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Nutritional supplement series

A–Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance—Part 27 Andrew M Jones,1 Satoshi Haramizu,2 Mayur Ranchordas,3 Louise Burke,4 Samantha Stear,5 Linda M Castell6 1School

of Sport and Health Sciences, University of Exeter, Exeter, UK 2Biological Science Laboratories, Kao Corporation, Haga-Gun, Japan 3Department of Sport, Sheffield Hallam University, Sheffield, UK 4 Australian Institute of Sport, Canberra, Australia 5Performance Influencers Limited, London, UK 6University of Oxford, Green Templeton College, Oxford, UK Correspondence to Linda M Castell, University of Oxford, Green Templeton College, Oxford OX2 6HG, UK; [email protected] Received 11 October 2011 Accepted 11 October 2011

INTRODUCTORY REMARKS Welcome to Part 27, where we fi nish ‘N’ with nitrates and nootkatone and move onto ‘O’ starting with octacosanol. The fi rst review focuses on what has become quite a hot topic in sport nutrition in the recent years with the BBC leading with a headline in August 2009 that ‘Beetroot Juice boosts Stamina’. The BBC was describing a study from Professor Andy Jones’ group: in his brief review for Part 27, he describes the link between supplementing the diet with nitrate-rich beetroot juice to enhance NO availability and the consequential proposed mechanisms that could lead to an improvement in exercise performance. The other two reviews deal with substances that are generally found as plant extracts: nootkatone, a chemical found in the essential oil of grapefruit and other plants including cedars, which is used predominantly as a fl avouring compound but also as a natural insecticide; and policosanol, a wheat-germ extract whose main component is octacosanol.

NITRATES AM Jones Nitric oxide (NO) is an important physiological signalling molecule that can modulate skeletal muscle function through its role in the regulation of blood flow, muscle contractility, glucose and calcium homeostasis and mitochondrial biogenesis and respiration.1 Until quite recently, it was considered that NO was generated solely through the oxidation of the amino acid L-arginine in a reaction catalysed by nitric oxide synthase (NOS). 2 It is now appreciated, however, that NO may also be produced by the reduction of nitrate to nitrite and subsequently of nitrite to NO. 3 This pathway may be particularly important in hypoxia. Nitrate and nitrite are present in the body as products of NO production through NOS and are also modulated through the diet. Nitrate in foods (particularly green leafy vegetables) can be reduced to nitrite by oral bacteria, leading to an increased plasma nitrite concentration that serves as a circulating ‘reservoir’ for NO production.4 Several recent studies have addressed the extent to which dietary nitrate supplementation might affect the physiological responses to exercise. Larsen et al 5 fi rst showed that 3 days of sodium nitrate supplementation (0.1 mmol/kg/day) reduced resting blood pressure and the O2 cost of submaximal cycle exercise. Subsequently, we 1246

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have reported that enhancing NO bioavailability through supplementation of the diet with a natural foodstuff (nitrate-rich beetroot juice) reduces resting blood pressure and the O2 cost of exercise and improves exercise performance.6–10 In the fi rst study,6 we found that 4–6 days of dietary nitrate supplementation (0.5 litres of beetroot juice per day containing ~6 mmol nitrate) reduced the ‘steady-state’ O2 cost of submaximal cycle exercise by 5% and extended the time to exhaustion during high-intensity cycling by 16%. In a follow-up study, 7 we used 31P-magnetic resonance spectroscopy to investigate the mechanistic bases of this phenomenon. Dietary nitrate supplementation resulted in both a reduced pulmonary O2 uptake and reduced muscle metabolic perturbation, enabling high-intensity knee-extension exercise to be tolerated for a greater period of time. These data imply that the reduced O2 cost of exercise following dietary nitrate supplementation is related to a reduced ATP cost of muscle force production, perhaps consequent to reduced cross-bridge cycling or sarcoplasmic reticulum Ca 2+-ATPase activity.11 It is also possible, however, that nitrate supplementation enhances mitochondrial efficiency. Larsen et al12 have reported that sodium nitrate reduced proton leakage and increased the mitochondrial P/O ratio. The positive effects of nitrate supplementation on the O2 cost of submaximal exercise can be manifest acutely (ie, 2.5 h following a 6 mmol nitrate ‘bolus’) and this effect can be maintained for at least 15 days if supplementation at the same daily dose is continued.8 Because beetroot juice contains compounds other than nitrate that might also be bioactive, we have developed a nitrate-depleted beetroot juice as a placebo. Nitrate-depleted beetroot juice had no physiological effects relative to a control condition, whereas nitrate-rich beetroot juice reduced the O2 cost of both walking and running and extended the time to exhaustion by 15%.9 Most recently, we have investigated the influence of acute dietary nitrate supplementation on 4 and 16.1 km time trial (TT) performance in competitive cyclists.10 We found that cyclists were able to produce a greater power output for the same rate of pulmonary O2 uptake, resulting in a 2.7% reduction in the time to complete both the TT distances. Collectively, recent studies 5–10 13 indicate that dietary nitrate supplementation reduces the O2 cost of physical activity and might enhance exercise performance. While these early fi ndings

Br J Sports Med 2011;45:1246–1248. doi:10.1136/bjsports-2011-090669

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Nutritional supplement series are clearly of considerable interest to athletes, it is possible that clinical populations and older people may also benefit if dietary nitrate intake can be shown to reduce the O2 cost of the ‘activities of daily living’.

