1. Coenzyme Q: Structure, Localization and Forms
Coenzyme Q (CoQ) is a naturally occurring molecule formed from the conjugation of a benzoquinone ring with a hydrophobic isoprenoid chain of varying chain length, depending on the species [
1,
2,
3]. It is mainly located in the hydrophobic domain of the phospholipid bilayer of the inner membrane system of the mitochondria, but it is also present in all the other biological membranes at significant levels [
4,
5,
6,
7,
8,
9], as well as in plasma lipoproteins [
10]. Moreover, CoQ is found in every plant and animal cell [
2,
11]. Due to its ubiquitous presence in nature and its quinone structure, it is also called ubiquinone [
2,
12]. Ubiquinone is referred to as “coenzyme” because of its unique ability to participate in chemical reactions but it remains at steady-state levels in the cell [
3,
13]. There are different ubiquinone molecules that are classified based on the length of their isoprenoid side chain with a subscript indicating the number of carbons in the chain (CoQ
n) [
1,
3]. CoQ
9 (2,3-dimethoxy-5-methyl-6-noneprenyl-1,4-benzoquinone) is the predominant form in rats and mice, whereas in humans and other long-living mammals, the major homologue is CoQ
10 (2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone) [
2,
3,
14]. The importance of the length of the polyisoprenyl chain is related to the stability of the molecule within the hydrophobic lipid bilayer. In addition, this feature seems to affect other properties, such as mobility, intermolecular interaction with membrane proteins, and autoxidizability [
3,
15,
16].
The benzoquinone ring of CoQ can assume three alternate redox states due to the existence of different possible levels of protonation yielding three alternative CoQ forms (
Figure 1): the fully oxidized (CoQ) or ubiquinone, the fully reduced (CoQH
2) or ubiquinol and the partially reduced (CoQH) or ubisemiquinone [
17,
18]. Because of its extreme hydrophobicity, it is possible to find natural CoQ in three physical states: dissolved in lipid bilayers, forming micellar aggregates, or bound to proteins. In cells, CoQ is distributed between the two first states [
18], whereas the importance of the last one is only experimental [
17]. All cells are able to synthesize functionally sufficient amounts of this molecule under normal physiological conditions [
19]. However, the content of CoQ as well as the ratios between its forms are different depending on the analyzed species, tissue or even organelle. For instance, murine kidney and heart show higher CoQ levels than brain or liver homogenates [
20,
21]. Likewise, it has been reported that lysosomes and Golgi membranes contain relatively higher concentrations of CoQ than mitochondrial membranes or microsomes [
22,
23]. In non-mitochondrial biological membranes, CoQ continuously cycles between reduced and oxidized states thanks to different enzymes with CoQ reductase activity [
24]. These enzymes are NAD(P)H dehydrogenases which form part of the plasma membrane redox system, an electron transport where CoQ acts as a mediator accepting electrons from cytosolic NAD(P)H [
6]. This system has been related to the maintenance of intracellular redox homeostasis, membrane antioxidant protection, regulation of cell signaling and other functions [
6] that will be discussed below.
5. Studies on Dietary Therapies with CoQ on Aging
According to previous observations, dietary supplementation with CoQ
10 could constitute an anti-aging strategy. In humans, there is evidence, mainly indirect, that exogenous orally administered CoQ
10 may be incorporated into mitochondria, at least in conditions of partial CoQ tissue deficiency, where it may enhance electron transfer and ATP synthesis with improvement of pathological situations such as cardiac failure [
182,
183], Parkinson’s disease [
115,
184,
185,
186], Alzheimer’s disease [
187,
188,
189] and Friedreich’s ataxia [
190].
Results from animal studies are not clear about the dietary CoQ effects on longevity. In
C. elegans, it has been reported that dietary CoQ prolonged lifespan [
162], but this was also noted with a CoQ-deficient diet [
191]. One possible explanation for poor diet effect could be in the adaptability of these nematodes to stressful conditions.
