Chapter 26

Physiological Aspects of Coenzyme Q10 in Plasma in Relationship with Exercise and Aging

Guillermo López-Lluch,    Universidad Pablo de Olavide, Sevilla, Spain

Abstract

Coenzyme Q is an essential factor in bioenergetics and in antioxidant protection of cell membranes. As the main antioxidant in blood, coenzyme Q prevents the oxidation of lipoproteins. This function and others related to the physiology of the heart and the vascular endothelium makes this molecule a key factor in preventing atherosclerosis and cardiovascular diseases. Over the last few years, we have found that coenzyme Q levels increase in people who maintain high levels of physical activity as they age. This increase is associated with lower lipid oxidation in plasma and low-density lipoproteins. In contrast, sedentary lifestyles and obesity are accompanied by lower coenzyme Q levels in plasma and higher oxidative damage. Statins are widely used to treat hypercholesterolemia, but these drugs also decrease coenzyme Q levels in plasma and organs. This chapter includes evidence about the positive role of coenzyme Q in human physiology and the effect exercise has on preventing aging-associated decreases in coenzyme Q decrease and in addressing the progression of atherosclerosis.

Keywords

Coenzyme Q; aging; exercise; cholesterol; blood; cardiovascular disease

Overview

Coenzyme Q (CoQ) is a lipophilic and active reduction–oxidation molecule located in all cell membranes and in blood lipoproteins (Ernster and Dallner, 1995; Ernster and Forsmark-Andree, 1993). It is composed of a quinone ring bound to a chain of isoprene units ranging from 6 to 10 units in length. The length of the isoprene chain determines the type of CoQ, which varies depending on the species. Saccharomyces cerevisiae has 6 units, Candida maritima has 7, Escherichia coli has 8, Caenorhabditis elegans and Drosophila melanogaster have 9, and rodents and humans have 10. CoQ cycles between its oxidized form and its reduced form, ubiquinone (oxCoQ) and ubiquinol (redCoQ), respectively, with redCoQ being the most abundant form in plasma and tissues. In fact, the ratio of redCoQ to oxCoQ is considered to be a marker of oxidative stress (Fig. 26.1) (Niklowitz et al., 2016).

image
Figure 26.1 CoQ structure and redox cycle. CoQ is composed of a benzene ring linked to a isoprene chain. The chain confers its lipidic characteristics whereas the ring acts in the electron transferences. Oxidized CoQ is known as ubiquinone, whereas the reduced and active form is known as ubiquinol. The isoprene chain length changes in different organisms. The number of isoprene units is indicated for each species.

In cells and tissues, CoQ’s main role is to carry electrons in the mitochondrial electron transport chain (METC). METC transfers electrons from reduced molecules such as nicotinamide adenine dinucleotide (NADH) or succinate—which are produced during oxidation of glucose by glycolysis and by Kreb’s cycle and by beta oxidation of lipids—to oxygen as the final electron acceptor with water as the product. During this process, the METC pumps protons from the matrix to the intermembrane space of mitochondria, inducing a gradient that is used by the mitochondrial ATPase to synthesize ATP from ADP + Pi (Fig. 26.2). In METC, CoQ is the only lipid directly involved in the transfer of electrons from complexes I or II to complex III (Lopez-Lluch et al., 2010). The importance of this lipid in the physiology of mitochondria is highlighted by the severity of rare diseases associated with deficiencies in CoQ synthesis that often produces a similar pathology than other mitochondria-associated rare diseases such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) or myoclonic epilepsy with ragged red fibers (MERFF) (Yubero et al., 2015). CoQ molecules are also internal components of METC complex III, and its presence is essential for the stabilization of this complex (Santos-Ocana et al., 2002).

image
Figure 26.2 Function of CoQ in cell membranes and lipoproteins. (A) Function of CoQ in the inner mitochondrial membrane. CoQ is an essential component of the mitochondrial electron transfer chain, accepting electrons from complex I or complex II and giving them to complex III. CoQ can also receive electrons from beta oxidation of the fatty acids. This function is essential in the mitochondrial oxidative metabolism. CoQ also receive electrons from dihydro-orotate dehydrogenase acting as an essential component in the synthesis of pyridine nucleotides. Furthermore, the physiology of the mitochondria can be also regulated by CoQ, thus affecting the activity of uncoupling proteins and mitochondrial pores. (B) In cell membranes, including mitochondrial membranes, CoQ is essential for preventing lipoperoxidation by itself or maintaining alpha-tocopherol in its reduced state. In mitochondria, CoQ is reduced by the electron transport chain components, but in other membranes it is reduced by CoQ-dependent enzymes such as Cyt b5 reductase and NQO1. (C) The presence of CoQ in lipoproteins has been associated with the prevention of lipid peroxidation of these particles. CoQ is associated with the particle’s phospholipid external surface where, together with alpha-tocopherol, it protects the particle against lipid peroxidation.

