveratrol does not ameliorate muscle wasting in different types of cancer cachexia models. Clin Nutr 2007;26(2):239-244.

Campbell WW, Barton ML, Cyr-Campbell D, et al. Effects of an omnivorous diet compared with a lacotovovegtarian diet on resistance-training induced changes in body composition and skeletal muscle in older men. Am J Clin Nutr 1999;70(6):1032-1039.

Candow DG, Little JP, Chilibeck PD., et al.  Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc 2008;40(9):1645-1652.

Carrocio A, Guarino A, Zuin G, et al. Efficacy of oral pancreatic enzyme therapy for the treatment of fat malabsorption in HIV-infected patients.  Aliment Pharmacol Ther 2001;15:1619-1625.

Cawthon PM, Marshall LM, Michael I, et al. Frailty in older men: Prevalence, progression, and relationship with mortality. J Am Geriatr Soc 2007;55(8):1216-1223.

CDC- US Centers for Disease Control.  State Indicator Reporty on Fruits and Vegetables 2013.    Washington, DC. 

Chanou K, Gerodimos V, Karatrantou K, Jamurtas A. Whole-Body Vibration and Rehabilitation of Chronic Diseases: A Review of the Literature. Journal of sports science & medicine. 2012;11(2):187-200.

Chapman CMC, Gibson GR, Rowland I.  Health benefits of probiotics: are mixtures more effective than single strains?  Eur J Nutr 2011;50:1-17.

Churchward-Venne TA, Breen L, Phillips SM.  Alterations in human muscle protein metabolism with aging: Protein and exercise as countermeasures to offset sarcopenia.  Biofactors 2013; In Press

Clark R, Feleke G, Din M, et al. Nutritional treatment for acquired immunodeficiency virus-associated wasting using HMB, glutamine and arginine: A double-blind, placebo controlled study. JPEN - J Parenter Enter Nutr 2000;24(3):133-139.

Cosqueric G, Sebag A, Ducolombier C, Piette F, Weill-Engerer S. Sarcopenia is predictive of nosocomial infection in the elderly. Br J Nutr 2006;96(5):895-901.

Coulson JM, Jones RD, Hubbard RE, et al.  Pancreatic insufficiency and weight loss in older patients.  QJM (Quartely Journal of Medicine) 2004;97:377-380.

Cruciani RA, Zhang JJ, Manola J, Cella D, Ansari B, Fisch MJ.  L-carnitine supplementation for the management of fatigue in patients with cancer: an Eastern Cooperative Oncology Group Phase III, randomized, double-blind, placebo-controlled trial.  J Clin Oncol 2012;30:3864-3869.

Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al.  Sarcopenia: European consensus on definition and diagnosis. Age Ageing 2010;39(4):412-423.

Dalton JT, Barnette KG, Bohl CE, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo controlled phase II trial. J Cachexia Sarcopenia Muscle 2011;2(3):153-161.

Dardevet D, Remond D, Peyron MA, Papet I, Savas-Auzeloux I, Mosoni I  Muscle wasting and resistance of muscle anabolism: The “Anabolic Threshold Concept” for adapted nutritional strategies during sarcopenia.  ScientificWorldJournal 2012; In Press

Dawson-Hughes B. Serum 25-hydroxyvitamin D and functional outcomes in the elderly.  Am J Clin Nutr 2008;88(supplement):537S-540S.

de Oliveira TRC, Frigerio MLMA. Association between nutrition and the prosthetic condition in edentulous elderly. Gerodontology 2004;21(4):205-208.

de Souza PML, Jacob-Filho W, Santarem JM, Zomignan AA, Burattini MN. Effect of progressive resistance exercise on strength evolution in patients living with HIV compared to healthy controls. Clinics (Sao Paulo) 2011;66(2):261-266.

de Souza Vasconcelos KS, Dias JM, De Araulo MC, et al.  Land-based versus aquatic resistance therapeutic exercises for older women with sarcopenia obesity: study protocol for a randomized controlled trial.Trials 2013;14(1):296.

