Coenzyme Q10

Coenzyme Q10 (CoQ10) is a pseudovitamin compound (sometimes,^[1] but falsely, called Vitamin Q) that is a vital component of cellular energy metabolism; placed within the electron transport chain of the mitochondria to facilitate ATP production (ATP being cellular energy currency, and the ultimate product of fatty acids and glucose being 'used' for energy). CoQ10 is named after its seemingly ubiquitous nature in the body, and differentially named after its reduced form (ubiquinol) and its oxidized form (ubiquinone) which are interchangeable in the body depending on the cell's oxidative state.^[2]

CoQ10 is a vitamin-like compounds that is produced in the body for proper functioning of mitochondria, and is also a component of the diet

Food sources of CoQ10 (sometimes both oxidized reduced forms of CoQ10 are measured collectively) include:

Meat (terrestrial):

• Reindeer meat at 157mg/kg^[3]
• Beef, including heart (113.3mg/kg^[3]), liver (39.2–50.5mg/kg^[3]) shoulder (40.1mg/kg^[4]), sirloin (30.6mg/kg^[5]), thigh (30.3mg/kg^[4]), tenderloin (26.5mg/kg^[5])
• Pork, including heart (118.1–282mg/kg^[3]), liver (22.7–54.0mg/kg^[3]) shoulder (45.0mg/kg^[4]), sirloin (14.0mg/kg^[5]) and thigh (13.8mg/kg^[4])
• Chicken, in the heart (92.3–192mg/kg^[6][4][5]), liver (116.2–132.2mg/kg^[7]), thigh (24.2–25.0mg/kg^[6][4]), breast (7.8–17.1mg/kg^[6][4][5]), and wing (11mg/kg^[6])

Terrestrial meats are the highest naturally occuring sources of CoQ10 in the diet, with cardiac tissue being the highest source followed by liver meats and then skeletal muscle

Meat (aquatic):

• Sardines, variable between 5.1–64.3mg/kg^[8][9][reference|url=http://www.sciencedirect.com/science/article/pii/S0889157507001755|title=Food content of ubiquinol-10 and ubiquinone-10 in the Japanese diet
• Yellowtail (12.8–20.7mg/kg^[8][4]) and higher (33.4mg/kg^[4]) in young fish
• Herring in heart (120.0–148.4mg/kg^[10]) and flesh (14.9–27.0mg/kg^[10][11])
• Baltic herring at 10.6–15.9mg/kg^[3][12]
• Mackerel, 43.3mg/kg in general^[8] with higher concentrations in the heart (105.5–109.8mg/kg^[10]) and red meat (67.5–67.7mg/kg^[10]) with lower content in the white meat (10.6–15.5mg/kg^[9][4][10])
• Horse mackerel, variable as low levels of 3.6-20.7mg/kg^[8][9] have been noted yet with one stating 130mg/kg^[4]
• Cuttlefish at 4.7–8.2mg/kg^[9][4]
• Salmon at 4.3–7.6mg/kg^[5][11][4]
• Albacore (Tuna) at 6.2mg/kg^[9] and tuna in general at 4.9mg/kg^[4] (although canned sources appear to be higher at 14.9-15.9mg/kg^[4][3])
• Pike at 5.4mg/kg^[9]
• Flat fish at 1.8–5.5mg/kg^[4]
• Shrimp at 2.8mg/kg^[9]
• Scallop at 5mg/kg^[4]
• Bogue 3.7mg/kg, Octopus at 3.5mg/kg, Annular sea bream 3.4mg/kg, Common pandora at 3.1mg/kg, European hake at 2.9mg/kg, Bondex murex and Red mullet at 2.6mg/kg, Striped mullet and Red band fish at 2.4mg/kg, Brill at 1.9mg/kg.^[9]
• Common mussel at 9.5mg/kg^[9]
• Grooved carpet shell at 6.6mg/kg^[9]

CoQ10 levels are also high in aquatic meats, with the same trend of heart tissue being a high source (with cardiac tissue from fish being comparable to cardiac tissue from terrestrial animals); the amount of CoQ10 in the meat of the fish is comparatively lower than seen with terrestrial meats

Dairy and Eggs:

