By Monica Mollica BrinkZone
Mitochondria are the ‘energy powerhouse of the cell’ that convert the foods we eat to usable energy our body uses to fuel life sustaining reactions within cells, our daily activities and athletic performance 1-4. While energy production capability and muscle performance might seem to be more relevant to sports, it also equally important for achievement and maintenance of health throughout the life span. In this article I will describe how chronological aging affects our mitochondria, its implications and the ins-and-outs of a new type of supplements marketed at “exercise mimetics”.
Age related mitochondrial changes and implications
Brain, heart, and skeletal muscle mitochondria are especially susceptible to age-induced declines in the capacity to produce energy (ATP), and ability to respond to increased energy demands 2-6. It is well documented that mitochondrial number, mass and function declines with aging 2-5, and that this decline plays an important role in the etiology of many disorders, including cardiovascular diseases, obesity, diabetes, neurodegenerative diseases, and cancer 7-15. Physical inactivity and poor exercise capacity is a risk factor not only for the development of these diseases 8 16-18, but also causes frailty, age-related physiologic functional declines 19-22, and accelerates secondary aging (i.e., aging caused by diseases and environmental factors) 15.
The importance of exercise for mitochondrial function and prevention of age-related declines
We all know that exercise training increases muscle mitochondria number, mass and function 23-26. Regular exercise counteracts the age-related decline in muscle mitochondrial expression and function 27-32 and protects against development of age-related metabolic diseases like the metabolic syndrome, obesity, and diabetes 9 28 29 33-36. Thus, regular exercise increases healthy life expectancy and prolongs life span through beneficial effects, in large part, at the level of the mitochondria 28.
Muscle is the tissue with the largest capacity to increase caloric expenditure and energy production, and possesses the unique ability to increase metabolic rate nearly 100-fold during the transition from a basal resting state to maximal contractile activity 37. Being such a metabolic prowess, the importance of mitochondria in muscle tissue is obvious. However, exercise training also has beneficial effects on mitochondria in other tissues, especially the heart 38 39, and brain 40. In the resting state, these tissues actually consume more calories on a per gram basis than does muscle tissue 41 42. Several of the beneficial cardioprotective effects of exercise training can be traced to improved cardiac mitochondrial function 38, and regular exercise also increases brain mitochondrial biogenesis 40. This may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction 40.
Recent advances in molecular biology have shed light on the mechanisms that regulate mitochondrial biogenesis (production of new mitochondria), and how exercise stimulates mitochondrial biogenesis. This is interesting not only from a physiological standpoint, but also from practical standpoint since it has allowed discovery of dietary substances (and potentially drugs) that could help us combat the age related mitochondrial decline. More on this in a bit. First, let’s take a quick look at what happens to our mitochondria when we exercise.
Mitochondria at the molecular level – exercise induced signaling targets
Energy stress from exercise triggers a host of signaling pathways in muscle cells 43-47. One of the identified exercise-induced signals is AMPK (AMP-activated protein kinase) 48-50. AMPK functions as a metabolic “fuel sensor” in muscle cells because it becomes activated in response to decreased energy levels (like for ex. during muscle contractions), and in turn activates catabolic processes that generate and restore ATP levels 48 51 52.
Another energy sensor is SIRT1 (Sirtuin-1) 51 53 54. There are actually seven sirtuins 55; they have generated a lot of scientific interest after the discovery that sitruins partly mediate the increase in longevity with calorie restriction that has been seen in lower organism and animals 56-60. But sirtuins regulate a wide range of important biological processes 61. One of them is muscle precursor cell (MPC) proliferation. The finding that SIRT1 increases muscle precursor cell proliferation is very interesting since MPC proliferation has important implications in regulating muscle growth, maintenance, repair, and the aging-related loss of skeletal muscle mass 62.
Adult muscle stem cells, also called satellite cells or muscle precursor cells (MPCs), play an important role in the remarkable ability of muscle fibers to grow in size, repair and regenerate 63 64. A hallmark of aging is diminished regenerative ability of muscle tissues, which is in large part due to age-related changes in tissue-specific stem cells 65. Muscle precursor cells are important not only for regeneration after tissue damage, but also for maintenance. Age-related muscle loss (sarcopenia) is caused in large part by atrophy of type II muscle fibers 66, which is associated with a fiber type-specific decline in muscle precursor cell content 66. Thus, SIRT1 is an attractive target for dietary/exercise interventions to prevent the loss of muscle mass and function with aging 66.
SIRT1 also works jointly with AMPK in regulating cellular fuel metabolism, inflammation, and mitochondrial function 51. In addition, SIRT1 activates and increases the activity of PGC-1 (peroxisome proliferator-activated receptor-γ coactivator, a transcriptional coactivator), which finally activates transcription factors that turn on genes in our DNA that produce new mitochondria 23-25 54 67. One such transcription factor is PPAR-gamma, which also contributes to mitochondrial biogenesis 68.
Of the mentioned “control points” (AMPK, SIRT1, PPAR-gamma and PGC-1), PGC-1 is considered the “master regulator” of mitochondrial biogenesis 69-71. It also increases oxidative phosphorylation and ATP (energy) production 71. As a result, increased expression of PGC-1 has been shown to increase peak oxygen uptake and delay fatigue during prolonged exercise 69. In addition to its stimulatory effect on mitochondrial biogenesis and function, PGC-1 also regulates muscle fueling stores by increasing muscle glucose uptake, augmenting muscle glycogen storage, and preventing muscle glycogen depletion during exercise 72.
Ok, now you know enough molecular biology to understand the rationale behind exercise mimetics, which we will focus on next.
Elucidation of the molecular mechanisms behind mitochondrial biogenesis and function, coupled with the identification of dietary substances that seem to increase the expression of PGC-1, SIRT1, AMPK etc. and/or their regulators, has led to great interest in developing drugs and dietary supplements to target the SIRT1-PGC-1 complex and related signaling pathways 47 50 73-75.