Delia P, Sansotta, Donato V, et al.  Use of probiotics for prevention of radiation-induced diarrhea. World J Gastroenterol 2007;13:912-915.

Diaz JJ, Pousman R, Mills B, et al. Critical Care Nutrition Practice Management Guidelines. Vanderbilt University Medical Center: TICU, SICU, NCU, BICU. Available at: http://www.mc.vanderbilt.edu/surgery/trauma/Protocols/nutrition-protocol.pdf. Last updated 11/2004. Accessed 1/22/2014.

Drey M. Sarcopenia- pathophysiology and clinical relevance. Wien Medical Wochenschr 2011;161(17-18):402-408.

Drummond MJ, Dickinson JM, Fry CS, et al. Bed rest impairs skeletal muscle amino acid transporter expression, mTORC1 signaling, and protein synthesis in response to essential amino acids in older adults. Am J Physiol Endocrin Metab 2012;302(9):E1113-1122.

Earleywine M, Barnwell SS.  Decreased repsuiratory symptoms in cannabis users who vaporize.  Harm Reduct J 2007;4:11.

Elliot B, Renshaw D, Getting S, Mackenzie R. The central role of myostatin in skeletal muscle body homeostasis. Acta Physiol (Oxford) 2012;205(3):324-340.

Evans WJ, Morley JE, Argiles JM, et al.  Cachexia: a new definition. Clin Nutr 2008;27:793-799.

Fearon K, Arends J, Baracos V.  Understanding the mechanisms and treatment options in cancer cachexia.  Nat Rev Clin Oncol 2013;10(2):90-99.

Fearon K, Evans WJ, Anker SD.  Myopenia- a new universal term for muscle wasting.  J Cachexia Sarcopenia Muscle  2011;2(1):1-3.

Fiatarone  MA, Marks EC, Ryan NC, Meredith CN, Lipsitz LA, Evans WJ. High-intensity strength training in nonagenerians. JAMA 1990;263(22):3029-3034.

Fillipas S, Cherry CL, Cicuttini F, Smirness L, Holland AE.  The effects of exercise training on metabolic and morphological outcomes for people living with HIV: A systematic review of randomized clinical trials. HIV Clin Trials 2010:11(5):270-283.

First Consult. Megestrol. Copyright © 2014 Elsevier, Inc. Clinical Key website. Drug Monograph page. Available at: https://www.clinicalkey.com/#!/ContentPlayerCtrl/doPlayContent/6-s2.0-370/{"scope":"all","query":"megestrol"}. Accessed 1/20/14.

Fox CB, Treadway AK, Blaszczyk AT, Sleeper RB.  Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly. Pharmacotherapy 2009;29(4):383-397.

Fuccio L, Guido A, Eusebi LH, et al. Effects of probiotics for the prevention and treatment of radiation-induced diarrhea. J Clin Gastroenterol 2009;43(5):506-513.

Ginde AA, Liu MC, Camargo CA, et al. Demographic differences and trends of vitamin D insufficiency in the US population. Arch Int Med 2009;169:629-632.

Glover EI, Phillips SM.  Resistance exercise and appropriate nutrition to counteract muscle wasting and promote muscle hypertrophy. Curr Opin Clin Nutr Metab Care 2010;13(6):630-634.

Gordon JN, Trebble TM, Ellis RD, Duncan HD, Johns T, Goggin PM.  Thaldomide in the treatment of cancer cachexia: a randomized placebo controlled trial.  Gut 2005;54:540-545.

Gramignano G, Lusso MR, Madeddu C, et al.  Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy.  Nutrition 2006;22:136-145.

Graziano F, Bisonni R, Catalano V, et al.  Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anemic cancer patients.  Br J Cancer 2002;86:1854-1857.

Grunfeld C, Kotler DP, Dobs A, Glesby M, Bhasin S. Oxandrolone in the treatment of HIV-associated weight loss in men: a randomized, double-blind, placebo-controlled study. Journal of acquired immune deficiency syndromes (1999). Mar 2006;41(3):304-314.

Gryson C, Walrand S, Giraudet C, et al.  “Fast proteins” with a unique amino acid content as an optimal nutrition in the elderly: Growing evidence. Clin Nutr 2013; In Press.

