Creatine. Creatine is a compound naturally produced in the body. It is also obtained through diet, predominantly meats and fish. Not only is supplemental creatine one of the most popular and well-researched ergogenic (performance-enhancing) aids used by athletes (UMMC 2014a; Cooper 2012), it is also an effective agent for preventing or slowing age-related muscle loss—known as sarcopenia—and has improved cognitive performance in the elderly (Devries 2014; Moon 2013; Wallimann 2011). Mouse studies indicate creatine may hold potential anti-aging effects (Klopstock 2011).
Numerous studies have shown that creatine supplements can increase muscle mass and enhance athletic performance (Wallimann 2011; Cooper 2012). Creatine is most effective as an aid to high-intensity, short-duration activities (eg, sprinting or weight lifting), which derive energy from creatine phosphate (UMMC 2014a; Baker 2010; Spillane 2009).
In older adults, creatine supplementation, with or without resistance exercise, has enhanced muscle strength and mass, increased bone strength, and slowed the rate of sarcopenia (Dalbo 2009; Moon 2013). Furthermore, according to one analysis, combining creatine supplementation with muscle strengthening exercise is more effective than exercise alone in increasing muscle mass, strength, and functional performance in older men and women (Devries 2014).
Creatine doses used in studies that enrolled aging subjects typically ranged from 5–21 grams per day, for a 150-pound individual, for limited periods of time (Dalbo 2009). Taking creatine supplements with carbohydrate, or protein and carbohydrate, may increase creatine muscle retention (Cooper 2012).
L-carnitine. L-carnitine is a compound obtained from food and synthesized in the body from the essential amino acids lysine and methionine. It is required for the burning of fats for energy production within the mitochondria, and can act as a free radical scavenger (Parandak 2014).
Studies have demonstrated that supplementation with L-carnitine can improve exercise performance and recovery (Parandak 2014; Wall 2011). In a randomized, double-blind, placebo-controlled trial, healthy male volunteers who ingested 2 grams L-carnitine along with 80 grams of carbohydrate twice daily for 24 weeks exhibited 21% increased muscle carnitine content, compared with no change in the control group. This was associated with reduced perception of effort and improvement in exercise performance (Wall 2011).
By reducing free radical generation and muscle soreness, L-carnitine supplementation supports muscle recovery after strenuous exercise (Pandareesh 2013; Huang 2012). In a placebo-controlled trial in healthy young men, oral supplementation with 2 grams L-carnitine for two weeks resulted in significantly reduced markers of oxidative stress and muscle damage following an acute bout of exercise (Parandak 2014).
Branched chain amino acids. The essential branched chain amino acids (BCAAs) leucine, isoleucine, and valine are important for the synthesis of muscle protein and burned by muscle cells for energy (Shimomura 2006; Gibala 2007; Benardot 2006; MSU 1998; Kanda 2013).
Human and animal studies have shown that supplemental intake of BCAAs increases exercise endurance (Falavigna 2012; Crowe 2006; Mittleman 1998). In a double-blind placebo-controlled study, BCAA supplementation for three days increased resistance to fatigue and enhanced fat burning for fuel during exhaustive endurance exercise that caused glycogen (stored carbohydrate) depletion (Gualano 2011).
Like other essential amino acids, BCAAs function as precursors (building blocks) for muscle protein synthesis (Fujita 2006). Importantly, the BCAAs, especially leucine, also exert anabolic effects by directly stimulating muscle growth and inhibiting muscle protein degradation (Karlsson 2004; Shimomura 2006; HCHS 2009).
By reducing breakdown of muscle proteins and promoting protein synthesis, BCAAs have improved recovery from exercise (HCHS 2009; Shimomura 2006). In a study in long-distance runners undergoing intense training, BCAA supplementation reduced soreness and fatigue, as well as markers of inflammation and muscle damage (Matsumoto 2009).
Vitamin D. Vitamin D plays an essential role in bone metabolism, muscle function, and immune health. Sufficient blood levels of vitamin D are important for musculoskeletal injury prevention and recovery, and are associated with reduced inflammation and pain, stronger muscles, and better athletic performance (Shuler 2012; Ogan 2013).
Apart from its role in preventing fractures and muscle injuries, research also suggests vitamin D may have performance-enhancing effects. Unfortunately, many athletes are vitamin D deficient (Dahlquist 2015; Shuler 2012). Trials of supplemental vitamin D at dosages of 3300 to 5000 IU daily have found improvements in sprinting and jumping performance as well as increased circulating testosterone (Dahlquist 2015; Shuler 2012; Holick 2011).