C. elegans life span is extended by the intake of antimycin A, an mtETC inhibitor, whereas this molecule is toxic to most other aerobic species [
192]. According to this observation, CoQ deficiency might induce a hypometabolic or a dauer-like state, which would facilitate survival under adverse conditions. However, a study focused on features of bacteria used to feed worms has evidenced that this phenomenon may be more complex. In this referred study, a diet based on respiratory incompetent
E. coli, regardless if they were CoQ-less or CoQ-replete, produced a robust life extension in wild-type
C. elegans [
193]. An explanation for these observations was that the fermentation-based metabolism of the
E. coli diet is an important parameter of
C. elegans longevity [
193].
As in invertebrates, simple dietary CoQ supplementation has shown no direct concluding results on lifespan extension in rodents. Information from this model indicates that CoQ
10 supplementation with daily dosages ranged from 10 to 370 mg/Kg has no effect on longevity [
117,
119,
129,
194]. Despite the absence of evidence supporting that dietary CoQ can increase lifespan in animals, some interventions in the same way have been found to retard certain aging detrimental aspects in different animal models for aging or age-related diseases. In SAMP mice, a mouse model for accelerated senescence and severe senile amyloidosis, life-long supplementation with CoQH
2 substantially decreased the senescence grading scores at different ages, although it did not alter some age-associated features of the model like the senile amyloid deposition rate. Again, this intervention did not have an effect on the lifespan [
195]. In older mice with clear cognitive and psychomotor impairments, short-time (15 days) CoQ-supplementation improved spatial learning [
196]. A cardinal event of diabetes like diabetic neuropathy has also been reported to be positively modified upon CoQ administration in diabetic rats [
140]. In the hypercholestolemic ApoE knockout mouse, dietary CoQ had an anti-atherogenic effect preventing the accumulation of lipid peroxides in aorta [
139]. In turn, in most of cases beneficial effects of CoQ over mitochondrial function and oxidative stress have been demonstrated [
139,
143,
196,
197]. However, long-term CoQ
10 intake in healthy mice fed a standard diet failed to modulate mitochondrial respiratory capacity in liver or levels of oxidative stress in liver, kidney, skeletal muscle or brain [
23,
119]. According to different findings, López-LLuch
et al. [
6] suggested that supplementation with CoQ is not needed when the organism is young and healthy because cell membranes seem to be nearly saturated at the functional level. However, this supplementation becomes necessary when the organism shows deficiency, as in aging. This could explain why CoQ effects are clearer in animal models of disease than on lifespan of healthy animals if they are related to low CoQ levels.
On the other hand, the combination of dietary treatments using CoQ supplements in certain nutritional conditions associated with higher oxidative stress levels and age-related detrimental effects offers interesting expectations. From this standpoint, studies comparing CoQ effects between isocaloric diets with different lipid profile are particularly interesting. The effects of long-term supplementation with daily CoQ
10 at 0.7 mg/kg on rats fed on MUFA-rich diets have been compared with those found in n-6 PUFA-rich diets [
118,
123,
198,
199,
200,
201]. One of the most interesting findings from such studies was that dietary CoQ
10 produced significant increases of mean and maximum lifespan in rats fed a diet rich in n-6 PUFA [
123,
199,
200]. At the histopathological level, when sunflower oil was the main fat in the diet, CoQ supplementation seemed to improve endocrine pancreas structure and in particular β-cell mass resembling positive effects of virgin olive oil [
201]. Similar effects were noted in rat alveolar bone loss associated to aging [
202]. Dietary CoQ treatments have also been shown to be effective in counteracting many of the high-fat diet consequences in animals [
129,
203,
204,
205,
206,
207,
208]. In other mouse models, post-weaning dietary supplementation with CoQ
10 rescued many of the detrimental effects of nutritional programming on cardiac aging by low birth-weight and catch-up growth [
197].