Guillory B, Splenser A, Garcia J.  The role of ghrelin in anorexia-cachexia syndrome.  Vitam Horm 2013;92:61-106.

Gullett NP, Hebbar G, Ziegler TR. Update on clinical trials of growth factors and anabolic steroids in cachexia and wasting. Am J Clin Nutr 2010;91(supplement):1143-1147S.

Gullett NP, Mazurak VC, Hebbar G, Ziegler TR. Nutritional interventions for cancer-induced cachexia. Current problems in cancer. Mar-Apr 2011;35(2):58-90.

Haney M, Gunderson EW, Rabkin J, et al.  Dronabinol and marijuana in HIV-positive marijuana smokers.  J Acquir Immune Defic Syndr 2007;45:545-554.

Hayes A, Cribb PJ. Effect of whey protein isolate on strength, body composition and muscle hypertrophy during resistance training. Curr Opin Clin Nutr Metab Care 2008; 11(1):40-44.

Holt PR.  Intestinal malabsorption in the elderly.  Dig Dis 2007;144-150.

Houston DK, Nicklas BJ, Ding J, et al. Dietary protein intake is associated with lean mass in older, community-dwelling adults: the Health, Aging and Body Composition (Health ABC) Study. Am J Clin Nutr 2008;87(1):150-155.

http://www.cdc.gov/nutrition/downloads/State-Indicator-Report-Fruits-Vegetables-2013.pdf Accessed November 22, 2013.

Hughes VA, Frontera WR, Roubenoff R, Evans WJ, Singh MA. Longitudinal changes in body composition in older men and women: Role of body weight change and physical activity. Am J Clin Nutr 2002;76(2):473-481.

Hutton B, Feine J, Morais J. Is there an association between edentulism and nutritional state? J Can Dent Assoc  2002;68(3):182-187.

Hwang AC, Liu LK, Lee WJ, et al. Association of androgen with skeletal muscle mass and muscle function among men and women age 50 years older in Taiwan.  Rejuvenation Res 2013; In Press

Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. The journals of gerontology. Series A, Biological sciences and medical sciences. Dec 2002;57(12):M772-777.

Jackson JR, Ryan MJ, Alway SE. Long term supplementation with resveratrol alleviates oxidative stress but does not attenuate sarcopenia in old mice. J Gerontol A- Biol Sci Med Sci 2011;66(7):751-754.

Jackson JR, Ryan MJ, Hao Y, Alway SE. Mediation of endogenous antioxidant enzymes and aptotic signaling by resveratrol following muscle disuse in the gastrocnemius muscles of young and old rats. Am J Physiol Regulat Integr Comp Physiol 2010;299(6):R1572-1581. 

Janssen I, Baumgartner RN, Ross R, Rosenberg IH, Roubenoff R. Skeletal muscle cutpoints associated with elevated physical disability risk in older men and women. Am J Epidemiol 2004;159(4):413-421.

Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R. The healthcare costs of sarcopenia in the United States. Journal of the American Geriatrics Society. Jan 2004;52(1):80-85.

Jiméenez Jiméenez FJ, Cervera Montes M, Blesa Malpica AL. [Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the Spanish Society of Intensive Care Medicine and Coronary Units-Spanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE): cardiac patient]. Medicina intensiva / Sociedad Espanola de Medicina Intensiva y Unidades Coronarias. Nov 2011a;35 Suppl 1:81-85.

Jiméenez Jiméenez FJ, Cervera Montes M, Blesa Malpica AL. Guidelines for specialized nutritional and metabolic support in the critically-ill patient: update. Consensus SEMICYUC-SENPE: cardiac patient. Nutricion hospitalaria. Nov 2011b;26 Suppl 2:76-80.

Jones TE, Stephenson KW, King JG, Knight KR, Marshall TL, Scott WB.  Sarcopenia- mechanisms and treatments.  J Geriatr Phys Ther 2009;32:39-45.

