Prolonged Intake Of Coenzyme Q10 Impairs Cognitive Functions In Mice

AlphaCog

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Prolonged Intake of Coenzyme Q10 Impairs Cognitive Functions in Mice

"Mice were fed a control nonpurified diet or that diet containing 0.68 mg/g (low dosage) or 2.6 mg/g (high dosage) CoQ10, starting at 4 mo of age, and were tested for sensory, motor, and cognitive function at 7, 15, and 25 mo of age. Amounts of the ubiquinols CoQ9H2 and CoQ10H2 measured in a parallel study were augmented in the cerebral cortex but not in any other region of the brain. Intake of the low-CoQ10 diet did not affect age-associated decrements in muscle strength, balance, coordinated running, or learning/memory, whereas intake at the higher amount increased spontaneous activity, worsened the age-related losses in acuity to auditory and shock stimuli, and impaired the spatial learning/memory of old mice."

"In summary, our present findings accord with those reported previously in that CoQ10 administration during adult life does not extend the life span of rodents (26,49,50). Although prolonged CoQ10 intake in low amounts did not have a discernable effect on cognitive and motor functions, intake at higher amounts exacerbated some of the cognitive and sensory impairments encountered in aged mice. Thus, regardless of whether CoQ10 ultimately proves to be ameliorative in specific disease conditions involving oxidative stress and/or mitochondrial dysfunctions, the current findings tend to controvert the view that CoQ plays a direct or significant role in the mammalian aging process and is a credible antiaging intervention."
 

Amazoniac

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upload_2020-1-6_16-0-22.png

Toxic. To be rebels, @haidut, @healthnatura and @LifeGivingStore, have you considered selling it? Poor intestinal absorption, quality and excipients are common issues with products on the market; you may be able to solve them all.
 
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Grapelander

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I have some CoQ10 - I mixed with MCT oil and keep in fridge. Have not been using too often - appreciate your post.
In looking at one of the referenced studies - it would appear that CoQ10 works with α-tocopherol.

"Current evidence suggests that ubiquinol and α-tocopherol act in concert to scavenge radicals during autoxidation of mitochondrial membranes (Kagan et al., 1990;Stoyanovsky et al., 1995;Lass and Sohal, 1998;2000;Sohal, 2004). α-Tocopherol seems to act as a direct scavenger forming tocopheroxyl radical, whereas ubiquinol reacts with tocopheroxyl radical to regenerate αtocopherol."

Here is a study showing it protects from PUFA:
Coenzyme Q supplementation protects from age-related DNA double-strand breaks and increases lifespan in rats fed on a PUFA-rich diet.
Animals supplemented on coenzyme Q reached a significantly higher mean life span (11,7% higher, i.e. 2,5 months) and a significantly higher maximum life span (24% higher, i.e. 6 months) than non-supplemented animals. These results suggest that a long-term supplementation with a small dosage of coenzyme Q10 might represent a good anti-aging therapy in rats fed on a PUFA-based diet.
 
OP
AlphaCog

AlphaCog

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Probably lessen supplementation and consume animal heart and liver. Another option is red palm oil.
 
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Just take a look at the image Amazoniac has uploaded; no discernable difference between verum and ctrl. Q10 still has much backing for increase of healthspan, this misleading study should not deter us.
 

Amazoniac

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That wasn't a proper modification of the image because it's inducing focus on graphs of similar colors when the purpose was the opposite: to compare reduced and oxidized ubiquinones after uq-10 supplementation..

upload_2020-9-4_12-14-9.png
upload_2020-9-4_12-14-15.png

Lines were added for only one part of the brain (in this case hippopotamus) to save time, you get the idea.


- Coenzyme Q10 supplementation: Efficacy, safety, and formulation challenges

"When compared to a single dose, divided dosages resulted in increased plasmatic levels of CoQ10. For this reason, high CoQ10 daily doses should be split into several doses (Bhagavan & Chopra, 2007; Liu & Artmann, 2009)."​

- Bioavailability of Coenzyme Q10: An Overview of the Absorption Process and Subsequent Metabolism

"Most of the body’s daily requirement for CoQ10 is produced within the body. Some CoQ10 is ingested from food (typically 5 mg/day [5]). It is estimated that the daily requirement for CoQ10, from both endogenous bio-synthesis and food sources, is about 500 mg; this estimate is based on a total body quantity of about 2 g of CoQ10 and based on an average turnover time of 4 days in tissue [5]. This estimate serves as the justification for the size of the dosage (typically 300 mg/day) that is used in many clinical trial studies."