Because these supplements and drugs activate some of the signaling pathways that are activated by exercise, they have been labeled as “exercise mimetics” 47 74. Here’s a rundown of some dietary bioactive substances that are currently in the scientific spotlight for their potential exercise mimetic effects.
PQQ (short for Pyrroloquinoline Quinone, and also called methoxatin) is a less well known dietary compound that was discovered 1979 76-78. PQQ is present in tissues and body fluids, including human milk 79-81 and in foods. The richest dietary sources are 82:
Natto (fermented soybeans) 61 ng PQQ/g
Parsley 34 ng PQQ/g
Green tea 30 ng PQQ/g
Green pepper 28 ng PQQ/g
Kiwi 27 ng PQQ/g
Papaya 27 ng PQQ/g
Tofu (soybean curd) 24 ng PQQ/g
Spinach 22 ng PQQ/g
Carrot 17 ng PQQ/g
When you read supplement labels, remember that 1 milligram (mg) = 1,000,000 nanogram (ng)
PQQ acts as an antioxidant 83, enzyme cofactor 84-91, nero-protectant 92-95, cardio-protectant 96-98, and may have an important role in cell signaling 92 99-101. In this context, the most interesting function of PQQ is that it affects the expression of genes involved in mithochondrial functions and biogenesis (most notably, PGC-1) 99 102.
The nutritional importance of PQQ has been demonstrated by feeding rats and mice a diet that is devoid of PQQ; the animals show growth retardation, reproductive failure, compromised immune responses, skeletal deformities aortic aneurysms, and fragile skin 91 103 104. This strongly suggests that PQQ is necessary for normal body functions and health. It is actually being debated whether PQQ might become the “next vitamin” 78 88.
What’s more interesting is that varying the amount of PQQ in diets causes modulation in mitochondrial content, alters lipid metabolism, and reverses inhibition elicited by classical mitochondrial function inhibitors 97 104-106. PQQ deficiency decreases both mitochondrial function and number 106. The most recent study on PQQ fed rats a nutritionally complete diet either with or without PQQ 105. The rats that got the PQQ diet not only exhibited lower blood triglycerides but also showed increased energy expenditure, hepatic (liver) mitochondrial content. In contrast, the rats that were fed the PQQ deficient diet instead exhibited deterioration in mitochondrial function, a lowered energy expenditure and reduced capacity to oxidize fat for energy (that is, reduced fat burning) 105. However, at the time of this writing, no human study has investigated the effect(s) of PQQ on metabolic, muscular and mitochondrial parameters. PQQ can already be found on the supplement market, but for now we will have to be our own lab rats.
A natural polyphenolic flavonoid, quercetin is present in a wide variety of food plants, including red onions, apples, and berries 107 108. Known for its multiple health benefits 109-118, it has recently been shown that quercetin also beneficially affects mitochondrial energetics 119 120 and stimulates mitochondrial biogenesis (by increasing expression of PGC-1alpha and SIRT1) 121. The quercetin-induced increase in mitochondrial biogenesis was accompanied 121 with both maximal endurance capacity and voluntary wheel-running activity in mice 121.
However, findings from the few research studies on the ergogenic (i.e. performance enhancing) effects of quercetin supplementation in humans are equivocal 122-127. A small preliminary study showed that when given in combination with other antioxidants for 6 weeks, quercetin improved endurance time-trial performance on a bicycle ergometer in humans 126. Another study, conducted by the same research team that showed performance enhancing effects in mice, gave healthy but untrained participants 500 mg of quercetin twice daily. After 7 days it was shown that the quercetin supplementation resulted in a modest increase in VO2max along with a substantial (13.2%) increase in ride time to fatigue 125. It was concluded that quercetin supplementation can increase endurance without previous exercise training in untrained participants 125. In contrast, another controlled study conducted by another research team, which gave young healthy recreationally active men 1 g/day of quercetin in a sports hydration for 16 days failed to show any benefits over placebo; the quercetin supplementation did not improve neither muscle oxidative capacity or performance in a 10 min maximal-effort cycling test 124. Also, supplementing with 1 g/day of quercetin for 3 weeks in trained cyclists failed to show a performance benefits 127.
A recently published meta-analysis of human studies on quercetin and performance concluded that quercetin supplementation significantly endurance performance, but that the effect is very small 128. The computed effect size for the performance enhancement was 3-5% over placebo 128. This can be compared to the effect size for the performance enhancement with caffeine, which is in the range of 12% over placebo 129. If at all, people with low fitness levels will probably most likely experience a performance benefit of quercetin supplementation, since highly fit individuals already have an elevated mitochondrial density and function.
There is a possibility that a longer supplementation duration is necessary for quercetin to exert a performance enhancing effect, and/or that it could be ergogenic in elderly. Hopefully, future studies will address that. Thus, while quercetin is a prudent supplement to take for its beneficial health effect, if you’re looking for a boost in mitochondrial function and/or performance, don’t expect too much.
Resveratrol is the most well known SIRT1 activator 130-132. A natural compound present in grapes (especially grape skin) 133 134, resveratrol has been in the spotlight since it was found to be one major factor explaining the French paradox and conferring the cardioprotective effect of red wine 135-140. Fresh grape skin contains about 0.05-0.1 mg resveratrol per gram, while red wine is a concentrated source of resveratrol providing up to 14 mg per liter. Resveratrol also protects against cancer 135, and induces several signaling pathways that are also seen with calorie restriction (I will cover this more in an upcoming article on calorie restriction mimetics).
More recently, it has been shown that resveratrol also might improve mitochondrial function and stimulate mothochondrial biogenesis 131 141. In mice, intake of resveratrol together with habitual exercise, suppresses the aging-related decline in physical performance 141. This effect was attributable, at least in part, to improved muscle mitochondrial function 141. Another mice study showed that resveratrol increases aerobic capacity, as evidenced by an increased running time to exhaustion 131. On a molecular level, this effect was paralleled by an induction of genes for oxidative phosphorylation, increase in PGC-1alpha activity and enhanced mitochondrial biogenesis 131. Resveratrol also seems to be able to counteract muscle atrophy during periods of physical inactivity (mechanical unloading) in rats 142.