Katsanos CS, Chinkes DL, Paddon-Jones D, Zhang XJ, Aarsland A, Wolfe RR   Whey protein ingestion in elderly results in greater muscle protein accrual than ingestion of its constituent amino acid content. Nutr Res 2008;28(10):651-658.

Kemmler W, Bebenek M, Engelke K, Von Stengel S. Impact of whole-body electromyo-stimulation on body composition in elderly women at risk for sarcopenia: the Training and Electrostimulation Tral (TEST-III). Age (Dordr) 2013; In Press.

Khan ZH, Simpson EJ, Cole AT.  Oesophageal cancer and cachexia: the effect of short-0term treatment with thalidomide on weight loss and lean body mass.  Aliment Pharmacol Ther 2003;17:677-682.

Kim JS, Wilson JM, Lee SR. Dietary implications on mechanisms of sarcopenia: roles of protein, amino acids, and antioxidants. J Nutr Biochem 2010;21(1):1-13.

Kim MK, Baek KH, Song KH, et al. Vitamin D deficiency is associated with sarcopenia in older Koreans, regardless of obesity: The Fourth Korea National Health and Nutrition Examination Surveys (KNHANES IV) 2009. J Clin Endocrinol Metab 2011;96(10):3250-3256.

Kong NP, Edmonds P. Testosterone therapy in HIV wasting syndrome: systematic review and meta-analysis. Lancet Infect Dis 2002;2(11):692-699.

Koopman R, Ryall JG, Church JE, Lynch GS. The role of β-adrenoceptor signaling in skeletal muscle: therapeutic implications for muscle wasting disorders. Curr Opin Clin Nutr Metab Care 2009;12(16):601-606.

Lee P, Day RO, Greenfield JR, Ho KK. Formoterol, a highly beta2-selective agonist, increases energy expenditure and fat utilisation in men. International journal of obesity (2005). Apr 2013;37(4):593-597.

Leeanders M, Verdijk LB, Van Den Hoeven L, et al.  Patients with type 2 diabetes show a greater decline in muscle mass, muscle strength, and functional capacity with aging.  J Am Med Directors Assoc  2013;14(8):585-592.

Leifke E, Gorenoi V, Wichers C, von zur Muhlen A, von Buren E, Brabant G.  Age-related changes in serum sex hormones, insulin like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort.  Clin Endrocrin (Oxford) 2000;53:689-695.

Liu H, Bravata DM, Olkin I, et al. Systematic review: The safety and efficacy of growth hormone in the healthy elderly.  Ann Intern Med 2007;146(2):104-115.

Logemann JA.  Swallowing disorders. Best Pract Res Clin Gastroenterol 2007;21(5): 563-573.

Machado A, Garcia-Lopez D, Gonazlez-Gallego J, Garatachea N. Whole-body vibration training increases muscle strength and mass in older women: a randomized-controlled trial. Scand J Med Sci Sports 2010;20:200-207.

Maclaran KI, Panay N.  The safety of postmenopausal testosterone therapy.  Women’s Health 2012;8:263-275.

Maesta N, Nahas EAP, Nahas-Neto, et al.  Effects of soy protein and resistance on body composition and blood lipids in postmenopausal women. Mauritas 2007;56(4): 350-358.

Mantovani G, Maccio A, Madeddu C, et al.  A phase II study with antioxidants, both in diet and supplemented, pharmaconutritional support, progrestagen, and anti-cyclooxygenase-2 showing efficacy and safety in patients with cancer-related anorexia/ cachexia and oxidative stress. Cancer Epidemiol Biomarkers Prevent 2006;15(5):1030-1034.

Mantovani G, Maccio A, Madeddu C, et al.  Randomized phase III clinical trial of 5 different arms of treatment in 332 patients with cancer cachexia.  Eur Rev Med Pharmacol Sci 2010;14:292-301.

Martin WF, Armstrong LE, Rodriguez NY. Dietary intake and renal function. Nutr Metabol (London) 2005;2:25.

Marzetti E, Calvani R, Cesari M, et al. Mitochondrial dysfunction and sarcopenia of aging: From signaling pathways to clinical trials. Int J Biochem Cell Biol 2013;45(10): 2288-2301.

