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).

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).

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).

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.