The role of CoQ in mitochondrial inner membrane is also associated with other essential activities in this organelle. CoQ is also involved in the transfer of electrons to the METC from beta oxidation, in the synthesis of purines by accepting electrons from dihydro-orotate dehydrogenase, in the control of the activity of uncoupling proteins, and the regulation of the permeability transition pore opening involved in mitochondrial swelling and apoptosis (Fig. 26.2) (Lopez-Lluch et al., 2010). Furthermore, redCoQ is a key lipid antioxidant in mitochondrial membranes as demonstrated many years ago (Takayanagi et al., 1980). Prevention of oxidative damage in mitochondrial membranes clearly depends on the amount of redCoQ through a direct antioxidant activity by recycling alpha-tocopherol to maintain its levels of the reduced form (Noack et al., 1994).

In other cell membranes, CoQ is involved in protecting the lipid bilayer against oxidative damage by maintaining alpha-tocopherol and vitamin C in their reduced and then active forms, respectively (Rodriguez-Aguilera et al., 2000). The maintenance of CoQ in its reduced form depends on different oxidoreductases that transfer electrons from nicotinamide adenine dinucleotide phosphate to the oxCoQ form reducing it (Villalba et al., 1997). To date, cytochrome b5 reductase and NQO1 (DT-diaphorase) have been found as the main enzymes involved in CoQ recycling in cell membranes. However, other enzymes such as cytoplasmic NADH-Q reductase, thioredoxin reductase, lipoamide dehydrogenase, and glutathione reductase have been reported as electron transfer enzymes to CoQ in cells (Fig. 26.2) (Lopez-Lluch et al., 2010).

Apart from its role in cells, CoQ has an important presence in blood plasma. In humans, the range of CoQ10 in plasma is around 0.5–2 nmol/mL (µM) (Lagendijk et al., 1996). CoQ is associated with lipoproteins that transfer cholesterol from the liver to other organs and from organs to the liver but is higher in low-density lipoprotein (LDL) particles than in high-density lipoprotein (HDL) particles (Bhagavan and Chopra, 2006). In fact, it has been considered that lipoproteins are the right carriers of CoQ in the circulation (Johansen et al., 1991; Laaksonen et al., 1995). Several studies have demonstrated the essential role of CoQ10 in the protection against oxidative damage of plasma lipoproteins. Higher levels of Q10 in lipoproteins are directly related to LDLs’ higher resistance to initiation of lipid peroxidation (Mohr et al., 1992). In LDLs isolated from healthy volunteers supplemented with CoQ10, induction of lipid peroxidation with chemical initiators was delayed in comparison with nonsupplemented particles (Littarru et al., 1994). In contrast, lower CoQ10 levels in plasma have been associated with higher lipid peroxidation (Stocker et al., 1991). It has been also demonstrated that CoQ10 is more efficient than alpha-tocopherol in the protection of LDL against oxidation, being considered the primary lipid-soluble antioxidant in these particles (Stocker et al., 1991).

Other in vitro experiments with LDLs isolated from human blood demonstrated that these lipoproteins are protected against oxidative damage while CoQ10 levels remain in the particle. After oxidative stress, CoQ10 levels decrease and the oxidation of lipids increases beyond the maintenance of alpha-tocopherol levels. Then cholesterol oxidation in LDLs starts only when almost all the CoQ10 is consumed. These experiments reinforce the idea that CoQ10 is the main antioxidant in human plasma lipoproteins (Yamamoto et al., 1991). This is critical because oxidized LDLs are key factors in the initiation and progression of atherosclerosis. This importance has been highlighted by the antiatherogenic effects of CoQ10 in apolipoprotein E knockout mice models (Witting et al., 2000). Furthermore, in a mice model of vitamin E deficiency associated with a high-fat diet, pharmacological doses of CoQ10 were capable of decreasing lipid peroxidation levels in atherosclerotic lesions probably by reducing the oxidation of LDLs (Littarru and Tiano, 2007). Among the positive cardiovascular effects of CoQ10, its capability to antagonize the oxidation of plasma LDLs has been considered one of the most important (Belardinelli et al., 2006).

Due to its essential bioenergetic role or to its key function as lipid antioxidant, CoQ10 has also been associated with several human age-related chronic diseases such as diabetes, hypercholesterolemia, cardiac insufficiency, and neurodegenerative diseases (Lopez-Lluch et al., 2010; Quinzii et al., 2007).

In this chapter, we will focus on the activity of this essential molecule in aging and how physical activity or exercise can modify its levels and activity (Del Pozo-Cruz et al., 2014a; Del Pozo-Cruz et al., 2014b).

Do Levels of CoQ Decrease During Aging?

Being an essential factor in the bioenergetic machinery in cells and a key factor in the membrane and lipoproteins-associated antioxidant system, a putative role of CoQ in physiological decline and in increased age-related oxidative damage is feasible. However, it remains unclear how CoQ behaves during aging. Early studies demonstrate a peak of CoQ in organs such as the lung, heart, spleen, liver, kidney, pancreas, and adrenal gland at 20 years of age followed by a continuous decrease with further aging (Kalen et al., 1989). In humans, most of the studies about CoQ10 levels during aging have been performed using blood. Besides the early studies indicating a decrease in this essential lipid during aging, the results in plasma or blood are controversial. Some reports have shown a decrease of CoQ10 during aging (Ernster and Dallner, 1995), whereas other studies have shown that levels of CoQ10 in older people are higher than in young people (Kaikkonen et al., 1999). This can reflect the differences in populations and life styles. A recent interesting but brief report suggested that the redox status of CoQ10 in human plasma—that is, the percentage of oxCoQ10 in the total amount of CoQ10—is greater in patients with geriatric diseases than in healthy patients (Wada et al., 2007).