However, while there is ample of human data on the health promoting effects of resveratrol, at the time of this writing there are no human studies on its potential mitochondrial, metabolic and/or performance enhancing effects.
A new kid on the block, nootkatone is another bioactive naturally occurring dietary compound that is found primarily in grapefruit (a whole grapefruit contains about 100 mg of nootkatone, mainly in the rind)143.
It was recently shown in mice that nootkatone potently activates the AMPK signaling pathway in both muscle and liver, increases energy expenditure, endurance performance, and also suppresses diet-induced development of obesity, abdominal fat accumulation, and insulin resistance 143. Body weight in nootkatone-fed mice was significantly decreased despite no significant decrease in energy intake 143. It was concluded that activation of AMPK and subsequent induction of PGC-1α, with a possibly enhanced oxidative energy metabolism and stimulation of energy expenditure, is an underlying mechanism of the antiobesity effects of nootkatone 143. This study supports the idea that AMPK activators could be useful as exercise mimetics or exercise-supporting supplements in preventing/treating obesity and/or metabolic syndrome, and for improving physical performance.
Nootkatone has a pleasant, citrusy grapefruit aroma, and is GRAS approved 144 for use as a food flavoring agent, and as a fragrance in perfumes and essential oils 145. You can even use it as a non-toxic effective repellent/insecticide against mosquitos and other insects 146. Being this multi-functional, we will most likely hear more about nootkatone, in one way or the other, it in the near future. It is interesting to speculate whether the nootkatone-induced AMPK activation is part of the mechanism underlying the weight loss and increased insulin sensitivity that has been reported after grapefruit supplementation 147. Even though nootkatone is currently not available as a dietary supplement in isolated form, you can always add some grapefruit to your regimen (remember that whole fruits are better than juice). However, if you are taking any medications, talk to your doctor first because grapefruit interferes with the enzymes that metabolize medications, and can cause a lethal buildup of medication in the body 148-151.
The potential of exercise mimetics certainly appeals to the huge mass of lazy folks who cannot get their butts off the couch, and the pharmaceutical and supplement industry that sees the tremendous market potential. So we’ll most certainly be hearing a lot about these “exercise pills” in the near future. However, I want to emphasize that an “exercise pill” will never ever be a substitute for actual exercise training. Why? For several reasons:
Firstly, mimicking activation of exercise signaling pathways could result in a chronic catabolic state. For example, activation of AMPK could inhibit protein synthesis 152 and stimulate autophagy (cell cannibalism, that is, degradation of a cell’s own components through the lysosomal machinery) 153. Also, while augmenting oxidative capacity in mice, overproduction of PGC-1α in muscle has been shown to result in severe muscle atrophy as mice aged 154. These effects would clearly be detrimental, especially for aging people. This underscores the importance of striking an optimum balance between continuous compared with transient activation of exercise signaling pathways.
Secondly, intense exercise bouts induce significant temporary stress on various organ systems. With an over 15-fold increase in whole body oxygen consumption when transitioning from complete rest to intense exercise, it is no surprise that a complex myriad of signaling pathways are activated in multiple tissues, of which we only know a few. Even though science is making progress in elucidating the exercise response on a molecular level, we are still barely just scraping the tip of the iceberg.
Thirdly, exercise training has multiple health benefits that do not, at least directly or entirely, relate to the muscle-specific adaptations. For example, cardiovascular adaptations like blood pressure reduction and improved blood lipid profile are not completely (albeit partly) due to muscle-specific adaptations 155 156. This is further underscored by the finding that beneficial effects of regular exercise are even seen in arteries of non-exercise-trained limbs 157-160. Additionally, regular exercise results in a host of other health benefits; it prevents or reduces the severity of dementia and other neurological disorders, osteoarthritis, osteoporosis, fall-related injuries, depression, certain cancers and cardiovascular diseases 16 18 161-165. Exercise also improves cardiac function and enhances stroke volume, increases VO2max (the maximal oxygen uptake, or aerobic capacity, which is the maximum capacity of the body to transport and use oxygen during exercise), increases nitric oxide levels in vascular endothelial cells, increases bone mass and strength, enhances the immune system, lowers TNF-α and other inflammatory markers, improves insulin sensitivity and blood lipid profiles, and increases muscle capillarization, muscle size and muscle strength 161 166. Obviously, no single pharmaceutical or dietary agent could mimic this multifaceted response.
Fourthly, in order for an “exercise mimetic” to mimic the effect of exercise on obesity, it would have to result in an increase in energy expenditure to the same degree as exercise. Even though PQQ increases energy expenditure in rats (see above), this increase is nowhere near the increase that is seen with exercise. An increase in muscle mitochondria enhances exercise capacity and endurance, making it possible to expend more total energy, or the same amount of energy in a shorter time. So, an increase in mitochondria enhances the capacity to expend calories by means of exercise, and thereby could make exercise more effective in preventing and/or treating obesity. However, an increase in mitochondria per se has no major independent effect (in the absence of exercise) on energy expenditure.
Finally, regular exercise has psychological effects on constructs like self-mastery 167, self-esteem 167, self-perception 167, self-efficacy 168 self-regulation 168 and also social engagement 167, which no “magic” mimetic pill ever will be able to reproduce. The psychological effects of exercise might actually be at least as important as the physiological effects in the achievement of fat loss 154. This is an areas that I think deserves more attention.
A poly-pill containing a number of agents aimed at selected targets could theoretically address the second and third objection. However, as indicated in objection one, it is likely to be associated with multiple unwanted effects, and to be of questionable long-term efficacy. Thus, with the discovery and development of tissue-specific targets, only limited aspects of the exercise response can be mimicked. The term ‘exercise mimetic’ is therefore misleading, and could lull a false sense of security and give lazy folk another excuse not to exercise “I took this exercise pill so I don’t have to go to the gym”…. These days, unfortunately the general tendency is to look for a pill to solve our problems anytime we face obstacles. This fact is aptly highlighted by a comment from one of the most prominent researchers on the health benefits of regular physical activity “When will we treat physical activity as a legitimate medical therapy…even though it does not come in a pill?” 169.