Marzetti E, Lees HA, Wohlgemuth SE, Leeuwenburgh C  Sarcopenia of aging: Underlying cellular mechanisms and protection by calorie restriction. Biofactors 2009;35(1):28-35.

Mathey MF, Vanneste V, De Graaf C, DeGroot LC, Van Stavern WA.  Health improvement of improved meal ambience in a Dutch nursing home: 1-year intervention study. Prev Med 2001;32(8):416-423.

May PE, Barber A, D’Olimpio JT,Hourihane A, Abumrad NN. Reversal of cancer-related wasting using oral supplementation with combination of β-hydroxy-β-methylbutyrate, arginine and glutamine.  Am J Surg 2002;183(1$):471-479.

Mayo Clinic. DHEA. Available at: http://www.mayoclinic.com/health/dhea/NS_patient-dhea. 2012.

McGlory C, Gorissen SHM, Kamal M, Bahniwal R, Hector AJ, Baker SK, . . . Phillips SM. Omega-3 fatty acid supplementation attenuates skeletal muscle disuse atrophy during two weeks of unilateral leg immobilization in healthy young women. The FASEB Journal. 2019;33(3):4586-4597.

Mercadante S. Parenteral versus enteral nutrition in cancer patients: indications and practice. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. Mar 1998;6(2):85-93.

Merck Manual 2013.  Cachexia in Cancer.  Last accessed 11/29/2013 at http://www.merckmanuals.com/

Mithal A, Bonjour JP, Boonen S, et al. Impact of nutrition on muscle mass, strength and performance in older adults. Osteoporos Int 2013;24(8):1555-1566.

Moeller LE, Peterson CT, Hanson KB, et al. Isoflavone-rich soy protein prevents loss of hip lean mass but does not prevent the shift in regional fat distribution in perimenopausal women. Menopause 2003;10(4):322-331.

Montero-Fernandez N, Serra-Rexach JA.  Role of exercise on sarcopenia in the elderly.  Eur J Phys Rehabil Med 2013;49(1):131-143.

Moon SS.  Low skeletal muscle mass is associated with insulin resistance, diabetes and metabolic syndrome in the Korean population: The Korea National Health and Nutrition Examination Survey (KNHANES) 2009-2010.  Endocr J, 2013, In Press.

Moore DR, Robinson MJ, Fry JL, et al.  Ingested protein dose response of muscle and albumin protein synthesis after resistance exercise in young men.  Am J Clin Nutr 2009; 89(1):161-168.

Morley JE, Thomas DR, Wilson MM. Cachexia: pathophysiology and clinical relevance. The American journal of clinical nutrition. Apr 2006;83(4):735-743.

Morley JE. Calories and cachexia. Curr Opin Clin Nutr Metab Care 2009;12(6):607-610.

Muscaritoli A, Lucia S, Molfino A, Cederholm MT, Rossi Fanelli F,  Muscle atrophy in aging and chronic diseases: is it sarcopenia or cachexia? Intern Emerg Med 2013;8: 553-560.

Muscaritoli M, Anker SD, Argiles J, Aversa Z, Bauer JM, Biolo G, . . . Sieber CC. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics". Clinical nutrition (Edinburgh, Scotland). Apr 2010;29(2):154-159.

Nicolini A, Ferrari P, Masoni MC, et al.  Malnutrition, anorexia, and cachexia in cancer patients: a mini-review on pathogenesis and treatment. Biomed Pharmacother 2013; In Press.

Nitenberg G, Raynard B. Nutritional support of the cancer patient: issues and dilemmas. Critical reviews in oncology/hematology. Jun 2000;34(3):137-168.

Norman K, Pichard C, Lochs H, Pirlich M. Prognostic impact of disease-related malnutrition. Clinical nutrition (Edinburgh, Scotland). Feb 2008;27(1):5-15.

NORML.  National Organization for the Reform of Marijuana Laws. Medical Marijuana- Laws by State 2013 accessed  1-27-14  at http://norml.org/legal/medical-marijuana-2

Orr R, Fiatarone Singh M. The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of efficacy and safety. Drugs. 2004;64(7):725-750.