Gender seems to be a factor that influences plasma levels of CoQ10, with levels being higher in men than in women (Aejmelaeus et al., 1997). This fact was recently confirmed in a study that determined the levels of CoQ10 in the plasma of European adults (Niklowitz et al., 2016). In this work, authors show that levels of CoQ10 in plasma increase in people between ages 41 and 60 and decrease after 61. Levels of CoQ10 in men were higher than in women, which confirmed results published 20 years before (Aejmelaeus et al., 1997). When related to cholesterol levels, this age-dependent evolution was maintained when the levels of CoQ10 in µmol/mol of cholesterol were determined (Niklowitz et al., 2016). As in the article published previously by Wada et al. (2007), the authors conclude that the antioxidant capacity of CoQ10 impairs during aging because CoQ10 levels decrease when compared with levels in mature people and the proportion of oxidized CoQ10 increases in plasma, which indicates a higher use of the molecule in its antioxidant role or a decreased capacity to maintain CoQ10 in its reduced and active form (Niklowitz et al., 2016).

Importance of CoQ in the Prevention of Cardiovascular Disease

Results from plasma indicate the importance of CoQ in the prevention of peroxidation in blood lipids and lipoproteins and in the progression of atherosclerosis. But CoQ10 is also an essential factor in several aspects of cardiovascular disease (CVD). The relationship between CoQ10 levels and cardiovascular disease was suggested in 1990 after a six-year study found that circulating levels of CoQ10 were significantly lower in patients suffering ischemic heart disease or dilated cardiomyopathy (Langsjoen et al., 1990). Some years before, Littarru and collaborators demonstrated that the concentrations of CoQ10 declined progressively in both blood and myocardial tissue with increasing severity of heart disease (Littarru et al., 1972).

A compilation of the mechanisms of CoQ10 against CVD was presented by Greenberg and Frishman in 1990 (Greenberg and Frishman, 1990). The positive effects of CoQ10 can be resumed in the improvement of cardiac bioenergetics, a higher antioxidant capacity, reduction of proinflammatory cytokines, and improvement of endothelial function, including vasodilatory effects and the stabilization of calcium and sodium and potassium channels. All of these effects confirm the essential role of this lipid in the prevention of CVD in humans (Fig. 26.3).

image
Figure 26.3 Functions of CoQ in the prevention of cardiovascular disease. CoQ has been associated with many positive effects in the prevention of cardiovascular disease and its progression. Apart from its antioxidant effects in muscle or lipoproteins, it also improves bioenergetics in the heart and endothelial functions and produces positive effects in vasodilatation and ion channel activities, as well as prevents proinflammatory processes.

Apart from these effects, there is also promising evidence of the beneficial effects of CoQ10 in the treatment of heart failure and hypertension (Pepe et al., 2007). Further, other studies have highlighted the important role of CoQ10 in CVD in general, reaching the conclusion that CoQ10 deficiency might be an important pathogenic mechanism involved in chronic heart failure (Littarru and Tiano, 2007). In fact, deficiency in plasma CoQ10 levels has been considered an independent predictor of mortality in patients suffering chronic heart failure (Molyneux et al., 2008). Further, in an interesting and recent paper, a negative relationship between the levels of redCoQ10 and the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), an indicator of the severity of heart failure, has been found. In heart failure patients, healthy subjects showed lower NT-proBNP levels, high redCoQ10 levels, and lower ratios of oxCoQ10 to redCoQ10. Further, treatment with redCoQ10 in patients reduced the expression of genes related with NT-proBNP levels (Onur et al., 2015). All of these findings demonstrate the importance of CoQ10 in the initial phases and progression of CVD.

CoQ10 Levels Can Be Modified by Physical Activity and Lifestyle

CoQ10 levels in tissues are mainly the product of the compound’s biosynthesis with probably a nonsignificant contribution from diet. However, we cannot discard a dietary effect because of the this lipid’s long half-life in circulation. The major dietary sources of CoQ10 in humans are meat (including poultry), fish (sardines, tuna, and mackerel), some vegetables (broccoli and peanuts) and oils (olive, soy, and fish oils) (Kamei et al., 1986; Weber et al., 1997). The normal dietary intake has been considered to be between 2–5 mg/day. This concentration is not enough to reach a diary intake that is beneficial in pathological conditions, which require around 30–60 mg/day to prevent CoQ10 deficiency or 100–200 mg/day in therapeutic doses to treat heart disease (Kumar et al., 2009). However, due to accumulative effects and the direct effect of dietary CoQ10 in liver as the first organ receiving the compound, the positive effects of a balanced diet on the levels of CoQ10 in plasma during aging cannot be discarded.