Exercise mimetics work by stimulating some of the molecular pathways that are also activated by actual exercise. Pharmacological stimulation of AMPK and PGC-1 in sedentary mice has been shown to induce metabolic genes and enhanced running endurance even without exercise 50. Similarly, SIRT1 activation could protect against metabolic disorders by stimulating fat burning (oxidation). Also, the question remains as to what extent data from cell culture and rodent studies can be extrapolated to humans.
However, the terms “exercise mimetic”, and its synonym “exercise pill”, are very misleading. I prefer the term “mitochondrial booster”, since it doesn’t erroneously imply that these types of pills can substitute for the real thing. A mitochondrial booster (or exercise mimetic, if you wish) supplement could be a great adjunct to exercise, but never ever a substitute.
Bearing all the caveats in mind, since actual exercise and exercise mimetics at least partly target the same molecular pathways at potentially complementary control points, it is extremely interesting to speculate on the possible synergistic effects between exercise and exercise mimetics on muscle, mitochondrial function, performance, and in preventing the age-related declines in muscular function…indeed, there are preliminary data pointing towards promising synergistic effects 50. Rest assured I will be keeping you posted here on BrinkZone.com.
However, exercise is and always will be necessary. Sorry folks, there are no magic bullets. There’s simply no way around it. Amen!!!
1. McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Current biology : CB 2006;16(14):R551-60.
2. Kwong LK, Sohal RS. Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse. Archives of biochemistry and biophysics 2000;373(1):16-22.
3. Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. American journal of physiology. Cell physiology 2007;292(2):C670-86.
4. Torii K, Sugiyama S, Takagi K, Satake T, Ozawa T. Age-related decrease in respiratory muscle mitochondrial function in rats. American journal of respiratory cell and molecular biology 1992;6(1):88-92.
5. Vina J, Gomez-Cabrera MC, Borras C, Froio T, Sanchis-Gomar F, Martinez-Bello VE, et al. Mitochondrial biogenesis in exercise and in ageing. Advanced drug delivery reviews 2009;61(14):1369-74.
6. Onyango IG, Lu J, Rodova M, Lezi E, Crafter AB, Swerdlow RH. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochimica et biophysica acta 2010;1802(1):228-34.
7. Calabrese V, Scapagnini G, Giuffrida Stella AM, Bates TE, Clark JB. Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity. Neurochemical research 2001;26(6):739-64.
8. Tarnopolsky MA, Raha S. Mitochondrial myopathies: diagnosis, exercise intolerance, and treatment options. Medicine and science in sports and exercise 2005;37(12):2086-93.
9. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annual review of genetics 2005;39:359-407.
10. Holloszy JO. The biology of aging. Mayo Clinic proceedings. Mayo Clinic 2000;75 Suppl:S3-8; discussion S8-9.
11. Castillo-Garzon MJ, Ruiz JR, Ortega FB, Gutierrez A. Anti-aging therapy through fitness enhancement. Clinical interventions in aging 2006;1(3):213-20.
12. Ren J, Pulakat L, Whaley-Connell A, Sowers JR. Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J Mol Med (Berl) 2010;88(10):993-1001.
13. Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem 2010;47:69-84.
14. Booth FW, Hargreaves M. Understanding multi-organ pathology from insufficient exercise. J Appl Physiol 2011.
15. Booth FW, Laye MJ, Roberts MD. Lifetime sedentary living accelerates some aspects of secondary aging. J Appl Physiol 2011.
16. Booth FW, Gordon SE, Carlson CJ, Hamilton MT. Waging war on modern chronic diseases: primary prevention through exercise biology. J Appl Physiol 2000;88(2):774-87.
17. Heckman GA, McKelvie RS. Cardiovascular aging and exercise in healthy older adults. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine 2008;18(6):479-85.
18. Kruk J. Physical activity in the prevention of the most frequent chronic diseases: an analysis of the recent evidence. Asian Pacific journal of cancer prevention : APJCP 2007;8(3):325-38.
19. Evans WJ, Campbell WW. Sarcopenia and age-related changes in body composition and functional capacity. The Journal of nutrition 1993;123(2 Suppl):465-8.
20. Hawkins SA, Wiswell RA, Marcell TJ. Exercise and the master athlete–a model of successful aging? The journals of gerontology. Series A, Biological sciences and medical sciences 2003;58(11):1009-11.
21. Marcell TJ. Sarcopenia: causes, consequences, and preventions. The journals of gerontology. Series A, Biological sciences and medical sciences 2003;58(10):M911-6.
22. Roubenoff R. Sarcopenia and its implications for the elderly. European journal of clinical nutrition 2000;54 Suppl 3:S40-7.
23. Coffey VG, Hawley JA. The molecular bases of training adaptation. Sports Med 2007;37(9):737-63.
24. Hamilton MT, Booth FW. Skeletal muscle adaptation to exercise: a century of progress. J Appl Physiol 2000;88(1):327-31.
25. Hawley JA, Holloszy JO. Exercise: it’s the real thing! Nutrition reviews 2009;67(3):172-8.
26. Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. The Journal of biological chemistry 1967;242(9):2278-82.
27. Lanza IR, Nair KS. Muscle mitochondrial changes with aging and exercise. The American journal of clinical nutrition 2009;89(1):467S-71S.
28. Lanza IR, Nair KS. Mitochondrial function as a determinant of life span. Pflugers Archiv : European journal of physiology 2010;459(2):277-89.
29. Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R, Joyner MJ, et al. Endurance exercise as a countermeasure for aging. Diabetes 2008;57(11):2933-42.
30. Nair KS. Aging muscle. The American journal of clinical nutrition 2005;81(5):953-63.
31. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proceedings of the National Academy of Sciences of the United States of America 2005;102(15):5618-23.