One team of scientists suggested supplementing with 4000 to 5000 IU per day of vitamin D3, along with 50 to 1000 mcg per day of a mixture of vitamins K1 and K2, which complement vitamin D’s role in bone and calcium metabolism, could support athletic performance by improving recovery time and muscle function (Dahlquist 2015).
Glutamine. Glutamine, because it is synthesized in the body, is a non-essential amino acid. However, glutamine becomes "conditionally essential" when blood levels are reduced in times of illness and stress (Alt Med Rev 2011; UMHS 2015; Legault 2015; Tao 2014).
Glutamine plays a role in immune response to muscle damage (Legault 2015; Stehle 2015; Mondello 2010). In a controlled two-week trial in male college-aged martial arts athletes, supplementation with 3 grams daily of glutamine for two weeks reduced muscle damage and prevented decline of immune function, including during a strenuous training period (Sasaki 2013). A controlled clinical trial that used 10 grams of glutamine daily for three weeks in athletes undergoing intensive training found an improvement in immunity as evidenced by white blood cell profiles, including an increase in natural killer cell activity (Song 2015). Another controlled clinical trial found athletes given 5 grams of glutamine immediately after and two hours after intense, prolonged exercise reported roughly 40% fewer upper respiratory infections than those given placebo (Castell 1996).
DHEA. Produced by the adrenal glands, dehydroepiandrosterone (DHEA), along with its sulfated form, DHEA-S, is the most abundant steroid hormone in circulation (Perrini 2005; Barrou 1997). DHEA is a precursor of sex hormones such as estrogens and androgens. DHEA levels peak around age 25 and decline by roughly 80% by age 75 (UMMC 2014b; Villareal 2006).
Studies show DHEA supplementation has exercise-enhancing effects (Liu 2013; Villareal 2006). In a study in elderly men and women, DHEA supplementation significantly enhanced muscle growth and strength in response to resistance exercise (Villareal 2006).
In a randomized controlled trial, a single dose of 50 mg DHEA increased free testosterone levels above baseline in middle-aged men. This dosing was followed by a bout of high-intensity interval training, after which free testosterone remained elevated in the DHEA-supplemented middle-aged individuals (Liu 2013).
Whey protein. Whey protein, a group of milk-derived proteins with a high concentration of essential amino acids and BCAAs, activates muscle protein synthesis and recovery in response to resistance exercise (Hayes 2008). Whey protein supplementation significantly decreases body weight and body fat, and increases lean body mass when combined with resistance training (Miller 2014; Buckley 2010; Farup, Rahbek, Knudsen 2014; Hayes 2008).
Whey protein is rapidly digested and absorbed. Leucine, one of the BCAAs in which whey protein is especially rich, plays an important role in muscle protein metabolism as well as healthy glucose metabolism and body weight maintenance (Kanda 2013; Pennings 2011; Hayes 2008).
In one study, whey protein given to healthy subjects during recovery from maximal-effort exercise significantly increased the amount of muscle satellite cells. These satellite cells, or stem cells, are essential for muscle regeneration (Farup, Rahbek, Knudsen 2014; Yin 2013). In another study, high-leucine whey protein hydrolysate was more effective than placebo at increasing muscle and tendon growth after 12 weeks of leg resistance exercise (knee extensor training) (Farup, Rahbek, Vendelbo 2014).
D-ribose. D-ribose is the biologically active form of the naturally occurring sugar, ribose, and is produced in the body from glucose. Ribose is involved in the synthesis of ATP, which provides energy to muscle cells during exercise. Supplementation with ribose has accelerated ATP synthesis following its depletion during intense exercise (Hellsten 2004; Peveler 2006; Dhanoa 2007).
A controlled trial in 12 male recreational body builders found that supplementation with 10 grams ribose per day for four weeks resulted in greater gains in muscle strength and endurance than placebo (Van Gammeren 2002). D-ribose may also help combat fatigue and improve mood and vitality in aging adults (Flanigan 2010); this may allow for increased exercise frequency. A dosing study found taking D-ribose on an empty stomach leads to more efficient absorption than taking it with food (Thompson 2014).
Periodically, concerns arise regarding the potential of D-ribose to promote damaging glycation reactions. While ribose can contribute to glycation reactions when present in high concentrations, the amount of D-ribose attained through supplementation is not worrisome. These concerns have been addressed thoroughly in an article titled "Restoring Cellular Energy Metabolism" in the October 2012 issue of Life Extension Magazine.