"As people mature into adulthood and begin to increase in age, the ability of the body to synthesise its own CoQ10 decreases; optimal human bio-synthesis occurs in the mid-twenties, with a continual gradual decline in tissue levels thereafter [6]. In addition to the normal aging process, CoQ10 levels have also been shown to be depleted in a number of disorders, particularly heart disease [7]. The synthesis of CoQ10 is a complex multistage process (governed by at least 13 genes), requiring a number of amino acids, vitamins, and trace element precursors and cofactors, deficiency of any of which can adversely affect normal CoQ10 production [8]. Nutritional supplementation with CoQ10 therefore provides a mechanism to maintain adequate levels within the body."

"[..]the body is limited in how much CoQ10 it can absorb at a given time, and thus if an individual takes several 100 mg capsules together, some of the CoQ10 tends to be wasted [15]."

"[..]the concept of the superior bioavailability of supplemental ubiquinol compared to ubiquinone would appear to be mistaken. This concept, widely disseminated on the Internet, seems in part to have originated from an inappropriate comparison between bioavailability data from studies by Shults et al. in 1998 [24] and Hosoe et al. in 2007 [25]. The older study involved the use of a dry powdered crystalline form of ubiquinone, which is poorly absorbed but was the only formulation available at the time. Thus, the comparison was not a head-to-head comparison in that it did not test the ubiquinol absorption results against a formulation of ubiquinone dissolved in appropriate carrier oils. The two studies being compared were conducted more than 10 years apart. They used different study subjects: healthy volunteers vs. patients with Parkinson’s disease, different investigators, different analytical labs, and different protocols."

"CoQ10 is a lipid soluble substance; therefore, the highest quality CoQ10 preparations have the CoQ10 dissolved in a well-suited carrier lipid (e.g., soy oil or palm oil). Typically, they are encapsulated in bovine gelatine capsules. The capsule material does not seem to be an important factor for absorption. The gelatine capsules readily dissolve within minutes inside the stomach and release the oil-dissolved CoQ10. The stomach transit time varies among individuals and varies according to the type of food eaten. The complete transit of the CoQ10 from the stomach through the small intestines, and the lymph to the blood typically takes between 5 and 8 h [26]. The transited CoQ10 enters the duodenum as part of the chyme. Although the CoQ10 is in transit from the stomach into the duodenum, any CoQ10 in the reduced form, the ubiquinol form, will be oxidised to the ubiquinone form; in studies of CoQ10 absorption under conditions that simulate gastric conditions, this process usually takes about 90 min (Figure 20 in [26])."

"The lipid solubility of CoQ10 is a consequence of its inherent chemical structure—technically, it is due to the presence of an isoprenoid chain within the CoQ10 molecule. CoQ10 is not at all water soluble, and, contrary to some manufacturers’ claims, cannot be made water-soluble [26]. Thus, any alteration to the structure of the CoQ10 molecule in an attempt to increase water solubility means that the molecule is no longer CoQ10. Similarly, the presence of two additional hydrogen atoms within the chemical structure of ubiquinol (compared to ubiquinone) has a negligible effect on potential water solubility [26]."

"In an attempt to understand CoQ10 absorption, Singh et al. [30] investigated the efficacy of various dosing strategies on serum CoQ10 levels in a group of 60 healthy adults. In the Singh study, a 200 mg CoQ10 dose yielded a larger increase in serum levels than a 100 mg dose. However, divided dosages of 2 × 100mg of CoQ10 yielded a larger increase in serum levels than a single 200 mg dose. The Singh data show that the human digestive system has a finite capacity to absorb CoQ10 in a single dose."​
 

johnwester130

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That wasn't a proper modification of the image because it's inducing focus on graphs of similar colors when the purpose was the opposite: to compare reduced and oxidized ubiquinones after uq-10 supplementation..

Lines were added for only one part of the brain (in this case hippopotamus) to save time, you get the idea.​


- Coenzyme Q10 supplementation: Efficacy, safety, and formulation challenges

"When compared to a single dose, divided dosages resulted in increased plasmatic levels of CoQ10. For this reason, high CoQ10 daily doses should be split into several doses (Bhagavan & Chopra, 2007; Liu & Artmann, 2009)."​

- Bioavailability of Coenzyme Q10: An Overview of the Absorption Process and Subsequent Metabolism