Many different studies have demonstrated the positive effect or the practice of physical activity in the prevention of CVD and many other age-related diseases. We have been working on the effects of physical activity on endogenous antioxidant capacities in animal models and humans, and over the last years we have demonstrated that exercise in mice positively affects the activities of endogenous antioxidants in different tissues such as liver (Tung et al., 2014) and muscle (Rodriguez-Bies et al., 2015). The effect of exercise and other age-delaying factors such as calorie restriction or resveratrol depends on the organism’s age (Rodriguez-Bies et al., 2015; Tung et al., 2014) and the tissue affected (Tung et al., 2015). Exercise increased CoQ9 and CoQ10 levels in mice muscle with a higher effect in older than in younger animals. This effect was accompanied by the higher presence and activity of CoQ-dependent antioxidant enzymes, Cyt b5 reductase, and NQO1 (Rodriguez-Bies et al., 2015). This effect was also found in liver, heart, and kidney tissues where NQO1 activity increased in exercised animals; whereas Cyt b5 reductase was only affected in the kidney (Tung et al., 2015). Our results agree with the findings of Rinaldi and collaborators on rat heart, indicating that prolonged exercise can counterbalance the age-related effects in antioxidant systems in this organ (Rinaldi et al., 2006).

In humans, only data related to the levels of CoQ10 in plasma are available. Few studies show results about the effect of exercise on the levels of CoQ10 in human blood. In a recent publication of our group, we determined that higher levels of functional capacity (mostly cardiovascular and strength) are associated with higher levels of CoQ10 in blood. These higher levels of CoQ10 in plasma were associated with lower levels of oxidized lipids in plasma (Del Pozo-Cruz et al., 2014a; Del Pozo-Cruz et al., 2014b). As in the case of animals, the response to exercise in the elderly was higher than in young individuals (Del Pozo-Cruz et al., 2014a). In elderly people, we found that higher levels of CoQ10 were associated with better levels of cardiovascular performance, even when this parameter was normalized to cholesterol or triacylglycerides levels or analyzed separately in men and women, indicating that this effect was independent on the gender (Del Pozo-Cruz et al., 2014b). Our findings agree with other previous studies that have correlated the intensity of physical activity and other antioxidant parameters in human plasma (Aguilo et al., 2005; Aguilo et al., 2003).

In a study using a training protocol based on stretching exercise and cycling applied to sedentary individuals over 8 weeks, low changes in plasma CoQ10 levels were found (Belardinelli et al., 2006). Although the protocol applied is probably not enough to significantly increase CoQ10 levels, the effect of exercise tends to increase CoQ10 levels in plasma and increase the ratio of CoQ10 to LDL. In fact, the mean concentration of CoQ10 to LDL was 0.713 µg/mg in sedentary people and 0.813 µg/mg in exercised individuals. These results agree with our findings for people who maintain higher levels of physical activity over longer periods of time (Del Pozo-Cruz et al., 2014a).

It is interesting that exercise also increased the levels of plasma CoQ10 in people supplemented with 100 mg/day of CoQ10 in comparison with sedentary and supplemented people (Belardinelli et al., 2006). This increase was associated with marked improvements in cardiovascular parameters. This indicates that physical activity could act as an adjuvant of the protective effect of CoQ10 supplementation on CVD and other age-related diseases.

Other studies have tried to determine whether supplementation with CoQ10 can ameliorate physical capacity in humans. Supplementation with 300 mg/day of redCoQ10 neither increased exercise performance nor decreased oxidative stress (Bloomer et al., 2012), indicating that higher levels of CoQ10 obtained from supplements do not improve physical performance. However, in agreement with our findings, this study found that active subjects had already a baseline of total CoQ10 in plasma higher than the normal value found in typical populations (Bloomer et al., 2012).

Our finding about the positive relationship between CoQ10 levels in plasma and in LDLs and the lower lipoperoxidation degree in these conditions agrees with other studies that show a positive relationship between physical activity and lower lipid peroxidation levels in plasma (Leelarungrayub et al., 2011). In a cohort of sedentary women, six weeks of aerobic dance were enough to decrease lipid peroxide levels in plasma (Leelarungrayub et al., 2011). In another study carried out in men who undertook progressive resistance training, plasma levels of lipid peroxidation decreased in around 40% of them, whereas total antioxidant capacity and glutathione peroxidase activity only showed lower increases (Azizbeigi et al., 2013). Considering the low increase in CoQ10 levels found in sedentary people trained during 8 weeks (Belardinelli et al., 2006), it seems clear that physical activity produces modest increases in plasma’s antioxidant capacity to protect cholesterol against oxidation and then to reduce CVD risk.

The increase of CoQ10 found in elderly people showing higher cardiovascular performance (Del Pozo-Cruz et al., 2014a,b) indicates higher protection not only against oxidative stress but also against the progression of cardiovascular disease.

Plasma CoQ10 and Obesity

Sedentarism is one of the most important risk factors in several age-associated diseases, including hypercholesterolemia, diabetes, and hypertension. Sedentarism is directly associated with the pandemic of obesity seen around the world, and exercise has largely been proposed as therapy to reduce it (Warburton et al., 2006). High body mass index (BMI) has been suggested as significantly contributing to poor health as people age (Gomez-Cabello et al., 2012).