NOOTKATONE S Haramizu Nootkatone (4,4a,5,6,7,8-hexahydro-6-isopropenyl-4,4a-dimethyl -2(3H)-naphthalenone), a kind of sesquiterpenoid, was fi rst isolated from the heartwood of Alaska yellow cedar (Callitropsis nootkatensis).14 Traceable amounts of nootkatone are found in major Citrus species such as grapefruit (Citrus paradisi), and a whole grapefruit contains approximately 100 mg of nootkatone, mainly in the peel. Nootkatone is now available through technological advances such as chemical synthesis, biosynthesis and biotransformation. Nootkatone has a grapefruit-like flavour, tastes slightly bitter and has an odour threshold of ~1 mg/l water. It is used predominantly as a flavouring compound. A recent animal study demonstrated that 0.2% (wt/wt) nootkatone feeding for 10 weeks improved swimming endurance (ie, swimming time to fatigue) and that long-term intake of diets supplemented with 0.1–0.3% nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation and the development of hyperglycaemia, hyperinsulinaemia and hyperleptinaemia.15 These beneficial effects of nootkatone might be due in part to enhanced energy metabolism through the activation of AMPactivated protein kinase in the muscle and liver.15 These fi ndings indicate that nootkatone is a potential candidate for being an ergogenic and antiobesity compound. A previous study indicated that consumption of a whole grapefruit or grapefruit juice for 12 weeks reduces body weight and improves insulin resistance in metabolic syndrome patients compared with placebo.16 On the other hand, there are no reports on the effects of grapefruit, including nootkatone, on physical performance in humans. Therefore, further studies are required to clarify the efficacy of nootkatone as an ergogenic compound, especially for atheletes.

OCTACOSANOL AND POLICOSANOL MK Ranchordas Octacosanol (CH3[CH 2]26CH 2O14) a high-molecular weight, primary aliphatic alcohol, is typically found in the natural wax extract of various plants and is commonly found in fruits, barks, leaves and whole seeds.17 18 Octacosanol supplementation has been purported to achieve several health benefits including lowering cholesterol, cytoprotective effects and antiaggregatory properties.18 The majority of the supplementation studies have used policosanol (wheat-germ oil extract), which contains a natural mixture of primary alcohols isolated from sugar cane wax, of which octacosanol is the main component.19 20 It has been suggested that policosanol reduces cholesterol by downregulating the cellular expression of hydroxymethylglutamyl coenzyme A reductase, although the exact mechanism remains to be elucidated. 21 A meta-analysis has reviewed the efficacy of plant sterols and stanols as well as policosanol in the treatment of coronary heart disease, as measured by a reduction in low-density lipoprotein cholesterol levels (LDL). It was found that policosanol was more effective than both plant sterols and stanols in reducing level LDL levels and more favourably altered the lipid profi le. 22 In the 29 eligible studies, 12 mg/day (range 5–40 mg/day in 1528 participants) was found to reduce significantly the LDL Br J Sports Med 2011;45:1246–1248. doi:10.1136/bjsports-2011-090669

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levels and the LDL:high-density lipoprotein (HDL) ratio. Moreover, policosanol was more effective in reducing the total cholesterol, increasing the HDL cholesterol and lowering the triglyceride levels when compared with a placebo, plant sterols and stanols. 22 Despite these positive fi ndings, it should be noted that, after this meta-analysis22 was published, several other studies found that policosanol was ineffective in the treatment of hypercholesterolaemia. 23-25 Fewer studies have examined the effects of octacosanol and policosanol on athletic performance. An early study found that 1000 μg of octacosanol significantly improved grip strength and reaction time in response to a visual stimulus. 20 Another study found that octacosanol supplementation reduced body fat in athletes. 26 However, limitations of this study included the lack of dietary control, lack of blinding of treatments and the involvement of athletes from different sporting backgrounds in the placebo and supplement groups. As a result, these fi ndings should be interpreted with caution. 26 In summary, research into the effects of octacosanol and policosanol supplementation on athletic performance is lacking and remains unclear.

Omega-3, -6 AND -9 Omega-3, -6 and -9 are families of unsaturated fatty acids and have been described earlier in this alphabetical series. Fatty acids were covered in Part 1427 of this series. The Omega-6 fatty acids linoleic acid and γ-linolenic acid were covered in Part 2328. The Omega-3 fatty acids found in fi sh oils were covered in Part 14. 27

CONCLUDING COMMENTS This review started by describing the growing evidence for the role of nitrates in exercise performance. Early studies have shown encouraging support for the ability of nitrate-rich beetroot juice dietary nitrate supplementation to enhance NO bioavailability and thereby reduce the oxygen cost of physical activity, that is, to make it less tiring, with the consequence that it might lead to an improvement in exercise performance. Nevertheless, athletes are cautioned against indiscriminate use of these supplements, since longterm studies on the effect of enhancing NO bioavailability are lacking. Furthermore, athletes are advised to refrain from the uncontrolled use of nitrate and nitrite salts as dietary supplements due to the potential toxicity from large doses. 29 Indeed, their use is strictly regulated in the UK for this reason. However, the move towards using more natural products such as nitrate-rich beetroot juice and citrulline-rich watermelon juice to enhance NO bioavailability is seen as a positive step and, at the time of going to press, no acute risks are foreseen. Although recent animal studies have shown some positive effects on endurance performance from nootkatone supplementation, there are currently no studies regarding efficacy as a potential ergogenic aid and these need to be done before nootkatone can be considered as a useful supplement for athletes. The same principle can be applied to octacosanol and policosanol. Although, theoretically, there may be some beneficial lipid and body composition effects; the evidence is inconclusive. Conflicts of interest None. Provenance and peer review Commissioned; not externally peer reviewed.

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A−Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance −−Part 27 Andrew M Jones, Satoshi Haramizu, Mayur Ranchordas, et al. Br J Sports Med 2011 45: 1246-1248

doi: 10.1136/bjsports-2011-090669

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