32. Booth FW, Zwetsloot KA. Basic concepts about genes, inactivity and aging. Scandinavian journal of medicine & science in sports 2010;20(1):1-4.
33. Booth FW, Shanely RA. The biochemical basis of the health effects of exercise: an integrative view. The Proceedings of the Nutrition Society 2004;63(2):199-203.
34. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003;300(5622):1140-2.
35. Petersen KF, Shulman GI. Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus. The American journal of cardiology 2002;90(5A):11G-18G.
36. Rogers MA, King DS, Hagberg JM, Ehsani AA, Holloszy JO. Effect of 10 days of physical inactivity on glucose tolerance in master athletes. J Appl Physiol 1990;68(5):1833-7.
37. Lanza IR, Sreekumaran Nair K. Regulation of skeletal muscle mitochondrial function: genes to proteins. Acta Physiol (Oxf) 2010;199(4):529-47.
38. Ascensao A, Lumini-Oliveira J, Oliveira PJ, Magalhaes J. Mitochondria as a target for exercise-induced cardioprotection. Current drug targets 2011;12(6):860-71.
39. Ascensao A, Ferreira R, Magalhaes J. Exercise-induced cardioprotection–biochemical, morphological and functional evidence in whole tissue and isolated mitochondria. International journal of cardiology 2007;117(1):16-30.
40. Steiner JL, Murphy EA, McClellan JL, Carmichael MD, Davis JM. Exercise Training Increases Mitochondrial Biogenesis in the Brain. J Appl Physiol 2011.
41. Illner K, Brinkmann G, Heller M, Bosy-Westphal A, Muller MJ. Metabolically active components of fat free mass and resting energy expenditure in nonobese adults. American journal of physiology. Endocrinology and metabolism 2000;278(2):E308-15.
42. Bosy-Westphal A, Kossel E, Goele K, Later W, Hitze B, Settler U, et al. Contribution of individual organ mass loss to weight loss-associated decline in resting energy expenditure. The American journal of clinical nutrition 2009;90(4):993-1001.
43. Bassel-Duby R, Olson EN. Signaling pathways in skeletal muscle remodeling. Annual review of biochemistry 2006;75:19-37.
44. Hawley JA, Hargreaves M, Zierath JR. Signalling mechanisms in skeletal muscle: role in substrate selection and muscle adaptation. Essays Biochem 2006;42:1-12.
45. Booth FW, Chakravarthy MV, Spangenburg EE. Exercise and gene expression: physiological regulation of the human genome through physical activity. The Journal of physiology 2002;543(Pt 2):399-411.
46. Pilegaard H, Saltin B, Neufer PD. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. The Journal of physiology 2003;546(Pt 3):851-8.
47. Matsakas A, Narkar VA. Endurance exercise mimetics in skeletal muscle. Current sports medicine reports 2010;9(4):227-32.
48. Hardie DG, Sakamoto K. AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda) 2006;21:48-60.
49. Jager S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proceedings of the National Academy of Sciences of the United States of America 2007;104(29):12017-22.
50. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 2008;134(3):405-15.
51. Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, et al. AMPK and SIRT1: a long-standing partnership? American journal of physiology. Endocrinology and metabolism 2010;298(4):E751-60.
52. Li X, Kazgan N. Mammalian sirtuins and energy metabolism. International journal of biological sciences 2011;7(5):575-87.
53. Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochimica et biophysica acta 2011;1813(7):1269-78.
54. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434(7029):113-8.
55. Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends in biochemical sciences 2010;35(12):669-75.
56. Hu Y, Liu J, Wang J, Liu Q. The controversial links among calorie restriction, SIRT1, and resveratrol. Free radical biology & medicine 2011;51(2):250-6.
57. Srivastava S, Haigis MC. Role of Sirtuins and Calorie restriction in Neuroprotection: Implications in Alzheimer’s and Parkinson’s Diseases. Current pharmaceutical design 2011.
58. Toiber D, Sebastian C, Mostoslavsky R. Characterization of nuclear sirtuins: molecular mechanisms and physiological relevance. Handbook of experimental pharmacology 2011(206):189-224.
59. Feige JN, Auwerx J. Transcriptional targets of sirtuins in the coordination of mammalian physiology. Current opinion in cell biology 2008;20(3):303-9.
60. Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell metabolism 2008;8(5):347-58.
61. Dali-Youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J. Sirtuins: the ‘magnificent seven’, function, metabolism and longevity. Annals of medicine 2007;39(5):335-45.
62. Rathbone CR, Booth FW, Lees SJ. Sirt1 increases skeletal muscle precursor cell proliferation. European journal of cell biology 2009;88(1):35-44.
63. Adams GR, Caiozzo VJ, Haddad F, Baldwin KM. Cellular and molecular responses to increased skeletal muscle loading after irradiation. American journal of physiology. Cell physiology 2002;283(4):C1182-95.
64. Barton-Davis ER, Shoturma DI, Sweeney HL. Contribution of satellite cells to IGF-I induced hypertrophy of skeletal muscle. Acta physiologica Scandinavica 1999;167(4):301-5.
65. Conboy IM, Conboy MJ, Smythe GM, Rando TA. Notch-mediated restoration of regenerative potential to aged muscle. Science 2003;302(5650):1575-7.
66. Verdijk LB, Koopman R, Schaart G, Meijer K, Savelberg HH, van Loon LJ. Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly. American journal of physiology. Endocrinology and metabolism 2007;292(1):E151-7.
67. Rohas LM, St-Pierre J, Uldry M, Jager S, Handschin C, Spiegelman BM. A fundamental system of cellular energy homeostasis regulated by PGC-1alpha. Proceedings of the National Academy of Sciences of the United States of America 2007;104(19):7933-8.
68. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, et al. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS biology 2004;2(10):e294.
69. Calvo JA, Daniels TG, Wang X, Paul A, Lin J, Spiegelman BM, et al. Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake. J Appl Physiol 2008;104(5):1304-12.
70. Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. The Journal of clinical investigation 2006;116(3):615-22.
71. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocrine reviews 2003;24(1):78-90.
72. Wende AR, Schaeffer PJ, Parker GJ, Zechner C, Han DH, Chen MM, et al. A role for the transcriptional coactivator PGC-1alpha in muscle refueling. The Journal of biological chemistry 2007;282(50):36642-51.
73. Sun M, Qian F, Shen W, Tian C, Hao J, Sun L, et al. Mitochondrial nutrients stimulate performance and mitochondrial biogenesis in exhaustively exercised rats. Scandinavian journal of medicine & science in sports 2011.
74. Carey AL, Kingwell BA. Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with ‘exercise mimetics’. Diabetologia 2009;52(10):2015-26.
75. Richter EA, Kiens B, Wojtaszewski JF. Can exercise mimetics substitute for exercise? Cell metabolism 2008;8(2):96-8.
76. Mincey T, Bell JA, Mildvan AS, Abeles RH. Mechanism of action of methoxatin-dependent alcohol dehydrogenase. Biochemistry 1981;20(26):7502-9.
77. Salisbury SA, Forrest HS, Cruse WB, Kennard O. A novel coenzyme from bacterial primary alcohol dehydrogenases. Nature 1979;280(5725):843-4.
78. Bishop A, Gallop PM, Karnovsky ML. Pyrroloquinoline quinone: a novel vitamin? Nutrition reviews 1998;56(10):287-93.
79. He K, Nukada H, Urakami T, Murphy MP. Antioxidant and pro-oxidant properties of pyrroloquinoline quinone (PQQ): implications for its function in biological systems. Biochemical pharmacology 2003;65(1):67-74.
80. Kumazawa T, Seno H, Urakami T, Matsumoto T, Suzuki O. Trace levels of pyrroloquinoline quinone in human and rat samples detected by gas chromatography/mass spectrometry. Biochimica et biophysica acta 1992;1156(1):62-6.
81. Mitchell AE, Jones AD, Mercer RS, Rucker RB. Characterization of pyrroloquinoline quinone amino acid derivatives by electrospray ionization mass spectrometry and detection in human milk. Analytical biochemistry 1999;269(2):317-25.
82. Kumazawa T, Sato K, Seno H, Ishii A, Suzuki O. Levels of pyrroloquinoline quinone in various foods. The Biochemical journal 1995;307 ( Pt 2):331-3.
83. Ouchi A, Nakano M, Nagaoka S, Mukai K. Kinetic study of the antioxidant activity of pyrroloquinolinequinol (PQQH(2), a reduced form of pyrroloquinolinequinone) in micellar solution. Journal of agricultural and food chemistry 2009;57(2):450-6.
84. Duine JA. Quinoproteins: enzymes containing the quinonoid cofactor pyrroloquinoline quinone, topaquinone or tryptophan-tryptophan quinone. European journal of biochemistry / FEBS 1991;200(2):271-84.
85. Felton LM, Anthony C. Biochemistry: role of PQQ as a mammalian enzyme cofactor? Nature 2005;433(7025):E10; discussion E11-2.
86. Kasahara T, Kato T. Nutritional biochemistry: A new redox-cofactor vitamin for mammals. Nature 2003;422(6934):832
87. McIntire WS. Newly discovered redox cofactors: possible nutritional, medical, and pharmacological relevance to higher animals. Annual review of nutrition 1998;18:145-77.
88. Rucker R, Storms D, Sheets A, Tchaparian E, Fascetti A. Biochemistry: is pyrroloquinoline quinone a vitamin? Nature 2005;433(7025):E10-1; discussion E11-2.
89. Steinberg F, Stites TE, Anderson P, Storms D, Chan I, Eghbali S, et al. Pyrroloquinoline quinone improves growth and reproductive performance in mice fed chemically defined diets. Exp Biol Med (Maywood) 2003;228(2):160-6.
90. Steinberg FM, Gershwin ME, Rucker RB. Dietary pyrroloquinoline quinone: growth and immune response in BALB/c mice. The Journal of nutrition 1994;124(5):744-53.
91. Stites TE, Mitchell AE, Rucker RB. Physiological importance of quinoenzymes and the O-quinone family of cofactors. The Journal of nutrition 2000;130(4):719-27.
92. Nunome K, Miyazaki S, Nakano M, Iguchi-Ariga S, Ariga H. Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1. Biological & pharmaceutical bulletin 2008;31(7):1321-6.
93. Hara H, Hiramatsu H, Adachi T. Pyrroloquinoline quinone is a potent neuroprotective nutrient against 6-hydroxydopamine-induced neurotoxicity. Neurochemical research 2007;32(3):489-95.
94. Zhang JJ, Zhang RF, Meng XK. Protective effect of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Neuroscience letters 2009;464(3):165-9.
95. Zhang Y, Rosenberg PA. The essential nutrient pyrroloquinoline quinone may act as a neuroprotectant by suppressing peroxynitrite formation. The European journal of neuroscience 2002;16(6):1015-24.
96. Tao R, Karliner JS, Simonis U, Zheng J, Zhang J, Honbo N, et al. Pyrroloquinoline quinone preserves mitochondrial function and prevents oxidative injury in adult rat cardiac myocytes. Biochemical and biophysical research communications 2007;363(2):257-62.
97. Zhu BQ, Simonis U, Cecchini G, Zhou HZ, Li L, Teerlink JR, et al. Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther 2006;11(2):119-28.
98. Zhu BQ, Zhou HZ, Teerlink JR, Karliner JS. Pyrroloquinoline quinone (PQQ) decreases myocardial infarct size and improves cardiac function in rat models of ischemia and ischemia/reperfusion. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy 2004;18(6):421-31.
99. Chowanadisai W, Bauerly KA, Tchaparian E, Wong A, Cortopassi GA, Rucker RB. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression. The Journal of biological chemistry 2010;285(1):142-52.
100. Kumazawa T, Hiwasa T, Takiguchi M, Suzuki O, Sato K. Activation of Ras signaling pathways by pyrroloquinoline quinone in NIH3T3 mouse fibroblasts. International journal of molecular medicine 2007;19(5):765-70.