The biochemical basis of potential beneficial effects of CoQ on lifespan or other aging detrimental effects may include enhancement of the cellular antioxidant protection systems in cell membranes, where CoQ sustains lipids in its reduced redox state preventing lipid peroxidation, particularly the unstable PUFA [
6,
209]. In previous studies in rats, diets containing CoQ were associated with lower lipid peroxidation markers [
118,
199], as well as with lower oxidative damage of other macromolecules such as DNA or proteins. A higher antioxidant capacity [
199,
200] compared to that found in animals maintained on the same diet without additional CoQ
10 has been reported [
118,
122,
198,
202]. In addition, a lower impairment in mitochondrial function was also observed in CoQ-fed animals [
118]. All these findings would indicate that dietary CoQ
10 avoids, at least in part, oxidative stress linked to aging under certain conditions. Furthermore, it has been shown that life-long dietary supplementation with CoQ
10 attenuated a variety of changes in enzymatic activities associated with aging in rats [
209,
210]. These include increases in the hepatic activities of Mg
2+-dependent sphingomielinase [
209] and of cytosolic and membrane-bound NQO1 activities [
210], as well as decreases in cytosolic glutathione-
S-transferase and microsomal Se-independent glutathione peroxidase in liver plasma membrane [
209]. Proteomic analysis in rats under similar conditions has shown that serum albumin, which decreases with age in the rat, was significantly increased by CoQ
10 supplementation. Additionally, it induced significant modifications of several proteins in plasma. These modifications support the beneficial role of dietary CoQ
10 decreasing both oxidative stress and cardiovascular risk, and modulating inflammation and osteogenesis during aging [
211].
In humans, some studies have suggested similar effects for dietary CoQ in relation to oxidative stress, at least in combination with certain dietary patterns. Short-term (4 weeks) dietary CoQ effects on aging have been tested in combination with the Mediterranean diet. In this regard, elderly subjects ingested a Western diet rich in saturated fatty acids (SFA), a Mediterranean diet (rich in MUFA), and a Mediterranean diet supplemented with CoQ following a cross-over design [
212,
213,
214,
215,
216]. CoQ
10 addition to MUFA-rich diet reduced some postprandial oxidative stress marker levels when subjects took a breakfast with a lipid profile similar to their experimental diets [
212], which correlated with a lower expression of antioxidant enzyme components [
212,
215]. Moreover, dietary CoQ has also been shown to improve DNA repair systems [
213,
214] and modulate inflammatory signaling cascade as well as to reduce endoplasmic reticulum stress [
214].
All these results suggest that although CoQ supplementation does not directly extend lifespan, it may help to prevent life span shortening due to oxidative insults [
6] as it has been suggested by its effect in all aspect related to mitochondrial function, oxidative stress and antioxidant defenses both in animals [
139,
196,
197] and humans [
114,
143]. However, despite animal studies have shown certain beneficial effects on the health of different disease models, there are clinical trials reported no significant effects on the progression of some nervous central system disease [
113,
114]. As has been stated, brain CoQ uptake is very low compared to other organs [
23] and animal studies reported beneficial effects on this organ [
195,
196] have used very high daily dosages in relation to body weight compared with those used in clinical trials [
113,
114]. Future trials in humans focused on diseases affecting tissues and organs that have shown low CoQ uptake capacity should be more careful at this respect and to use higher CoQ dosages and/or chemical formulation with higher bioavailability such as those nanoparticulated or solubilized [
83]. In the same sense, possible differences in bioavailability and efficacy between ubiquinol and ubiquinone should also be taken into account. On the other hand, CoQ effectivity for different disease treatment could depend on many other conditions not considered in clinical trials: among others, possible differences in etiology and pathophysiology among animal models and human diseases.
Due to differences in dosage, duration, chemical formulation and subject age at the beginning of the treatment, it is very difficult to establish “ideal conditions” for CoQ use as “anti-aging therapy”. Notwithstanding, according some to animal studies [
118,
122,
198,
202], life-long dietary interventions could result useful to prevent negative consequences of different health insults throughout life, particularly in relation to lifestyle. However, ubiquinone dosages used (0.7 mg/kg) already seem very high to take them. In this sense, supplementing with some foods, particularly those that are more “pro-oxidant”, could result useful.