The relationship of CoQ10 to obesity is currently controversial. Different studies carried out with adult individuals have shown discrepancies in the relationship between BMI and CoQ10 levels. Some studies have shown similar, others increased, and still others decreased CoQ10 levels in obese people in comparison with nonobese individuals. A study demonstrated that plasma CoQ10 levels increased to a small degree in people showing metabolic syndrome (Miles et al., 2004). However, another study performed later did not show differences between people with BMIs around 54 and normal individuals around 28.5 (Mancini et al., 2008). However, when obese people were treated with biliopancreatic diversion, the reduction in BMI was accompanied by a drop in plasma CoQ10 reaching even lower levels than the group showing lower BMI. This indicates that the metabolic regulation after chirurgic reduction of the stomach was accompanied by changes in plasma CoQ10 levels (Mancini et al., 2008).

Our study has demonstrated that sedentarism and higher BMI are associated with decreased plasma CoQ10 levels and increased lipid peroxidation in elderly people (Del Pozo-Cruz et al., 2014b). There was a clear negative relationship between plasma total CoQ10 or its ratio with cholesterol (CoQ10/cholesterol or CoQ10/LDL) and BMI. This negative relationship was very clear in people showing a BMI higher than 30. In agreement with our findings, studies performed in other populations showed similar relationships. In Kenyans, plasma CoQ10 levels were higher and BMIs lower for people living in the countryside than people living in Nairobi, the capital, who showed higher BMIs (Theuri et al., 2013). These results also agree with the decrease of plasma CoQ10 levels found in young obese people age 25 in Missouri in the United States (Butler et al., 2003). However, similar determinations performed in children aged 11–12 years in Germany showed no differences in total plasma CoQ10 levels or in relationship with cholesterol or LDL between obese and normal individuals (Menke et al., 2004). These differences probably indicate the effect of the age in the amount of CoQ10 in plasma probably related with the deleterious effect of time on liver activity in obese people since assembly of CoQ10 and lipoproteins occurs in the liver.

Due to the controversial studies performed to date establishing the relationship between continuous exercise or obesity with CoQ10 levels and lipid peroxidation in human plasma, larger prospective cohort studies are required to confirm the importance of maintaining functional levels of CoQ10 in plasma. Longitudinal studies implementing programs designed to increase physical fitness (mainly cardiovascular capacity and muscle strength) will also clarify the relationships between the effects of such interventions on aging and on age-related disease biomarkers.

Regulation of CoQ10 Levels in Plasma

As already indicated, dietary sources of CoQ10 do not explain the variation of plasma levels of this molecule. Regulation of CoQ10 synthesis in the liver by exercise and other lifestyle choices such as caloric intake or the presence of bioactive compounds such as resveratrol can be important parameters to consider. Animal models indicate that the peroxisome proliferator-activated receptor (PPAR) plays a key role in the regulation of CoQ10 synthesis. In rodents, it has been demonstrated that several drugs alter hepatocellular organization. Treatment of rats with di(2-ethylhexyl)phthalate, an activator of PPAR, increases CoQ content in liver as well as in muscle, blood, and heart, which indicates that these factors are involved in the regulation of CoQ synthesis (Hruban et al., 1974). Furthermore, PPARα is required for the elevation of CoQ caused by peroxisomal inducers, although it is not required for its biosynthesis (Bentinger et al., 2008).

One recent paper showed that exercise increases the expression of PPARα in rat livers, an effect that improves whole body metabolism (Zhang et al., 2011). This would explain how exercise induces increases in CoQ levels in muscles of exercised mice (Rodriguez-Bies et al., 2015). In humans, the generation of PPARγ ligands by exercise activates PPARγ signaling affecting genes related to lipid metabolism (Thomas et al., 2012) in monocytes. This has been associated with the control of reverse cholesterol transport and antiinflammatory effects. Furthermore, the regulation of plasma lipids by PPARγ in liver has also been demonstrated in healthy adults. In this study, a significant increase in oxidized LDL in plasma was found in the exercised group before and after working out. However, the trend showed a biphasic response in time that increased after 4 weeks of exercise and decreased after that to reach normal levels at 8 weeks of exercise (Butcher et al., 2008). These results suggest that the duration of the practice of exercise is an important factor to consider in these studies. Our previous results and other interventions indicate that CoQ10 synthesis and levels can increase after the practice of exercise for more than eight weeks. How PPARs are activated and their role in CoQ10 synthesis and assembly to lipoproteins remains to be clarified but opens an interesting field in the prevention of atherosclerosis.

Selenium is another interesting factor in the synthesis of CoQ in the liver (Vadhanavikit and Ganther, 1994). Although no further research has been performed, a deficiency of selenium reduced the levels of CoQ9 and CoQ10 in rat liver to around 50%, indicating an important effect of this oligo-element. The authors suggested that selenium preserves tissue against oxidative damage and is thus an integral part of the enzyme glutathione peroxidase (GPX) and preserves the capacity of cells to synthesize CoQ. Our research on mice demonstrate that age shows a clear decline in GPX and that exercise or resveratrol maintain higher levels of this enzyme during aging (Tung et al., 2015). However, the importance of GPX in CoQ10 synthesis and assembly with lipoproteins remain to be elucidated.

