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.

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.

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).

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).

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).

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.

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).

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.

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).

Supplemental Protein and Amino Acids

Increasing protein and amino acid intake is critical for slowing and possibly reversing muscle loss (Prado 2020). The benefits of increased protein and amino acid intake on muscle mass may be more pronounced when combined with exercise and when implemented in the early stages of cachexia (Antoun 2018, Prado 2020).

Whey protein and branched chain amino acids. Individual amino acids have different effects on health and muscle metabolism, and the optimal balance of amino acids in cachexia is not known. However, the branched chain amino acids leucine, isoleucine, and valine are especially important in promoting muscle tissue growth (de Campos-Ferraz 2014; Prado 2020). Some evidence suggests intake of 2–4 grams daily of leucine in particular may be important for stimulating muscle protein synthesis (de Campos-Ferraz 2014; Antoun 2018; Prado 2020; Soares 2020). Whey protein supplements are rich in leucine and the other branched chain amino acids, and clinical trials have shown whey protein may benefit cachexia patients (Teixeira 2019; Prado 2020). One study found that 14 grams per day of a high-leucine blend of essential amino acids more effectively induced protein synthesis in healthy volunteers and those with advanced cancer than a supplement with a balance of essential and non-essential amino acids similar to whey protein (Engelen 2015).

A placebo-controlled trial tested the effects of a leucine-enriched protein supplement in people with sarcopenia. One hundred twenty-seven older adults enrolled in an in-patient rehabilitation program completed the study. The leucine-enriched whey protein-based supplement contained 20 grams whey protein (providing 2.8 grams of leucine), plus vitamins, minerals, and fiber. Subjects took this blend or an isocaloric control blend twice daily for four to eight weeks. Subjects taking the leucine-enriched whey blend had greater increases in walking speed, muscle mass, and muscle strength than those taking the control blend. Moreover, a higher proportion of those taking the leucine-enriched blend were discharged home, had shorter rehabilitation, and could undergo greater rehabilitation intensity (Rondanelli 2020).

Another controlled trial included 46 men with moderate-to-severe COPD, a condition often associated with cachexia and muscle wasting. Although there were no significant changes in body weight, those treated with a daily supplement providing 15.9 grams whey protein plus 275 mg magnesium and 685 mg vitamin C for eight weeks had increases in fat-free mass, body protein, and hand grip strength, as well as reduced levels of an inflammatory cytokine (IL-6) relative to placebo (Ahmadi 2020). In a trial in patients with heart failure, however, the addition of 10 grams per day of branched chain amino acids for three months did not add to the positive effects of a strength training exercise program on muscle strength and fitness, nor on symptoms like fatigue, dizziness when rising from lying down, and shortness of breath (Pineda-Juárez 2016).

Soy protein. Supplementation with soy protein has also been reported to significantly increase muscle mass, strength, and function when combined with strength training exercise in older adults (Orsatti 2018; Liao 2019). Although soy and other plant proteins have long been thought to have weaker muscle-building effects than whey and other animal proteins due to their relatively low content of essential amino acids, including leucine (Devries 2015; van Vliet 2015; Devries 2018), a meta-analysis of nine trials with 266 participants found soy protein and whey protein, in combination with strength-building exercise, produced similar gains in muscle mass and strength (Messina 2018). In one study in healthy men and women, supplementing with 19 grams whey protein isolate or 26 grams soy protein isolate, amounts that provided approximately 2 grams leucine, resulted in the same degree of muscle growth during a 12-week strength training program (Lynch 2020).

Another strategy that may improve the effect of soy protein is fortification with the leucine metabolite HMB. In a small crossover trial with eight participants, muscle growth after 36 hours of fasting was similarly enhanced by a soy protein supplement fortified with 3 grams per day HMB as by a leucine-rich whey protein supplement (Rittig 2017). Although there is little research on the effects of soy protein on cachexia, one placebo-controlled trial that included 73 patients with burns on 20–50% of their body surface area found three weeks of treatment with a soy protein isolate resulted in less weight loss and greater muscle retention (Babajafari 2018). In addition to increasing muscle protein synthesis, soy protein can improve cardiovascular and metabolic health, and some evidence suggests protease inhibitors found in soy may help mitigate muscle breakdown in conditions associated with cachexia (Nikawa 2002; Morris 2005; Paul 2015).

Egg and other proteins. Egg, meat, and fish are sources of high-quality protein that have been correlated with greater muscle mass in adults (Alexandrov 2018). However, in a clinical trial of 36 older subjects participating in a 12-week strength training program, a diet providing 1.2 grams of protein per kilogram of body weight, mainly from eggs, meat, and dairy, had the same effect on muscle mass as a diet providing 0.9 grams of protein per kg of body weight (Bhasin 2018). Egg protein is rich in leucine and branched chain amino acids, and therefore could have positive effects on muscle growth and maintenance in older people and those with conditions that can cause muscle wasting (Miranda 2015; Smith 2016). Nevertheless, findings from animal research suggest whey protein may be more effective than egg protein for stimulating muscle growth (Mobley 2015).

Beta-hydroxy-beta-methylbutyrate (HMB). HMB, a metabolite of leucine, has been shown to increase muscle protein synthesis and inhibit muscle breakdown, especially when combined with exercise, in trials in healthy adults and the elderly (Molfino 2013; Holeček 2017). In a placebo-controlled trial in elderly women, a supplement containing 2 grams HMB, 5 grams arginine, and 1.5 grams lysine increased whole body protein synthesis by 20% more than placebo, increased muscle size and strength, and improved “get up and go” functionality (Flakoll 2004). In another trial with 77 elderly participants, taking HMB plus arginine and lysine resulted in a 1.2% increase in lean mass compared with a control supplement providing the same amount of nitrogen (Baier 2009).

Other clinical research suggests adequate vitamin D is needed to support the positive impact of HMB/arginine/lysine on muscle strength, but not muscle mass (Fuller 2011). HMB, at a dose of 3 grams daily, along with 14 grams per day each of arginine and glutamine, has also been found to increase body mass and fat-free mass in people with muscle wasting due to cancer and HIV/AIDS (Clark 2000; May 2002). A meta-analysis of 15 randomized controlled trials in elderly participants with conditions frequently associated with muscle wasting concluded treatment with 3 grams HMB daily, alone or with other amino acids, for four weeks or longer can induce small increases in muscle strength and mass without affecting body weight (Bear 2019).

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).