Omega-3 fatty acids. A growing body of evidence supports the use of omega-3 fats to improve recovery from strenuous exercise (Corder 2016; Jouris 2011). Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA), can be beneficial in the prevention and treatment of sarcopenia as well (Jeromson 2015; Smith 2011). In a controlled study in older adults, daily supplementation with omega-3 fatty acid containing over 1.8 grams EPA and 1.5 grams docosahexaenoic acid (DHA) increased the rate of muscle protein synthesis compared with a corn oil, which provided no benefit (Smith 2011).
Coenzyme Q10. Coenzyme Q10 (CoQ10) is an essential component of the series of biochemical reactions that generate energy in the cell’s mitochondria. CoQ10 also functions as a free radical scavenger, protecting cells against oxidative damage (Sarmiento 2016; Pala 2016; Kumar 2009).
Clinical studies have demonstrated an exercise-enhancing effect of CoQ10 supplementation (Gokbel 2010; Cooke 2008). In a study in trained and untrained individuals, supplementation with 100 mg CoQ10 for 14 days increased the length of time participants could exercise before reaching exhaustion (Cooke 2008). A randomized controlled study in male runners found that 14 days of CoQ10 supplementation reduced the spike in blood levels of lactate, interleukin-6, tumor necrosis factor-alpha, and C-reactive protein induced by a bout of middle-distance competitive running (Armanfar 2015). The dose of CoQ10 used in the study was 5 mg/kg/day, or about 350 mg per day for a 155-pound person.
In an animal study, rats were supplemented with CoQ10 for six weeks during exercise training. This produced beneficial changes in levels of key regulatory proteins, including nuclear factor-kappaB and Nrf2, both involved in inflammation and defense against oxidative stress (Pala 2016).
Arginine. Arginine is a conditionally essential amino acid that participates in a variety of metabolic pathways, including protein synthesis. Importantly, arginine is a precursor of nitric oxide (NO), a potent vasodilator. Because of this contribution to vasodilation, arginine supplementation may increase blood flow to muscles (Camic 2010; Campbell 2004; McConell 2007).
In a controlled clinical trial in competitive male cyclists, supplementation with 6 grams L-arginine daily for three days increased 20 kilometer time trial performance, reduced oxygen consumption, and reduced systolic and diastolic blood pressure (Ranchordas 2011). In another controlled clinical trial in untrained college-aged men, supplementation with a product containing 1.5 grams or 3 grams of arginine (along with grape seed extract) for four weeks reduced the time to onset of cycling-induced fatigue compared with placebo (Camic 2010).
Animal studies indicate arginine supplementation may be beneficial for exercise recovery (Lomonosova 2014; Huang 2008). In one study, L-arginine supplementation before a single bout of exercise reduced muscle fiber damage and maintained exercise performance capacity in rats. These effects were attributed to increased muscle nitric oxide content (Lomonosova 2014).
Resveratrol. Resveratrol is a polyphenol compound found in plants and plant foods such as grapes, red wine, peanuts, and Japanese knotweed (Boozer 2001; Burns 2002). Resveratrol has been shown to favorably influence several factors involved in chronic degenerative diseases, including inflammation, insulin sensitivity, oxidative stress, and endothelial dysfunction (Polley 2016; Mohammadi Sartang 2017; Diaz 2016; Oyenihi 2016; Chen 2015).
There is clinical and preclinical evidence that resveratrol can augment the effects of exercise on muscle mitochondrial capacity, increasing energy production and utilization (Menzies 2013; Polley 2016). In a double-blind placebo-controlled trial in healthy young adults, daily supplementation with 500 mg resveratrol (plus 10 mg piperine, a black pepper extract) combined with low-intensity endurance exercise for four weeks significantly increased muscle mitochondrial capacity (Polley 2016).
Two animal studies found resveratrol supplementation improved exercise performance compared with exercise alone (Wu 2013; Dolinsky 2012). In one animal study, rats fed a diet supplemented with resveratrol during 12 weeks of exercise training were able to run longer and further than rats trained without resveratrol. Improved muscle strength was also noted in resveratrol-treated rats (Dolinsky 2012).
Gynostemma pentaphyllum. Gynostemma pentaphyllum is an herb with a long history of use in Chinese medicine as a health tonic. Components of Gynostemma have been shown in preclinical research to activate AMPK—a major regulator of glucose, fat, and energy metabolism in the body (Lin-Na 2014; Nguyen 2011).
Animal studies have demonstrated anti-fatigue effects of Gynostemma(Lin-Na 2014; Chi 2012). In one of these studies, polysaccharides derived from Gynostemma extended the exhaustive swimming time of rats. The Gynostemma polysaccharide extracts also lowered blood lactic acid levels and increased liver and muscle glycogen concentrations (Lin-Na 2014).