"Most of the body’s daily requirement for CoQ10 is produced within the body. Some CoQ10 is ingested from food (typically 5 mg/day [5]). It is estimated that the daily requirement for CoQ10, from both endogenous bio-synthesis and food sources, is about 500 mg; this estimate is based on a total body quantity of about 2 g of CoQ10 and based on an average turnover time of 4 days in tissue [5]. This estimate serves as the justification for the size of the dosage (typically 300 mg/day) that is used in many clinical trial studies."​
"As people mature into adulthood and begin to increase in age, the ability of the body to synthesise its own CoQ10 decreases; optimal human bio-synthesis occurs in the mid-twenties, with a continual gradual decline in tissue levels thereafter [6]. In addition to the normal aging process, CoQ10 levels have also been shown to be depleted in a number of disorders, particularly heart disease [7]. The synthesis of CoQ10 is a complex multistage process (governed by at least 13 genes), requiring a number of amino acids, vitamins, and trace element precursors and cofactors, deficiency of any of which can adversely affect normal CoQ10 production [8]. Nutritional supplementation with CoQ10 therefore provides a mechanism to maintain adequate levels within the body."​
"[..]the body is limited in how much CoQ10 it can absorb at a given time, and thus if an individual takes several 100 mg capsules together, some of the CoQ10 tends to be wasted [15]."​
"[..]the concept of the superior bioavailability of supplemental ubiquinol compared to ubiquinone would appear to be mistaken. This concept, widely disseminated on the Internet, seems in part to have originated from an inappropriate comparison between bioavailability data from studies by Shults et al. in 1998 [24] and Hosoe et al. in 2007 [25]. The older study involved the use of a dry powdered crystalline form of ubiquinone, which is poorly absorbed but was the only formulation available at the time. Thus, the comparison was not a head-to-head comparison in that it did not test the ubiquinol absorption results against a formulation of ubiquinone dissolved in appropriate carrier oils. The two studies being compared were conducted more than 10 years apart. They used different study subjects: healthy volunteers vs. patients with Parkinson’s disease, different investigators, different analytical labs, and different protocols."​
"CoQ10 is a lipid soluble substance; therefore, the highest quality CoQ10 preparations have the CoQ10 dissolved in a well-suited carrier lipid (e.g., soy oil or palm oil). Typically, they are encapsulated in bovine gelatine capsules. The capsule material does not seem to be an important factor for absorption. The gelatine capsules readily dissolve within minutes inside the stomach and release the oil-dissolved CoQ10. The stomach transit time varies among individuals and varies according to the type of food eaten. The complete transit of the CoQ10 from the stomach through the small intestines, and the lymph to the blood typically takes between 5 and 8 h [26]. The transited CoQ10 enters the duodenum as part of the chyme. Although the CoQ10 is in transit from the stomach into the duodenum, any CoQ10 in the reduced form, the ubiquinol form, will be oxidised to the ubiquinone form; in studies of CoQ10 absorption under conditions that simulate gastric conditions, this process usually takes about 90 min (Figure 20 in [26])."​
"The lipid solubility of CoQ10 is a consequence of its inherent chemical structure—technically, it is due to the presence of an isoprenoid chain within the CoQ10 molecule. CoQ10 is not at all water soluble, and, contrary to some manufacturers’ claims, cannot be made water-soluble [26]. Thus, any alteration to the structure of the CoQ10 molecule in an attempt to increase water solubility means that the molecule is no longer CoQ10. Similarly, the presence of two additional hydrogen atoms within the chemical structure of ubiquinol (compared to ubiquinone) has a negligible effect on potential water solubility [26]."​
"In an attempt to understand CoQ10 absorption, Singh et al. [30] investigated the efficacy of various dosing strategies on serum CoQ10 levels in a group of 60 healthy adults. In the Singh study, a 200 mg CoQ10 dose yielded a larger increase in serum levels than a 100 mg dose. However, divided dosages of 2 × 100mg of CoQ10 yielded a larger increase in serum levels than a single 200 mg dose. The Singh data show that the human digestive system has a finite capacity to absorb CoQ10 in a single dose."​


the dismissal of coq10 and ubiquinol of this forum is very strange.