101. Sato K, Toriyama M. Effect of pyrroloquinoline quinone (PQQ) on melanogenic protein expression in murine B16 melanoma. Journal of dermatological science 2009;53(2):140-5.
102. Tchaparian E, Marshal L, Cutler G, Bauerly K, Chowanadisai W, Satre M, et al. Identification of transcriptional networks responding to pyrroloquinoline quinone dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways. The Biochemical journal 2010;429(3):515-26.
103. Killgore J, Smidt C, Duich L, Romero-Chapman N, Tinker D, Reiser K, et al. Nutritional importance of pyrroloquinoline quinone. Science 1989;245(4920):850-2.
104. Bauerly KA, Storms DH, Harris CB, Hajizadeh S, Sun MY, Cheung CP, et al. Pyrroloquinoline quinone nutritional status alters lysine metabolism and modulates mitochondrial DNA content in the mouse and rat. Biochimica et biophysica acta 2006;1760(11):1741-8.
105. Bauerly K, Harris C, Chowanadisai W, Graham J, Havel PJ, Tchaparian E, et al. Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PloS one 2011;6(7):e21779.
106. Stites T, Storms D, Bauerly K, Mah J, Harris C, Fascetti A, et al. Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. The Journal of nutrition 2006;136(2):390-6.
107. Erlund I, Freese R, Marniemi J, Hakala P, Alfthan G. Bioavailability of quercetin from berries and the diet. Nutr Cancer 2006;54(1):13-7.
108. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2007;45(11):2179-205.
109. Chirumbolo S. The role of quercetin, flavonols and flavones in modulating inflammatory cell function. Inflammation & allergy drug targets 2010;9(4):263-85.
110. Davis JM, Murphy EA, Carmichael MD. Effects of the dietary flavonoid quercetin upon performance and health. Current sports medicine reports 2009;8(4):206-13.
111. Ishizawa K, Yoshizumi M, Kawai Y, Terao J, Kihira Y, Ikeda Y, et al. Pharmacology in health food: metabolism of quercetin in vivo and its protective effect against arteriosclerosis. Journal of pharmacological sciences 2011;115(4):466-70.
112. Jagtap S, Meganathan K, Wagh V, Winkler J, Hescheler J, Sachinidis A. Chemoprotective mechanism of the natural compounds, epigallocatechin-3-O-gallate, quercetin and curcumin against cancer and cardiovascular diseases. Current medicinal chemistry 2009;16(12):1451-62.
113. Murakami A, Ashida H, Terao J. Multitargeted cancer prevention by quercetin. Cancer Lett 2008;269(2):315-25.
114. Ossola B, Kaariainen TM, Mannisto PT. The multiple faces of quercetin in neuroprotection. Expert opinion on drug safety 2009;8(4):397-409.
115. Perez-Vizcaino F, Duarte J, Andriantsitohaina R. Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols. Free radical research 2006;40(10):1054-65.
116. Teixeira S. Bioflavonoids: proanthocyanidins and quercetin and their potential roles in treating musculoskeletal conditions. The Journal of orthopaedic and sports physical therapy 2002;32(7):357-63.
117. Vargas AJ, Burd R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutrition reviews 2010;68(7):418-28.
118. Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. European journal of pharmacology 2008;585(2-3):325-37.
119. Dorta DJ, Pigoso AA, Mingatto FE, Rodrigues T, Prado IM, Helena AF, et al. The interaction of flavonoids with mitochondria: effects on energetic processes. Chemico-biological interactions 2005;152(2-3):67-78.
120. Trumbeckaite S, Bernatoniene J, Majiene D, Jakstas V, Savickas A, Toleikis A. The effect of flavonoids on rat heart mitochondrial function. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2006;60(5):245-8.
121. Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. American journal of physiology. Regulatory, integrative and comparative physiology 2009;296(4):R1071-7.
122. Nieman DC, Henson DA, Davis JM, Dumke CL, Gross SJ, Jenkins DP, et al. Quercetin ingestion does not alter cytokine changes in athletes competing in the Western States Endurance Run. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2007;27(12):1003-11.
123. Nieman DC, Henson DA, Maxwell KR, Williams AS, McAnulty SR, Jin F, et al. Effects of quercetin and EGCG on mitochondrial biogenesis and immunity. Medicine and science in sports and exercise 2009;41(7):1467-75.
124. Cureton KJ, Tomporowski PD, Singhal A, Pasley JD, Bigelman KA, Lambourne K, et al. Dietary quercetin supplementation is not ergogenic in untrained men. J Appl Physiol 2009;107(4):1095-104.
125. Davis JM, Carlstedt CJ, Chen S, Carmichael MD, Murphy EA. The dietary flavonoid quercetin increases VO(2max) and endurance capacity. International journal of sport nutrition and exercise metabolism 2010;20(1):56-62.
126. MacRae HS, Mefferd KM. Dietary antioxidant supplementation combined with quercetin improves cycling time trial performance. International journal of sport nutrition and exercise metabolism 2006;16(4):405-19.
127. Dumke CL, Nieman DC, Utter AC, Rigby MD, Quindry JC, Triplett NT, et al. Quercetin’s effect on cycling efficiency and substrate utilization. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 2009;34(6):993-1000.
128. Kressler J, Millard-Stafford M, Warren GL. Quercetin and Endurance Exercise Capacity: A Systematic Review and Meta-Analysis. Medicine and science in sports and exercise 2011.
129. Doherty M, Smith PM. Effects of caffeine ingestion on exercise testing: a meta-analysis. International journal of sport nutrition and exercise metabolism 2004;14(6):626-46.
130. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425(6954):191-6.
131. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006;127(6):1109-22.
132. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004;430(7000):686-9.
133. Mark L, Nikfardjam MS, Avar P, Ohmacht R. A validated HPLC method for the quantitative analysis of trans-resveratrol and trans-piceid in Hungarian wines. Journal of chromatographic science 2005;43(9):445-9.
