Catabolic Wasting - Cachexia and Sarcopenia
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, 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
Consumption of sufficient amounts of omega-3 fatty acids is helpful in preventing and treating catabolic wasting. Omega-3 fatty acids are found in high concentrations in certain fatty fish/fish oil and flaxseed/flax oil. A study of 16 healthy older adults reported that 4 g daily of an omega-3 supplement (containing 1.86 g EPA and 1.5 g DHA) for 8 weeks was associated with significantly greater protein synthesis rates compared to controls given 4 g of corn oil daily (Smith 2011). A British study of 2983 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 g fish oil (containing 18% EPA and 12% DHA) daily, authors reported an average weight gain of 0.7 pounds/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 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.
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).
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).
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).
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:
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).
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