• Butter at 7.1mg/kg^[8]
• Cheeses (in general, 1.4-2.1mg/kg^[8][6]) including Emmental (1.3mg/kg^[3]), Edam (1.2mg/kg^[3])
• Cow milk at 0.5-1.9mg/kg, with a trend for lower levels in UHT milk and lower fat products^[3][13]
• Yogurt, kefir, cream, and curd at 0.3-1.2mg/kg, highly (positively) correlated with fat content^[13]
• Eggs at 0.7-3.7mg/kg^[6][8] with the yolk being up to 5.2mg/kg^[6]

Dairy and eggs are somewhat decent sources, but relative to meat products they are much less substantial sources of CoQ10

Collectively, nuts and legumes tend to be moderate sources (the highest being peanuts at 26.7mg/kg and sesame at 17.6–23.0mg/kg) while their processed oils may also be decent sources (highest being extra virgin olive oil at 114–160mg/kg, corn oil at 13-139mg/kg, and soybean oil at 53.8-279mg/kg).^[6] Vegetables are inhernetly lesser in quantity, with the best sources being parsley (7.5–26.4mg/kg), soybeans (6.8–19.0mg/kg), perilla leaves (2.1–10.2mg/kg), and broccoli (5.9–8.6mg/kg).^[6]

Grains seem somewhat comparable to vegetable sources (being much lower than meats) although they appear to mostly only possess a CoQ9 content with nearly undetectable CoQ10 levels.^[6]

CoQ10 appears to be somewhat (14–32%) destroyed by frying with boiling not significantly influencing CoQ10 content of foods.^[14] It appears to be a bit more heat resistant than some other food-based compounds (such as Vitamin E or Sulforaphane, which are readily destroyed in cooking).

Nuts and oils are the highest plant sources of CoQ10 (although they are only decent sources when consumed in excessive amounts which is not practical) with vegetables being fairly poor sources of CoQ10. Grains are also a seemingly poor source of CoQ10

CoQ10 can be extracted from biological tissues of food sources (despite being expensive to produce en masse)^[15] but can also be produced in a laboratory setting using bacteria^[2][16] or outright synthesized.^[17] Microbial fermentation appears to be desirable due to less solvent usage and being cheaper to produce on a large scale^[18][19] and the bacteria Agrobacterium tumefaciens being commonly used due to good synthesis rates.^{[2][16][20][21][22]}

CoQ10 can be extracted from living tissue (expensive) although more commonly the CoQ10 is synthesized by bacteria, making CoQ10 supplements usually vegan (important due to interactions of CoQ10 and veganism, as most food sources are derived from animal tissue)

Coenzyme Q10 belongs to a class of molecules characterized by their benzoquinone ring structure at the end of an isoprenoid side chain, similar to a medieval flail. The length of the sidechain determines the designation of the coenzyme, with CoQ10 possessing ten isoprenoid units in its tail.^[23]

In its reduced form (ubiquinol) it can sequester some free radicals directly (an antioxidant effect) via conversion to its oxidized form (ubiquinone); a mechanism that is used to donate electrons through the electron transport chain to make ATP. Despite being in an oxidized form, ubiquinone still appears to be an antioxidant.^[24]

Coenzyme Q10 (henceforth CoQ10) primarily exists and is synthesized in the body for the purpose of being integrated into the Electron Transport Chain (ETC); one of the final stages in cellular energy production.^[25][26] The mechanism by which it acts is by a shuttle between segments of the ETC, in which electrons and protons are attracted to the benzoquinone head and the isoprenoid tail 'swings' the head from one segment to the next. Being a component of the cell's membrance (the lipid bilayer), CoQ10 is lipophilic or fat-soluble and should be supplemented with some form of dietary fat or lipophilic transport.^[27]

CoQ10 is endogenously produced by 4-hydroxybenzoic acid (produced from L-tyrosine)^[1][28] with this intermediate combining with polyprenyl pyrophosphate (produced from farsenyl pyrophosphate (FPP) of the mevalonate pathway^[29]) via the enzyme polyprenyl 4-hydroxybenzoic acid transferase into the molecule 4-hydroxypolyprenyl benzoic acid, which is then converted into CoQ10.^[30] Synthesis is somewhat impaired by statins as the inhibition of HMG-CoA reduced the free FPP pool, and CoQ10 synthesis rates appear to be somewhat dependent on the FPP pool (increasing this pool via inhibiting alternate pathays has been noted to increase CoQ10 synthesis^[31][32]).