Paddon-Jones D, Rasmussen BB. Dietary protein recommendations and the prevention of sarcopenia. Curr Opin Clin Nutr Metab Care 2009;12(1):86-90.

Park S, Johnson MA, Fischer JG. Vitamin and mineral supplements: Barrier and challenges for older adults. J Nutr Elderly 2008;27(3-4):297-317.

Penna F, Busquets S, Pin F, Toledo M, Baccino FM, Lopez-Soriano FJ, . . . Argiles JM. Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise. Journal of cachexia, sarcopenia and muscle. Jun 2011;2(2):95-104.

Pennings B, Senden JMG, Gijsen AP, Gijsen AP, Kuipers H, Van Loon LJ.  Whey protein stimulates postprandial protein accretion more effectively than do casein and casein hydrolysate in older men. Am J Clin Nutr 2011;93:997-1005.

Petersen AM, Magkos F, Atherton P, et al.  Smoking impairs muscle protein synthesis and the expression of myostatin and MAFbx in muscle. Am J Physiol Endocrinol Metab  2007;293(3):E843-848.

Peterson MD, Sen A, Gordon PM. Influence of resistance exercise on lean body mass in aging adults: a meta-analysis. Med Sci Sports Exerc 2011;43(2):249-258.

Phillips SM, Tang JE, Moore DR. The role of milk- and soy-bean protein in support of muscle protein synthesis and muscle protein accretion in young and elderly persons.  J Am Coll Nutr 2009;28(4):343-354.

Poulsen MM, Jorgensen JOL, Jessen N, et al. Resveratrol in metabolic health: an overview of the current evidence and perspectives. Ann NY Acad Sci 2013;1290:74-82.

Prado CMM, Bekaii-Saab T, Doyle LA, et al. Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma. Br J Cancer 2012;106(10):1583-1586.

Price DA, Schmid ML, Ong ELC, Adjukeiwicz KMB, Peaston B, Snow MH.  Pancreatic exocrine unsufficiency in HIV-positive patients.  HIV Medicine 2005;6:33-36.

professional/hematology_and_oncology/principles_of_cancer_therapy/cachexia_in_cancer.html

Rahman MM, Halade GV, El Jamali A, Fernandes G. Conjugated linoleic acid (CLA) prevents age associated skeletal muscle loss. Biochem Biophys Res Commun 2009;383(4):513-518.

Rawson ES, Venezia AC. Use of creatine and evidence for effects of cognitive function in the young and old.  Amino Acids 2011;40(5):1349-1362.

Reagan-Shaw S, Nihal M, Ahmad N.  Dose translation from animal to human studies revisited.  FASEB J 2007;22:659-661.

Ringseis R, Keller J, Eder K.  Mechanisms underlying the anti-wasting effect of l-carnitine supplementation under pathologic conditions: evidence from experimental and clinical studies.  Eur J Nutr 2013;52:1421-42.

Robinson SM, Jameson KA, Batelaan SF, et al. Diet and its relationship with grip strength in community-dwelling older men and women: the Hertfordshire Cohort Study.  J Am Geriatr Soc 2008;56(1):84-90.

Rolland Y, VanKan GA, Gillette-Guyonnet S, Vellas B.  Cachexia versus sarcopenia.  Curr Opin Clin Nutr Metab Care. 2010;14(1):15-21.

Rom O, Kaisari S, Aizenbud D, Reznick AZ. Identification of possible cigarette smoke constituents responsible for muscle catabolism. J Muscle Res Cell Motil 2012;33(3-4):199-208.

Ruiz Garcia V, Lopez-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S. Megestrol acetate for treatment of anorexia-cachexia syndrome. The Cochrane database of systematic reviews. 2013;3:Cd004310.

Samaras  N, Samaras D, Frangos E, et al.  A review of age-related dehydroepiandrosterone decline and its association with well-known geriatric syndromes: Is treatment beneficial?  Rejuvenation Res 2013;16(4):285-294.

Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-associated wasting. Ann Intern Med 1996;125(11):873-882.