Effect of Statins on CoQ10 Levels

Statins are widely used as anticholesterol drugs and mainly by older people who show high cholesterol levels as a chronic disease. As cholesterol, dolichol, prenylation, and CoQ share the same biosynthetic pathway, the inhibition of the first enzyme of this pathway, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), will also inhibit the synthesis of CoQ (Folkers et al., 1990). In the early 1990s, some studies demonstrated that CoQ10 decreases in human plasma due to the attenuation of CoQ10 synthesis (Folkers et al., 1990; Ghirlanda et al., 1993). When statins lower cholesterol, they simultaneously reduce serum CoQ10 by as much as 40% (Kumar et al., 2009). However, this effect has also been associated with the net decrease of cholesterol in blood, although some studies demonstrated that the decrease in plasma CoQ10 found in statin-treated individuals was also evident after adjusting to cholesterol levels (Kaikkonen et al., 1999). If we add the CoQ10 deficiency occurring with age to the chronic intake of statins to control cholesterol levels in an older population, the reduction of CoQ10 in plasma can aggravate the progression of atherosclerosis.

The side effects of statins appear to be a direct consequence of CoQ10 and short-chain isoprenoid depletion rather than cholesterol reduction (Littarru and Langsjoen, 2007). Supplementation of statin patients with CoQ10 shows conflicting results and thus far the beneficial aspects are not clear. However, in recent studies, significant CoQ10 depletion occurs secondary to statin therapy (Hargreaves et al., 2005). In this case, supplementation with CoQ10 is highly recommended. In fact, a study of 103 patients treated with statins and CoQ10 have demonstrated beneficial effects in dilated cardiomyopathy with decreasing side effects from the statins (Kumar et al., 2009). Furthermore, statins have been associated with myopathies. Supplementation with CoQ10 may decrease much of the pain associated with statin treatment (Caso et al., 2007).

Taking into consideration the long-term effects of statins and the common use of these drugs in an older population suffering hypercholesterolemia, a suitable alternative would be to increase physical activity. This would increase endogenous CoQ10 synthesis and reduce LDL oxidation and at least help to reduce the doses of these drugs and thus prevent their side effects.

Concluding Remarks

In many studies, only total cholesterol, LDL, HDL, and triglycerides are determined, but there is no parallel determination of lipid peroxidation or LDL oxidation levels. Probably, depending on an individual’s lifestyle and level of exercise, the effect of CoQ10 in plasma can prevent LDL oxidation and reduce the risk of atherosclerosis even with moderate levels of cholesterol in blood. In fact, in a recent systematic review about supplementation with CoQ10 in humans, the authors concluded that CoQ10 has a potential to be a nutritional supplement to improve exercise capacity and reduce exercise-induced oxidative stress, muscle damage, and inflammation, although more studies are needed. The main problem is that the different CoQ10 formulations used in these studies, the timing of supplementation, and exercise tests make the interpretation of the data extremely difficult (Sarmiento et al., 2015).

Acknowledgments

The author is funded by the Andalusian Government grant BIO177 (FEDER funds of European Commission). Part of the research has been funded by the Spanish Ministry of Economy and Competitiveness grant DEP2012-39985. Author is also member of the CIBERER, Instituto Carlos III, of the Spanish Ministry of Health.

References

1. Aejmelaeus R, Metsa-Ketela T, Laippala P, Solakivi T, Alho H. Ubiquinol-10 and total peroxyl radical trapping capacity of LDL lipoproteins during aging: the effects of Q-10 supplementation. Mol Aspects Med. 1997;18(Suppl):S113–S120.

2. Aguilo A, Tauler P, Pilar Guix M, et al. Effect of exercise intensity and training on antioxidants and cholesterol profile in cyclists. J Nutr Biochem. 2003;14:319–325.

3. Aguilo A, Tauler P, Fuentespina E, Tur JA, Cordova A, Pons A. Antioxidant response to oxidative stress induced by exhaustive exercise. Physiol Behav. 2005;84:1–7.

4. Azizbeigi K, Azarbayjani MA, Peeri M, Agha-alinejad H, Stannard S. The effect of progressive resistance training on oxidative stress and antioxidant enzyme activity in erythrocytes in untrained men. Int J Sport Nutr Exerc Metab. 2013;23:230–238.

5. Belardinelli R, Mucaj A, Lacalaprice F, et al. Coenzyme Q10 and exercise training in chronic heart failure. Eur Heart J. 2006;27:2675–2681.

6. Bentinger M, Tekle M, Brismar K, Chojnacki T, Swiezewska E, Dallner G. Stimulation of coenzyme Q synthesis. Biofactors. 2008;32:99–111.

7. Bhagavan HN, Chopra RK. Coenzyme Q10: absorption, tissue uptake, metabolism, and pharmacokinetics. Free Radic Res. 2006;40:445–453.

8. Bloomer RJ, Canale RE, McCarthy CG, Farney TM. Impact of oral ubiquinol on blood oxidative stress and exercise performance. Oxid Med Cell Longev. 2012;2012:465020.

9. Butcher LR, Thomas A, Backx K, Roberts A, Webb R, Morris K. Low-intensity exercise exerts beneficial effects on plasma lipids via PPARgamma. Med Sci Sports Exerc. 2008;40:1263–1270.

10. Butler MG, Dasouki M, Bittel D, Hunter S, Naini A, DiMauro S. Coenzyme Q10 levels in Prader-Willi syndrome: comparison with obese and non-obese subjects. Am J Med Genet A. 2003;119A:168–171.

11. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007;99:1409–1412.

