In 2013, Professor Urban Alehagen and a team of researchers reported on the beneficial effects of daily supplementation of elderly Swedish citizens with a combination of 200 mg of Coenzyme Q10Coenzyme Q10 molecules are fat-soluble molecules that are both bsynthesized in the body and ingested in the diet and in supplements. Coenzyme Q10 is synthesized in the body in the same biological pathway as cholesterol. Bio-synthesis of Coenzyme Q10 begins to decline once humans reach their adult years. The reduced production of Coenzyme Q10 cannot be compensated in any practical... Read more about this term and 200 mcg of seleniumSelenium (symbol Se, atomic number 34) is a trace element that is an essential nutrient and an essential component of some of the most important antioxidants in the body, in particular the selenoproteins glutathione peroxidase, thioredoxin reductase, and selenoprotein P. Selenium is involved in the optimal functioning of the immune system. Professor Alehagen has pointed out that there exists a... Read more about this term, in divided doses with meals, over a four-year period.
Compared to the study participants in the placebo group, the KiSel-10 studyThe KiSel-10 study was a four-year randomized, double-blind, placebo-controlled study of 443 Swedish citizens aged 70 to 88 who received either a combined daily supplementation of high-selenium yeast and Coenzyme Q10 or matching placebos. The elderly Swedish citizens who received the active treatment of selenium and Coenzyme Q10 had significantly reduced risk of death from heart disease, significantly better heart... Read more about this term participants who received the active treatment had significantThe outcome of a clinical trial is thought to have statistical significance, or to be statistically significant, if the outcome is likely not caused by chance at a given statistical significance level, typically at the 0.05 level. Statistically significant outcomes may or may not be clinically significant. ... Read more about this term heart health benefits [Alehagen 2013]:
- reduced risk of death from heart disease
- better heart function as shown on echocardiograms
- lower blood levels of the NT-proBNP protein, a bio-marker for the risk of heart failureThe Mayo Clinic defines heart failure, also known as congestive heart failure and/or chronic heart failure, as the failure of the heart muscle to pump blood to the body adequately. In other words, heart failure is not a heart attack, and it is not death from heart disease, which its name might seem to imply. Heart failure is a condition... Read more about this term
In 2015, Professor Alehagen and I analyzed what we knew, as clinicians, about selenium and Coenzyme Q10 and heart disease [Alehagen & Aaseth 2015]. We asked ourselves why that combination had protected against heart disease in elderly people.
Coenzyme Q10 and Selenium and Heart Disease
To start, we knew from the research literature that ischemic heart diseaseIschemic heart disease is heart disease caused by reduced blood flow to the heart. Ischemic heart disease is, in most cases, coronary artery disease. Blockage of the coronary arteries reduces the flow of blood and oxygen to the heart.... Read more about this term and heart failure are two conditions where increased oxidative stress plays a role. More about oxidative stress in a moment.
The results of the KiSel-10 study indicated that there exists an interrelationship between selenium and Coenzyme Q10, which makes it beneficial to administer them to populations with deficiencies of both.
Reactive Oxygen Species and Antioxidants
First, it is important to give some background information about oxidative stress and antioxidants.
Reactive oxygen speciesThe free radicals of most concern in the bio-medical field are the free radicals derived from oxygen, they are called reactive oxygen species. Specifically, there are the superoxide anions, the peroxides including hydrogen peroxide, and the hydroxyl radicals. Free radicals are unstable and highly reactive molecules that are produced in the body during normal oxygen metabolism. Free radicals play both... Read more about this term – popularly referred to as “free radicalsFree radicals are unstable and highly reactive molecules that are produced in the body during normal oxygen metabolism. Free radicals derived from oxygen are known as reactive oxygen species. Free radicals play both helpful and harmful roles in the body. Free radicals steal electrons from other substances in order to become stable. In so doing, the free radicals oxidize those... Read more about this term” – are natural products of cell metabolism. The process of aerobic metabolism in the mitochondriaThe mitochondria are the bean-shaped organelles in the cells. They are the key organelles with responsibility for the production of ATP energy molecules.... Read more about this term seems to be a primary source of reactive oxygen species production [Alehagen & Aaseth 2015].
The cell signaling role of moderate numbers of reactive oxygen molecules contributes to good health and involves participation in the biosynthesis of complex organic molecules, detoxification of invasive chemical substances, and protection against pathogens such as bacteria and viruses [Nordman 2003].