K2 is no replacement for it which is commonly believed
 

Amazoniac

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- Vanillic acid - Wikipedia

- Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6

Abstract said:
Coenzyme Q (CoQ), a redox-active lipid, is comprised of a quinone group and a polyisoprenoid tail. It is an electron carrier in the mitochondrial respiratory chain, a cofactor of other mitochondrial dehydrogenases, and an essential antioxidant. CoQ requires a large set of enzymes for its biosynthesis; mutations in genes encoding these proteins cause primary CoQ deficiency, a clinically and genetically heterogeneous group of diseases. Patients with CoQ deficiency often respond to oral CoQ10 supplementation. Treatment is however problematic because of the low bioavailability of CoQ10 and the poor tissue delivery. In recent years, bypass therapy using analogues of the precursor of the aromatic ring of CoQ has been proposed as a promising alternative. We have previously shown using a yeast model that vanillic acid (VA) can bypass mutations of COQ6, a monooxygenase required for the hydroxylation of the C5 carbon of the ring. In this work, we have generated a human cell line lacking functional COQ6 using CRISPR/Cas9 technology. We show that these cells cannot synthesize CoQ and display severe ATP deficiency. Treatment with VA can recover CoQ biosynthesis and ATP production. Moreover, these cells display increased ROS production, which is only partially corrected by exogenous CoQ, while VA restores ROS to normal levels. Furthermore, we show that these cells accumulate 3-decaprenyl-1,4-benzoquinone, suggesting that in mammals, the decarboxylation and C1 hydroxylation reactions occur before or independently of the C5 hydroxylation. Finally, we show that COQ6 isoform c (transcript NM_182480) does not encode an active enzyme. VA can be produced in the liver by the oxidation of vanillin, a nontoxic compound commonly used as a food additive, and crosses the blood-brain barrier. These characteristics make it a promising compound for the treatment of patients with CoQ deficiency due to COQ6 mutations.
 

Amazoniac

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- The Complexity of Making Ubiquinone

"The conserved biochemical pathway of UQ synthesis starts with the synthesis of the polyisoprenoid tail and its attachment to the aromatic ring precursor of UQ. The ring structure is then modified in successive steps to yield UQ (Figure 2). In eukaryotes, the isoprene carbon units for making the UQ side-chain are derived from the mevalonate pathway. The most common precursor for the benzoquinone ring is 4-hydroxybenzoic acid (4-HB), derived from tyrosine [33]. Recent studies have started to reveal steps necessary for the synthesis of 4-HB from tyrosine, which include the activities of the transaminases Aro8p and Aro9p and the aldehyde dehydrogenase Hfd1 [34,35] (see more details in Box 2). The budding yeast S. cerevisiae can also use para-aminobenzoic acid (pABA), a well-known precursor of folate [36,37]. However, human and E. coli cells do not utilize pABA for UQ synthesis [38]. Interestingly, resveratrol and coumarate can be used as head group precursor of UQ across species [38]. On a related note, studies have demonstrated that cells can also use unnatural precursors of UQ biosynthesis, namely 2,4-dihydroxybenzoate, 3,4 dihydroxybenzoate, and vanillic acid [11,39–42]. When provided, they enter the UQ biosynthetic pathway and compete with the natural precursor 4-HB and natural intermediates for the pathway enzymes [40,41]."

"Both the tail and ring precursors are made in the cytosol but all the next steps, starting with the attachment of the tail to the ring precursor, occur in association with the matrix side of the IMM [25]."

"We can imagine that for a pathway composed of multiple components and several consecutive enzymatic reactions spatial restriction of steady state components would be advantageous as it would allow for local enrichment of key pathway components as well as facilitate efficient substrate accessibility. It is reasonable to assume that the CoQ synthome lives in the CoQ domains. One important potential significance of these findings is that they provide a first hint as to why mitochondrial disorders are often associated with UQ deficiency (which might in turn exacerbate the disease pathophysiology). SUD has been described in patients with various mitochondrial respiratory chain defects, especially those involving mtDNAmutations or depletion [30,31,83,84]. If the final steps of UQ biosynthesis need to be carried out in the CoQ domain, then disturbance of the IMM structure, which is commonly observed in dysfunctional or aged mitochondria [85–88], could impair CoQ domain formation and thus UQ production."

"The possibility that CoQ domain formation is vulnerable to the pathophysiological changes in IMM organization provides a mechanism for why mitochondrial dysfunction is often associated with secondary UQ deficiency (Figure 3). For example, it is reported that 75% of patients with mtDNA depletion syndrome presented with a decreased level of muscle UQ [31]. In mice, a systematic comparative analysis of five heart conditional knockout models targeting key genes that regulate mtDNA gene expression (Twnk, Tfam, Polrmt, Lrpprc, or Mterf4) revealed, remarkably, that one of the very few features shared by these mice is lower levels of UQ in the heart (a 25% to 50% decrease) [65]. Aberrant heart mitochondrial morphology was described for all five cardiac-specific models [87,88,96–98]."

"It is very unlikely that targeting a single component of the biosynthetic machinery could be sufficient to boost UQ production. However, understanding the structure of and need for CoQ domains could lead to new ideas about possible treatments. Yet, for patients with severe mitochondrial defects, including ultrastructural defects, effective supplementation of exogenous UQ might be the only possible treatment option."
 