12. Del Pozo-Cruz J, Rodriguez-Bies E, Ballesteros-Simarro M, et al. Physical activity affects plasma coenzyme Q10 levels differently in young and old humans. Biogerontology. 2014a;15:199–211.

13. Del Pozo-Cruz J, Rodriguez-Bies E, Navas-Enamorado I, Del Pozo-Cruz B, Navas P, Lopez-Lluch G. Relationship between functional capacity and body mass index with plasma coenzyme Q10 and oxidative damage in community-dwelling elderly-people. Exp Gerontol. 2014b;52:46–54.

14. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995;1271:195–204.

15. Ernster L, Forsmark-Andree P. Ubiquinol: an endogenous antioxidant in aerobic organisms. Clin Investig. 1993;71:S60–S65.

16. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA. 1990;87:8931–8934.

17. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol. 1993;33:226–229.

18. Gomez-Cabello A, Pedrero-Chamizo R, Olivares PR, et al. Sitting time increases the overweight and obesity risk independently of walking time in elderly people from Spain. Maturitas. 2012;73:337–343.

19. Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol. 1990;30:596–608.

20. Hargreaves IP, Duncan AJ, Heales SJ, Land JM. The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Saf. 2005;28:659–676.

21. Hruban Z, Gotoh M, Slesers A, Chou SF. Structure of hepatic microbodies in rats treated with acetylsalicylic acid, clofibrate, and dimethrin. Lab Investig. 1974;30:64–75.

22. Johansen K, Theorell H, Karlsson J, Diamant B, Folkers K. Coenzyme Q10, alpha-tocopherol and free cholesterol in HDL and LDL fractions. Ann Med. 1991;23:649–656.

23. Kaikkonen J, Nyyssonen K, Tuomainen TP, Ristonmaa U, Salonen JT. Determinants of plasma coenzyme Q10 in humans. FEBS Lett. 1999;443:163–166.

24. Kalen A, Appelkvist EL, Dallner G. Age-related changes in the lipid compositions of rat and human tissues. Lipids. 1989;24:579–584.

25. Kamei M, Fujita T, Kanbe T, et al. The distribution and content of ubiquinone in foods. Int J Vitam Nutr Res. 1986;56:57–63.

26. Kumar A, Kaur H, Devi P, Mohan V. Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacol Ther. 2009;124:259–268.

27. Laaksonen R, Riihimaki A, Laitila J, Martensson K, Tikkanen MJ, Himberg JJ. Serum and muscle tissue ubiquinone levels in healthy subjects. J Lab Clin Med. 1995;125:517–521.

28. Lagendijk J, Ubbink JB, Vermaak WJ. Measurement of the ratio between the reduced and oxidized forms of coenzyme Q10 in human plasma as a possible marker of oxidative stress. J Lipid Res. 1996;37:67–75.

29. Langsjoen PH, Langsjoen PH, Folkers K. A six-year clinical study of therapy of cardiomyopathy with coenzyme Q10. Int J Tissue React. 1990;12:169–171.

30. Leelarungrayub D, Saidee K, Pothongsunun P, Pratanaphon S, YanKai A, Bloomer RJ. Six weeks of aerobic dance exercise improves blood oxidative stress status and increases interleukin-2 in previously sedentary women. J Bodyw Mov Ther. 2011;15:355–362.

31. Littarru GP, Langsjoen P. Coenzyme Q10 and statins: biochemical and clinical implications. Mitochondrion. 2007;7(Suppl):S168–S174.

32. Littarru GP, Tiano L. Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol Biotechnol. 2007;37:31–37.

33. Littarru GP, Ho L, Folkers K. Deficiency of coenzyme Q 10 in human heart disease II. Int J Vitam Nutr Res. 1972;42:413–434.

34. Littarru GP, Battino M, Tomasetti M, et al. Metabolic implications of coenzyme Q10 in red blood cells and plasma lipoproteins. Mol Aspects Med. 1994;15(Suppl):s67–s72.

35. Lopez-Lluch G, Rodriguez-Aguilera JC, Santos-Ocana C, Navas P. Is coenzyme Q a key factor in aging? Mech Ageing Dev. 2010;131:225–235.

36. Mancini A, Leone E, Festa R, et al. Evaluation of antioxidant systems (coenzyme Q10 and total antioxidant capacity) in morbid obesity before and after biliopancreatic diversion. Metabolism. 2008;57:1384–1389.

37. Menke T, Niklowitz P, de Sousa G, Reinehr T, Andler W. Comparison of coenzyme Q10 plasma levels in obese and normal weight children. Clin Chim Acta. 2004;349:121–127.

38. Miles MV, Morrison JA, Horn PS, Tang PH, Pesce AJ. Coenzyme Q10 changes are associated with metabolic syndrome. Clin Chim Acta. 2004;344:173–179.

39. Mohr D, Bowry VW, Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim Biophys Acta. 1992;1126:247–254.

40. Molyneux SL, Florkowski CM, George PM, et al. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol. 2008;52:1435–1441.

41. Niklowitz P, Onur S, Fischer A, et al. Coenzyme Q10 serum concentration and redox status in European adults: influence of age, sex, and lipoprotein concentration. J Clin Biochem Nutr. 2016.