The total body stores of CoQ10 are approximately 2g in an otherwise healthy adult and require 500mg of CoQ10 to be replaced daily (combination of endogenous synthesis and dietary intake)^[33][34] with an approximately 4 day turnover rate.^[35] The suggested daily exogenous intake (from the diet) ranges from 30–100mg in otherwise healthy persons but can be increased to 60–1200mg in some medical conditions such as statin usage.^[36][37] When assessing average dietary intake, however, the average intake appears to be around 3-6mg per day (european and asian data) due to the highest sources of cardiac meat and liver not commonly being ingested.^{[6][14][4][3]}

At least one study in rats administering oral CoQ10 assessed whether endogenous production was hindered (via mevalonate injections and subsequent CoQ9 production, as rats produce CoQ9 rather than CoQ10 via a similar pathway) failed to note any suppression after 4 days of supplementation.^[38]

Typically, tissues with higher metabolic activity in the body (heart, brain, kidneys, liver, skeletal muscle) have higher levels of CoQ10 relative to other areas of the body and are typically where most supplemental benefits are seen.^[23]

Approximately 14.5% of CoQ10 is located in the cell's cytosol or organelles within the cytosol whereas 41% is located in the mitochondria, with a relativly large portion (37.5%) in the cell nucleus (the final 7% being detected in supernatant)^[39] and mostly on the inner mitochondrial membrane.^[40] CoQ10 has been found not to correlate well with the lipid disposition of a cell (conversely, VItamin E is known to be highly correlated)^[41] and some detectable CoQ10 is found in specific organelles including lysosomes (120pmol/mg), golgi apparati (92pmol/mg), peroxisomes (13pmol/mg) as well as being free in the cytosol (11pmol/mg) or found in the plasma membrane (27pmol/mg); this particular data being derived from rats (known to have more CoQ9 relative to CoQ10, thus may not be the same in humans).^[42]

CoQ10, in the cell, appears to be highly localized in the mitochondria although it is not uniquely located in this organelle. Some CoQ10 can be detected in the cytoplasm as well as the nucleus

Note: CoQ10 'deficiency' is currently not legitimate terminology. The following states are those which are highly correlated with a lower serum and/or cellular level of CoQ10 when compared to an average an otherwise healthy population

Frequent smokers may be insufficient in CoQ10.^[43]

When in circulation, 95% of CoQ10 is in the reduced form (ubiquinol).^[23]

After oral ingestion, supplemental CoQ10 passes the stomach relatively unaffected (whereby CoQ10 from food products experiences enhanced bioavailability due to the denaturation of the protein containing products it exists in).^[23]

Similar to other lipophilic nutrients, CoQ10 is taken up into the lymphatic system alongside fat absorption contained in chylomicrons. There is no specific transport identified for CoQ10 in the human or rat intestines.^[44] Somewhere before or during packaging into chylomicrons, CoQ10 (ubiquinone) seems to be reduced to its anti-oxidative substrate, ubiquinol as is assessed in in vitro human cells.^[45]

CoQ10 can appear in serum fairly rapidly following oral ingestion^[40][46][38] where single dose administration appears to have a half-life between 5.80-8.10 hours and a (corrected as to exclude basal levels) C_max of 1.16-1.47μmol/L and an AUC of 44.94-64.01μmol/h/L (180mg liquid based CoQ10 dosing).^[47]

Following chronic supplementation, the basal level of approximately 1.1μmol/L in otherwise healthy adults^[48] has been noted to be increased with oil based supplements by 0.524μmol/L (100mg),^[49] 0.530μmol/L (300mg, but 1 week in length),^[50] 1.008μmol/L (120mg),^[51] 1.200μmol/L (90mg),^[52] 1.214μmol/L (90mg),^[53] and 1,900μmol/L (90mg)^[54] and with no significant differences observed between time frames (ranging from two weeks to nine months). Powder based supplements increase serum levels to a similar degree by 0.568μmol/L (100mg),^[55] 1.124μmol/L (100mg, sustained release),^[55] 1.309μmol/L (120mg),^[51] and 1.810μmol/L (90mg)^[54] while the one study on solubilized CoQ10 (120mg) noted a serum increase of 3.255μmol/L (120mg)^[51] while a 1 week trial using an emulsion failed to note any significant improvement over standard oil based supplements (0.500μmol/L with emulsion and 0.530μmol/L with oil with both at 300mg).^[50]

This solubilized version of CoQ10 (of which PureSorb-Q40 is a brand name) is a water soluble version of CoQ10 with an average particle size of 0.19µm when dispersed in water,^[56] has been confirmed to have a similarly enhanced bioavailability relative to oil based supplements,^[57] and appears to exert a similar safety profile to other forms of CoQ10 (no side effects at 2000mg/kg in rats^[58] nor at 2250mg daily in humans^[56]).