Amazoniac

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- Stability of Reduced and Oxidized Coenzyme Q10 in Finished Products

Abstract said:
The efficiency of coenzyme Q10 (CoQ10) supplements is closely associated with its content and stability in finished products. This study aimed to provide evidence-based information on the quality and stability of CoQ10 in dietary supplements and medicines. Therefore, ubiquinol, ubiquinone, and total CoQ10 contents were determined by a validated HPLC-UV method in 11 commercial products with defined or undefined CoQ10 form. Both forms were detected in almost all tested products, resulting in a total of CoQ10 content between 82% and 166% of the declared. Ubiquinol, ubiquinone, and total CoQ10 stability in these products were evaluated within three months of accelerated stability testing. Ubiquinol, which is recognized as the less stable form, was properly stabilized. Contrarily, ubiquinone degradation and/or reduction were observed during storage in almost all tested products. These reactions were also detected at ambient temperature within the products’ shelf-lives and confirmed in ubiquinone standard solutions. Ubiquinol, generated by ubiquinone reduction with vitamin C during soft-shell capsules’ storage, may lead to higher bioavailability and health outcomes. However, such conversion and inappropriate content in products, which specify ubiquinone, are unacceptable in terms of regulation. Therefore, proper CoQ10 stabilization through final formulations regardless of the used CoQ10 form is needed.
 

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Jon2547

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So the takeaway is the Q10 is okay to use?
 

shine

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So the takeaway is the Q10 is okay to use?

"In humans and most mammals, including dogs, the predominant form of coenzyme Q is coenzyme Q10 , whereas the primary form in rodents is coenzyme
Q9 (CoQ9 )."

I think that's the issue with studying Q10's effects in rodents.
 

Amazoniac

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- Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

"To replenish CoQ levels in CoQ deficient cells and organisms, the use of bypass 4-HB analogs may be advantageous over CoQ10 supplementation for the following reasons. (i) 4-HB analogs will allow to preserve the endogenous ratio between the major and minor isoforms of CoQ. Indeed, many species have a prominent CoQ isoform (CoQ9 in rodents, CoQ10 in humans) but also synthesize minor isoforms (CoQ10 in rodents, CoQ9 in humans). The ratio of both isoforms varies significantly depending on the organs (Turunen et al., 2004), yet, it remains unknown whether these varying ratios have any physiological consequences. (ii) Thanks to their hydrophilic nature, 4-HB analogs may have a superior bioavailability than exogenously supplied CoQ10, which accumulates efficiently in the liver but not in other organs (Miles, 2007). Indeed, CoQ10 supplementation of CoQ deficient mouse models did not increase CoQ10 content in kidney (Saiki et al., 2008) or heart or muscle (Wang et al., 2015). However, a new formulation of CoQ10 demonstrated improved bioavailability as it increased CoQ10 levels in all tested organs of Coq9R239X mice, although to a limited extent formost of them (Garcia-Corzo et al., 2014). (iii) 4-HB analogs may achieve higher CoQ levels in organs than CoQ10 supplementation. 2,4-diHB doubled the kidney CoQ9 content of Coq9R239X mice (Luna-Sanchez et al., 2015) and tripled that of Mclk1-deficient mice (Wang et al., 2015), although WT levels were not reached in either model. For comparison, CoQ10 supplementation yielded a 50% increase of total kidney CoQ (CoQ9+CoQ10) in the former model (Garcia-Corzo et al., 2014) and none in the latter (Wang et al., 2015). (iv) CoQ produced from 4-HB analogs should distribute normally between subcellular compartments whereas exogenously supplied CoQ10 has difficulties to reach mitochondria and their inner membrane (Bentinger et al., 2003). (v) Short chains analogs of CoQ like idebenone and decylubiquinone have been reported to increase superoxide production (Genova et al., 2003), but 4-HB analogs are not expected to have such effect since they don’t have a redox-active benzoquinone moiety."

"[..]investigations with animal models will establish whether this approach is realistic."​
 

miquelangeles

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Mice were fed a control nonpurified diet or that diet containing 0.68 mg/g (low dosage) or 2.6 mg/g (high dosage) CoQ10

[...] estimate mean daily CoQ10 intakes of 106 or 352 mg/kg body weight for mice receiving the low- or high-CoQ10 diets

Not really a low dosage. That's the equivalent daily dose of 600mg for an adult human. A standard Q10 dose ranges from 90 mg to 200 mg per day. The average intake from food is estimated to be 3-5 mg per day, mainly from meat and poultry.
 

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