A study in mice found that prolonged time to exhaustion from exercise after administration of Gynostemma polysaccharides was linked to reduced oxidative stress and enhanced muscle glycogen levels (Chi 2012).
Cordyceps sinensis. Cordyceps sinensis is a medicinal mushroom used for centuries in traditional medicine in China and India to promote vigor, endurance, and longevity (Chen 2010; Chen 2014; Panda 2011). Scientific studies have found that Cordyceps mycelia boosts exercise performance (Kumar 2011; Chen 2014).
In a double-blind placebo-controlled trial in adults aged 50 to 75 years, 12 weeks of supplementation with an extract of Cordyceps sinensis fermented mycelium delayed fatigue and resulted in improved aerobic performance on an exercise test (Chen 2010).
Another animal study found Cordyceps sinensis mycelia may mimic some of the metabolic benefits of exercise. Supplementation with Cordyceps sinensis in rats increased exercise endurance despite lack of training. Significant AMPK activation was thought to be partly responsible for this effect (Kumar 2011).
Potential mechanisms for the exercise-enhancing effects of Cordyceps include improved blood sugar regulation, increased insulin sensitivity, and greater production of ATP—the cell’s energy source (Kumar 2011; Chen 2010).
Panax ginseng. Panax ginseng (also called Chinese or Korean ginseng) is a popular herbal medicine used worldwide to increase physical strength and reduce fatigue (Wang 2010; Oliynyk 2013; Chen 2012). Potential mechanisms for the performance-enhancing effects of ginseng root include improved fat utilization for energy (while sparing glycogen), increased levels of the vasodilating molecule nitric oxide, and mild central nervous system stimulation (Oliynyk 2013; Bucci 2000; Wang 2010; Wang 1998; Zhao 2009; Nocerino 2000; Kim 2005). Multiple clinical trials and animal studies have shown ginseng improves exercise performance and prevents fatigue, and may have stronger effects in older and recreational athletes (Kim 2005; Liang 2005; Oliynyk 2013; Zhao 2009; Bucci 2000; Jung 2004).
Ginseng appears capable of delaying exercise-induced fatigue (Oliynyk 2013; Chen 2012; Jia 2009; Nocerino 2000). In a controlled study in healthy male subjects, eight weeks of supplemental Panax ginseng root extract prior to exercise on a treadmill decreased formation of malondialdehyde—a marker of oxidative stress. As a consequence of diminished oxidative stress, exercise time to exhaustion was significantly prolonged (Kim 2005).
Two types of compounds in ginseng—polysaccharides and ginsenosides—are thought to contribute to the fatigue-fighting properties of ginseng (Wang 2010; Zhao 2009; Wang 1998).
Ginsenosides are converted to bioactive compounds, such as compound K, by intestinal bacteria (Kim 2015). Compound K possesses anticancer, anti-inflammatory, and anti-allergic properties, and contributes to the health-enhancing effects of ginseng (Kim 2015; Bae 2002). Fermented ginseng contains compound K, making fermentation one method of enhancing the bioavailability of this important compound (Jin 2012; Hasegawa 2004).
Rhodiola rosea. Found in mountainous areas of Europe, Asia, and North America, Rhodiola rosea is an herb with a long history of use in traditional medicine as an anti-fatigue, anti-stress, and mood-enhancing agent. Studies have also shown that Rhodiola has positive effects on exercise performance and endurance in humans and animals (Noreen 2013; Duncan 2014; Lee 2009; De Bock 2004).
Rhodiola is an adaptogen, increasing the body’s ability to adapt to the stress of physical exercise (Parisi 2010; Walker 2006). Rhodiola also increases utilization of fat for energy, improves mitochondrial function, and suppresses free radicals (Chen 2014; Parisi 2010; Walker 2006).
In one controlled trial in active young women, rhodiola improved endurance exercise performance by reducing perceived effort. Subjects given a single oral dose (3 mg/kg body weight, or about 200 mg for a 150-pound person) of rhodiola completed a six-mile time trial on a stationary bicycle significantly faster that subjects given placebo. Rhodiola also lowered the heart rate response to submaximal exercise in this study (Noreen 2013).
Another placebo-controlled trial measured the effect of arhodiola extract standardized to contain 3% rosavins and 1% salidroside in 24 participants. Researchers noted endurance exercise capacity improved one hour after an acute dose of 200 mg of rhodiola extract (De Bock 2004).
Rhodiola may lessen exercise-induced muscle damage. In a study in male athletes, four weeks of rhodiola supplementation prior to exhaustive endurance exercise significantly decreased markers of muscle damage. Notably, serum levels of creatine kinase, which rise after vigorous exercise, substantially decreased after rhodiola ingestion (Parisi 2010).