Schols AM. Pulmonary cachexia. International journal of cardiology. Sep 2002;85(1):101-110.

Scott D, Blizzard L, Fell J, Giles G, Jones G. Associations between dietary nutrient intake and muscle mass and strength in community-dwelling older adults: The Tasmanian older adult cohort study. J Am Geriatr Soc 2010;58:2129-2134.

Semba RD, Lauretani F, Ferrucci L. Carotenoids as protection against sarcopenia in older adults.  Arch Biochem Biophys 2007;458(2):141-145.

Seo MH, Kim MK, Park SE, et al. The association between daily calcium intake and sarcopenia in older, non-obese Korean adults: the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) 2009. Endocr J 2013;60(5):679-686.

Shadfar S, Couch ME, McKinney KA, Weinstein LJ, Yin X. Oral resveratrol inhibits cancer-induced skeletal and cardiac atrophy in vivo. Nutr Cancer 2011;63(5):749-762.

Sheffield-Moore M, Dillon EL, Casperson SL, et al.  A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men. J Clin Endocrinol Metab 2011;96(11):E1831-1837.

Sheffield-Moore M, Paddon-Jones D, Casperson SL, et al.  Androgen therapy induces muscle protein anabolism in older women. J Clin Endocrin Metab 2006;91(10):3844-3849.

Siddiqui R, Pandya D, Harvey K, Zaloga GP. Nutrition modulation of cachexia/ proteolysis. Nutr Clin Pract 2006;21(2):155-167.

Silverio R, Laviano A, Rossi Fanelli FR, Seelander M.  L-carnitine and cancer cachexia: Clinical and experimental aspects. J Cachexia Sarcopenia Muscle 2011;2:37-44.

Sirola J, Kroger H. Similarities in acquired factors related to postmenopausal osteoporosis and sarcopenia. J Osteroporos 2011. Doi: 4061/2011/536735

Smith GI, Atherton P, Reeds DN, et al.  Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial. Am J Clin Nutr 2011;93(2):402-412.

Smith GI, Yoshino J, Reeds DN, Bradley D, Burrows RE, Heisey HD, . . . Mittendorfer B. Testosterone and progesterone, but not estradiol, stimulate muscle protein synthesis in postmenopausal women. The Journal of clinical endocrinology and metabolism. Jan 2014;99(1):256-265.

Solheim TS, Blum D, Fayers PM, Hjermstad MJ, Stene GB, Strasser F, Kaasa S. Weight loss, appetite loss and food intake in cancer patients with cancer cachexia: Three peas in a pod? - analysis from a multicenter cross sectional study. Acta oncologica (Stockholm, Sweden). Sep 2 2013.

Solheim TS, Laird BJA.  Evidence base for multimodal therapy in cachexia. Curr Opin Support Palliat Care 2012;6(4):424-431.

Srinivas-Shankar U, Roberts SA, Connolly MJ, et al.  Effects of testosterone in muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: A randomized, double-blind, placebo-controlled study.  J Clin Endocrinol Metab 2010;95:639-650.

Stene GB, Helbostad JL, Balstad TR, Riphagen II, Kaasa S, Oldervoll LM. Effect of physical exercise on muscle mass and strength during treatment- A systematic review. Crit Rev Oncol Hematol 2013; In Press,

Strawford A, Barbieri T, Van Loan M, Parks E, Catlin D, Barton N, . . . Hellerstein MK. Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: a randomized controlled trial. JAMA : the journal of the American Medical Association. Apr 14 1999;281(14):1282-1290.

Sullivan DH, Roberson PK, Smith ES, Price JA, Bopp MM.  Effects of muscle strength training and megestrol acetate on strength, muscle mass, and function in frail older people. J Am Geriatr Soc 2007;55(1):20-28.

Suzuki H, Asakawa A, Amitani H, Fujitsuka N, Nakamura N, Inui A. Cancer cachexia pathophysiology and translational aspect of herbal medicine. Japanese journal of clinical oncology. Jul 2013;43(7):695-705.