134. Pervaiz S. Resveratrol: from grapevines to mammalian biology. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003;17(14):1975-85.
135. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature reviews. Drug discovery 2006;5(6):493-506.
136. Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the ‘French paradox’? European journal of endocrinology / European Federation of Endocrine Societies 1998;138(6):619-20.
137. Zern TL, Fernandez ML. Cardioprotective effects of dietary polyphenols. The Journal of nutrition 2005;135(10):2291-4.
138. Zern TL, Wood RJ, Greene C, West KL, Liu Y, Aggarwal D, et al. Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress. The Journal of nutrition 2005;135(8):1911-7.
139. Lippi G, Franchini M, Favaloro EJ, Targher G. Moderate red wine consumption and cardiovascular disease risk: beyond the “French paradox”. Seminars in thrombosis and hemostasis 2010;36(1):59-70.
140. Sun AY, Simonyi A, Sun GY. The “French Paradox” and beyond: neuroprotective effects of polyphenols. Free radical biology & medicine 2002;32(4):314-8.
141. Murase T, Haramizu S, Ota N, Hase T. Suppression of the aging-associated decline in physical performance by a combination of resveratrol intake and habitual exercise in senescence-accelerated mice. Biogerontology 2009;10(4):423-34.
142. Momken I, Stevens L, Bergouignan A, Desplanches D, Rudwill F, Chery I, et al. Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2011;25(10):3646-60.
143. Murase T, Misawa K, Haramizu S, Minegishi Y, Hase T. Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK. American journal of physiology. Endocrinology and metabolism 2010;299(2):E266-75.
144. FEMA. Nootkatone – FEMA GRAS no. 3166.
145. Zviely M. Molecule of the Month: Nootkatone. P&F magazine 2009(November).
146. Knox R. Repelling Bugs With The Essence Of Grapefruit. NPR 2011(October 20).
147. Fujioka K, Greenway F, Sheard J, Ying Y. The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome. Journal of medicinal food 2006;9(1):49-54.
148. Bressler R. Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs. Geriatrics 2006;61(11):12-8.
149. Hanley MJ, Cancalon P, Widmer WW, Greenblatt DJ. The effect of grapefruit juice on drug disposition. Expert opinion on drug metabolism & toxicology 2011;7(3):267-86.
150. Kiani J, Imam SZ. Medicinal importance of grapefruit juice and its interaction with various drugs. Nutrition journal 2007;6:33.
151. Seden K, Dickinson L, Khoo S, Back D. Grapefruit-drug interactions. Drugs 2010;70(18):2373-407.
152. Bolster DR, Crozier SJ, Kimball SR, Jefferson LS. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. The Journal of biological chemistry 2002;277(27):23977-80.
153. Meley D, Bauvy C, Houben-Weerts JH, Dubbelhuis PF, Helmond MT, Codogno P, et al. AMP-activated protein kinase and the regulation of autophagic proteolysis. The Journal of biological chemistry 2006;281(46):34870-9.
154. Miura S, Tomitsuka E, Kamei Y, Yamazaki T, Kai Y, Tamura M, et al. Overexpression of peroxisome proliferator-activated receptor gamma co-activator-1alpha leads to muscle atrophy with depletion of ATP. The American journal of pathology 2006;169(4):1129-39.
155. Jennings G, Nelson L, Nestel P, Esler M, Korner P, Burton D, et al. The effects of changes in physical activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: a controlled study of four levels of activity. Circulation 1986;73(1):30-40.
156. Kingwell BA, Jennings GL. Effects of walking and other exercise programs upon blood pressure in normal subjects. The Medical journal of Australia 1993;158(4):234-8.
157. DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan KD, Tanaka H, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation 2000;102(12):1351-7.
158. Green DJ, Bilsborough W, Naylor LH, Reed C, Wright J, O’Driscoll G, et al. Comparison of forearm blood flow responses to incremental handgrip and cycle ergometer exercise: relative contribution of nitric oxide. The Journal of physiology 2005;562(Pt 2):617-28.
159. Lavrencic A, Salobir BG, Keber I. Physical training improves flow-mediated dilation in patients with the polymetabolic syndrome. Arteriosclerosis, thrombosis, and vascular biology 2000;20(2):551-5.
160. Linke A, Schoene N, Gielen S, Hofer J, Erbs S, Schuler G, et al. Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training. Journal of the American College of Cardiology 2001;37(2):392-7
161. Booth FW, Lees SJ. Fundamental questions about genes, inactivity, and chronic diseases. Physiological genomics 2007;28(2):146-57.
162. Lee DC, Sui X, Blair SN. Does physical activity ameliorate the health hazards of obesity? British journal of sports medicine 2009;43(1):49-51.
163. Sui X, Laditka JN, Church TS, Hardin JW, Chase N, Davis K, et al. Prospective study of cardiorespiratory fitness and depressive symptoms in women and men. Journal of psychiatric research 2009;43(5):546-52.
164. Lautenschlager NT, Almeida OP, Flicker L, Janca A. Can physical activity improve the mental health of older adults? Annals of general hospital psychiatry 2004;3(1):12.
165. Deslandes A, Moraes H, Ferreira C, Veiga H, Silveira H, Mouta R, et al. Exercise and mental health: many reasons to move. Neuropsychobiology 2009;59(4):191-8.
166. Brooks GA, Fahey TD, Baldwin KM. Exercise Physiology: Human Bioenergetics and Its Applications. 4th ed: McGraw-Hill, 2004.
167. Fox KR. The influence of physical activity on mental well-being. Public health nutrition 1999;2(3A):411-8.
168. Annesi JJ. Behaviorally supported exercise predicts weight loss in obese adults through improvements in mood, self-efficacy, and self-regulation, rather than by caloric expenditure. The Permanente journal 2011;15(1):23-7.
169. Church TS, Blair SN. When will we treat physical activity as a legitimate medical therapy…even though it does not come in a pill? British journal of sports medicine 2009;43(2):80-1.