Orally ingested CoQ10 levels can increase serum concentrations of CoQ10, with repeated daily dosing able to increase serum CoQ10 concentrations in the range of a 50-150% increase with 90-120mg. There is a degree of unreliability in the spike observed with CoQ10 supplementation in serum, and although there does not appear to be any clear differences in powdered and oil-based supplementation (usually advised to be taken with a meal) there is some evidence a solubilized version may increase serum levels to a higher degree.

In serum CoQ10 exists as part of the chylomicron it was absorbed from (able to exert some antioxidant properties on its carrier^[59][60]) and, after deposition in the liver, is carried via lipoproteins such as LDL-C or HDL-C.^[23] The vast majority (96%) of CoQ10 at this stage is in the reduced form of ubiquinol^[48]

CoQ10 appears in serum fairly rapidly after oral administration^[40][46][38] (although acute doses are somewhat unreliable^[54][61]) and can be detected in skeletal muscle, the brain, kidneys, and the heart following prolonged (14wk) supplementation.^[62][63][64] Specifics of tissue concentration and transport can be found in the respective subsection, although in general the heart has the greatest concentration of CoQ10 followed by skeletal muscle, the liver and kidneys (similar concentrations at 63.6 and 77nmol/g, respectively) and then with lower concentrations in the intestines (13.3nmol/g), lungs (9.2nmol/g), and brain (15.5nmol/g).^[23]

Concentrations in tissues (excluding the liver and spleen) are seen with chronic rather than acute loading, with acute loading not significant raising tissue concentrations of CoQ10.^[65][66][67]

When measuring red blood cells, CoQ10 levels return to baseline after 12 weeks of supplementation.^[68]

An in vitro assay in rat microsomes found that the activity of cytochrome enzymes 1A1 and 1A2 were not affected by CoQ10 at concentrations up to 30µg/mL.^[69]

CoQ10 has been seen to interact in vitro with P-glycoprotein, a key transporter of xenobiotics which pumps them out of cells, at a concentration of 10µM; this opens up the possibility of drug interactions between CoQ10 and drugs which are transported by P-glycoprotein.^[70]

In vitro studies have indicated that CoQ10 activates hydroxylation of both enantiomers of warfarin in human and rat microsomes,^[71] an effect that has been seen to reduce the efficacy of warfarin in thinning the blood in rats.^[72] as well as in human case reports,^[73]|published=1998 May 25|authors=Landbo C1, Almdal TP|journal=Ugeskr Laeger]^[74] which was explained by one author as possibly being caused by the structural similarities of vitamin K and CoQ10.^[74] An observational study of patients being prescribed warfarin found that intake of CoQ10 was significantly associated with an increased risk of self-reported bleeding (odds ratio 3.69, 95% confidence interval 1.88-7.24).^[75] However, a double-blind, placebo-controlled crossover study using 100mg CoQ10 on middle-aged outpatients on stabilized warfarin treatment found no statistically significant difference in INR between the CoQ10 group and placebo.^[76]

A rat study using a single dose of theophylline (a drug used for asthma and COPD) has indicated that CoQ10 may interact with this drug; after giving the rats varying doses of 300-1200mg/kg of CoQ10 for five consecutive days before administring theophylline, C_max was raised by 2-3 times that of control, and the AUC of theohylline was approximately doubled, while the t_max increased from 0.5 hours to 2 hours (or 3 hours in the case of the highest dose) and the half-life decreasing by over an hour.^[69] The reasons for this change were unclear, as serum protein binding of theophylline and the activity of cytochrome enzymes 1A1 and 1A2 were not affected with concentrations up to 30µg/mL.^[69]

Theoretical drug interactions with CoQ10 exist due to its interaction with P-glycoprotein. There is mixed clincial evidence that CoQ10 can also interact with warfarin, and animal studies suggest that it could also interact with theophylline.