Suzuki H, Asakawa A, Li B, et al. Zinc as an appetite stimulator- the possible role of zinc in the progression of diseases such as cachexia and sarcopenia. Recent Pat Food Nutr Agric  2011;3(3):226-231.

Taaffe DR. 2006. Sarcopenia: Exercise as a treatment strategy. Aust Fam Physician 35(3):130-133.

Tang B, Eslick G, Nolwson C, Smith C, Bensoussan A. Use of calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years or older: a meta-analysis. Lancet 2007;370(9844):657-666.

Tarnopolsky M, Zimmer A, Paikin J, et al. Creatine monohydrate and conjugated linoleic acid improve strength and body composition following resistance exercise in older adults. PLoS One 2007;2(10):e991.

Tassinari D, Fochessati F, Panzini I, Poggi B, Sartori S, Ravaioli A. Rapid progression of advanced "hormone-resistant" prostate cancer during palliative treatment with progestins for cancer cachexia. Journal of pain and symptom management. May 2003;25(5):481-484.

Thomas DR. Loss of skeletal muscle mass in aging: Examining the relationship of starvation, sarcopenia and cachexia. Clin Nutr 2007;26(4): 389-399.

Tieland M, Brouwer-Brolsma EM, Nienaber-Rousseau C, van Loon LJ, De Groot LC. Low vitamin D status is associated with reduced muscle mass and impaired physical performance in frail elderly people. European journal of clinical nutrition. Oct 2013;67(10):1050-1055.

Timmers SW, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans.  Cell Metab 2011;14(5):612-622.

UMMC. University of Maryland Medical Center (UMMC). Dehydroepiandrosterone. Available at: http://umm.edu/health/medical/altmed/supplement/dehydroepiandrosterone. 2013.

Vaitkevicius PV, Ebersold C, Shah MS, et al. Effects of exercise training in community-based subjects aged 80 and older: A pilot study. J Am Geriatr Soc 2002;50(12):2009-2013.

Vaquero MP. Magnesium and trace elements in the elderly: Intake, status, and recommendations. J Nutr Health Aging 2002;6(2):147-153.

von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. Journal of cachexia, sarcopenia and muscle. Sep 2010;1(1):1-5.

Weiss EP, Shah K, Fontana L, Lambert CP, Holloszy J, Villareal DT.  Dehydroepidandrosterone replacement therapy in older adults: 1- and 2- year effects on bone. Am J Clin Nutr 2009;89(5):1459-1467.

Wigmore SJ, Ross JA, Falconer JS, et al.  The effect of polyunsaturated fatty acids with the progress of cachexia in patients with pancreatic cancer.  Nutrition 1996;12 (supplement 1):S27-S30.

Wolfe RA. Protein summit: consensus and further research. Am J Clin Nutr 2008;87(supplement 5 )1582S-1583S.

Wong YY, McCaul KA, Yeap BB, Hankey GJ, Flicker L. Low vitamin D status is an independent predictor of increased frailty and all-cause mortality in older men: the Health in Men Study. The Journal of clinical endocrinology and metabolism. Sep 2013;98(9):3821-3828.

Wright L, Hickson M, Frost G. Eating together is important: using a dining room in acute elderly medical wards increases energy intake. J Human Nutr Diet 2006;19(1):23-26.

Yeh KY, Wang HM, Change JWC, et al.  Omega-3 fatty acid-, micronutrient-, and probiotic-enriched nutrition helps body weight stabilization in head and neck cancer cachexia.  Oral Surg Oral Med Oral Path Oral Radiol 2013;116(1):41-48.

Yeh SS, Marandi M, Thode HC, et al.  Report of a pilot, double-blind, placebo-controlled study of megestrol acetate in elderly dialysis patients with cachexia. J Ren Nutr 2010;20(1):52-62.

Zacker RJ. Health-related implications and management of sarcopenia. JAAPA 2006;19(10):24-29.

Zamboni M, Mazzali G, Fantin F, Rossi A, Di Francesco V.  Sarcopenic obesity: A new category of obesity in the elderly. Nutr Metab Cardiovasc Dis. 2008;18(5):388-395.