42. Noack H, Kube U, Augustin W. Relations between tocopherol depletion and coenzyme Q during lipid peroxidation in rat liver mitochondria. Free Radic Res. 1994;20:375–386.

43. Onur S, Niklowitz P, Jacobs G, Lieb W, Menke T, Doring F. Association between serum level of ubiquinol and NT-proBNP, a marker for chronic heart failure, in healthy elderly subjects. Biofactors. 2015;41:35–43.

44. Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL. Coenzyme Q10 in cardiovascular disease. Mitochondrion. 2007;7(Suppl):S154–S167.

45. Quinzii CM, DiMauro S, Hirano M. Human coenzyme Q10 deficiency. Neurochem Res. 2007;32:723–727.

46. Rinaldi B, Corbi G, Boccuti S, et al. Exercise training affects age-induced changes in SOD and heat shock protein expression in rat heart. Exp Gerontol. 2006;41:764–770.

47. Rodriguez-Aguilera JC, Lopez-Lluch G, Santos-Ocana C, Villalba JM, Gomez-Diaz C, Navas P. Plasma membrane redox system protects cells against oxidative stress. Redox Rep. 2000;5:148–150.

48. Rodriguez-Bies E, Navas P, Lopez-Lluch G. Age-dependent effect of every-other-day feeding and aerobic exercise in ubiquinone levels and related antioxidant activities in mice muscle. J Gerontol A Biol Sci Med Sci. 2015;70:33–43.

49. Santos-Ocana C, Do TQ, Padilla S, Navas P, Clarke CF. Uptake of exogenous coenzyme Q and transport to mitochondria is required for bc1 complex stability in yeast coq mutants. J Biol Chem. 2002;277:10973–10981.

50. Sarmiento A, Diaz-Castro J, Pulido-Moranb M, Kajarabille N, Guisado R, Ochoa JJ. Coenzyme Q10 supplementation and exercise in healthy humans: a systematic review. Curr Drug Metab. 2015.

51. Stocker R, Bowry VW, Frei B. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci USA. 1991;88:1646–1650.

52. Takayanagi R, Takeshige K, Minakami S. NADH- and NADPH-dependent lipid peroxidation in bovine heart submitochondrial particles Dependence on the rate of electron flow in the respiratory chain and an antioxidant role of ubiquinol. Biochem J. 1980;192:853–860.

53. Theuri G, Dallner G, Brismar K, Tekle M. Effects of lifestyle on plasma levels of the IGF system and the antioxidants coenzyme Q10 and vitamin E in Kenyan rural and urban populations. Growth Horm IGF Res. 2013;23:68–75.

54. Thomas AW, Davies NA, Moir H, et al. Exercise-associated generation of PPARgamma ligands activates PPARgamma signaling events and upregulates genes related to lipid metabolism. J Appl Physiol (1985). 2012;112:806–815.

55. Tung BT, Rodriguez-Bies E, Ballesteros-Simarro M, Motilva V, Navas P, Lopez-Lluch G. Modulation of endogenous antioxidant activity by resveratrol and exercise in mouse liver is age dependent. J Gerontol A Biol Sci Med Sci. 2014;69:398–409.

56. Tung BT, Rodriguez-Bies E, Thanh HN, et al. Organ and tissue-dependent effect of resveratrol and exercise on antioxidant defenses of old mice. Aging Clin Exp Res. 2015;27:775–783.

57. Vadhanavikit S, Ganther HE. Selenium deficiency and decreased coenzyme Q levels. Mol Aspects Med. 1994;15(Suppl):s103–s107.

58. Villalba JM, Navarro F, Gomez-Diaz C, Arroyo A, Bello RI, Navas P. Role of cytochrome b5 reductase on the antioxidant function of coenzyme Q in the plasma membrane. Mol Aspects Med. 1997;18(Suppl):S7–13.

59. Wada H, Goto H, Hagiwara S, Yamamoto Y. Redox status of coenzyme Q10 is associated with chronological age. J Am Geriatr Soc. 2007;55:1141–1142.

60. Warburton DE, Nicol CW, Bredin SS. Prescribing exercise as preventive therapy. CMAJ. 2006;174:961–974.

61. Weber C, Bysted A, Hllmer G. The coenzyme Q10 content of the average Danish diet. Int J Vitam Nutr Res. 1997;67:123–129.

62. Witting PK, Pettersson K, Letters J, Stocker R. Anti-atherogenic effect of coenzyme Q10 in apolipoprotein E gene knockout mice. Free Radic Biol Med. 2000;29:295–305.

63. Yamamoto Y, Kawamura M, Tatsuno K, Yamashita S, Niki E, Naito C. Formation of lipid hydroperoxides in the cupric ion-induced oxidation of plasma and low density lipoprotein. In: Davies KJA, ed. Oxidative damage and repair Chemical, biological and medical aspects. Elmsford: Pergamon Press; 1991.

64. Yubero D, Montero R, Armstrong J, et al. Molecular diagnosis of coenzyme Q10 deficiency. Expert Rev Mol Diagn. 2015;15:1049–1059.

65. Zhang S, Liu Y, Li Q, et al. Exercise improved rat metabolism by raising PPAR-alpha. Int J Sports Med. 2011;32:568–573.

..................Content has been hidden....................

You can't read the all page of ebook, please click here login for view all page.
Reset