When looking at calorie-restricted mice (one of the only currently reliable manners of life extension), an increase in both CoQ9 and CoQ10 is detected in skeletal muscle and a decrease in Q9 (no effect on Q10) detected in cardiac tissue relative to normal-fed mice,^[77] an increase in skeletal muscle has been noted elsewhere^[78][79] as well as an increase in kidney CoQ9/Q10^[80] although for both cardiac tissue and the liver there is contrasting results.^[77][81]

One study noting that statin drugs were able to increase the lifespan of drosophilia noted that this effect was independent of ubiquinone status.^[82]

CoQ10 appears to be altered in calorically restricted mice, but it is possible this is merely a biomarker for something else associated with longevity

In nematodes (Caenorhabditis elegans), dietary exclusion of all CoQ10 increases lifespan by around 59%^[83] and ablating biosynthesis to reduce levels similarly increases lifespan^[84] and clk-1 mutants (who cannot synthesis CoQ9) see a similar increase in lifespan.^[85] The dietary exclusion study is somewhat contested, as another study found that life extension properties were due to bacterial metabolism alterations and not dietary CoQ10.^[86]

Supplementation of 93mg/kg or 371mg/kg CoQ10 to mice (human estimates for a 150lb person being 507mg and 2,023mg) from 3.5 months of age until their deaths failed to significantly increase lifespan and similarly failed to increase the levels of any antioxidant enzymes (glutathione, catalase, and superoxide dismutase).^[87] This lack of effect on lifespan has been noted with lower supplemental dosages in rats^[88] and mice.^[88][89]

There is currently no convincing evidence that supplemental CoQ10 enhanced the lifespan, with some limited evidence that absolute deprivation enhances lifespan (contested and not yet conducted in mammals)

Before supplementation, CoQ10 (as ubiquinol) is located in all tested brain regions with highest concentrations in the cerebral cortex, followed by the hippocampus and striatum (fairly equal) and then progressively less are noted in the midbrain-diencephalon, cerebellum, and brainstem; similar trends are seen with ubiquinone although the striatum and midbrain were lowest while the cortex was equal to the hippocampus and striatum.^[90]

Oral CoQ10 at 200mg/kg in rats for 2 months is able to increase brain CoQ10 content in young (12 month) rats (approximately 30% from baseline) and increase CoQ10 levels in aged (24 month) rats to a similar level seen in young rats given CoQ10, and both CoQ9 and Vitamin E also appeared to be increased.^[64] An increase in 22% has been noted in another study in the cortex, with no significant influence was found in any other brain region tested (hippocampus, striatum, midbrain-diencephalon, cerebellum, or brainstem) following lifetime ingestion of 0.72mg/g or 2.81mg/g in mice.^[90]

An increase in cerebral CoQ10 concentrations are noted in animals given CoQ10 supplementation over a prolonged period of time (no human studies at the moment, due to complications in detecting CoQ10 supplementation in a living person) and the increase is lesser than that of other organs and serum

One study using CoQ10 at a low and high dose (0.72mg/g or 2.81mg/g) in young mice for up to 21 months (lifetime study) noted that high CoQ10 increased physical activity in old age (independent of motor control testing, which was similar between groups) but was associated with reduced spatial memory performance and sensory acuity in older age;^[90] the overall dosing was approximately 106mg/kg and 352mg/kg respectively,^[90] and estimated human equivalent doses are 8.5mg/kg and 28mg/kg respectively (for a 150lb person, 580mg and 1,909mg daily) based on standard conversion factors.^[91] These doses are similar to those seen in another study using lifetime administration of CoQ10 that failed to note any influence on antioxidant enzyme status or lifespan (cognition not measured)^[87] and in a study where cognition in older mice was improved, but CoQ10 therapy was 12 weeks in duration and started in older age.^[92]

Limited animal evidence to assess lifetime usage of CoQ10, but there does not appear to be any significant influences with standard or slightly elevated doses of CoQ10 although higher doses have been associated with a worsening cognitive profile during aging yet protective when started during advanced age

A study feeding rats 1% of the feed as CoQ10 before MPTP injections (toxin that mimics Parkinson's disease^[93]) noted that 2 weeks of feeding was able to preserve some dopaminergic function, reducing the loss in dopamine to 26% (control toxin reduced dopamine 56%) which was slightly more protective than creatine although their benefits were additive.[reference|url=http://www.ncbi.nlm.nih.gov/pubmed/19476553|title=Combination therapy