Oxidative Stress = Imbalance of Free Radicals and Antioxidants
The term “oxidative stress” is used to describe a state in the cells in which reactive oxygen molecules are present in far greater numbers than are needed for acting as cell signaling molecules. When the reactive oxygen molecules exist in excessively high levels, they are strongly associated with the development of degenerative diseases and perhaps even with the aging process [Nordman 2003].
Typically, the thing that contributes to the volatility of the reactive oxygen molecules is that they are seeking to attract and accept one or two electrons from other molecules. Whenever they steal electrons from molecules that then become unstable and seek to attract other electrons, they can start a harmful chain reaction and cause oxidative damage to the cells and their DNA, proteins, and lipids.
Consequently, our cells need the means to neutralize these reactive oxygen species that are produced in excess of the need for the beneficial cell signaling functions. The molecules that can safely scavenge free radicals are called antioxidants.
Antioxidants are molecules in their reduced state, the state in which they have electrons that they can donate without becoming unstable themselves.
Coenzyme Q10 and Selenoproteins with Antioxidant Effects
The reduced state of Coenzyme Q10 molecules, called ubiquinol, and some of the selenium containing selenoproteins such as the glutathione peroxidases, the thioredoxin reductases, and selenoprotein P protect against oxidative stress.
- Ubiquinol protects against lipid peroxidationOxidation is the chemical reaction of a substance with oxygen. Peroxidation is the extreme form of oxidation that results from free radicals’ stealing electrons from lipids, either in the cell membranes or in the lipoproteins. The final product of lipid peroxidation is highly reactive malondialdehyde, a bio-marker for oxidative stress and damage.... Read more about this term and also reduces the inflammatory response.
- The glutathione peroxidases, the most studied seleno-enzymes, donate electrons to hydrogen peroxide molecules and catalyze H2O2’s reduction to water and oxygen; they also catalyze the reduction of other peroxide radicals to alcohols and oxygen.
- The seleno-enzymes, the thioredoxin reductases, are the most efficient enzymes for reducing molecules in the the ubiquinoneUbiquinone, the oxidized form of Coenzyme Q10, expressed as Q10 or CoQ10, is absolutely essential for the mitochondrial ATP energy production process. Ubiquinone is the form of Coenzyme Q10 that the body synthesizes, and ubiquinone is the form of Coenzyme Q10 that has been extensively tested for safety, absorption, and efficacy in clinical trials.... Read more about this term state of Coenzyme Q10, thus regenerating the lipid-soluble antioxidantAntioxidants are substances that protect the cells and lipoproteins against the harmful effects of free radicals. They are substances that prevent the oxidation of other molecules and compounds. There are two broad categories of antioxidants: enzymatic and non-enzymatic. Non-enzymatic antioxidants are substances like Coenzyme Q10, vitamin C, vitamin E, glutathione, and various carotenoids. Prominent enzymatic antioxidants include catalase, glutathione peroxidase,... Read more about this term ubiquinol.
Regenerating Ubiquinol with the Help of Selenium Containing Seleno-enzymes
Once the ubiquinol molecules donate electrons to quench reactive oxygen molecules, they themselves are oxidized. They have no electrons to donate and are stable. They become electron acceptors.
To replenish the supply of the antioxidant ubiquinol in the cells, it is necessary for some of these molecules in their oxidized state – called ubiquinone – to be regenerated in their reduced state – the electron donor state.
This is important because the mitochondria – those bean-shaped energy factories in the cells – are very vulnerable to oxidative damage. In heart disease, reactive oxygen species in the mitochondria and in the cytosol of the cells become distorted, leading to an oxidative imbalance, to mitochondrial dysfunctionMitochondrial dysfunction is the loss of efficiency in the process of ATP energy production. As such, mitochondrial dysfunction is a factor in the ageing process and in virtually all chronic diseases including cancer, cardiovascular diseases, chronic fatigue syndrome and fibromyalgia, diabetes and metabolic syndrome, and neurodegenerative diseases. Coenzyme Q10 is an essential component in the mitochondrial production of ATP energy.... Read more about this term, and eventually to cell death [Alehagen & Aaseth 2015].
Reduced Reserve of Ubiquinol in Elderly People
Elderly people may have a reduced reserve of ubiquinol for two reasons:
1. The cells’ endogenous synthesis of Coenzyme Q10 declines with increasing age such that an 80-year-old person may synthesize only one half the amount of the Coenzyme Q10 that a 20-year-old person does [Kalen 1989]. Elderly people synthesize less ubiquinone; consequently, there is less ubiquinone to be used for energy production and to be converted to the antioxidant state, ubiquinol.
2. Elderly people living in a region with low selenium content in the soil and the food may have less selenium and fewer selenoproteins available to regenerate ubiquinol from the available ubiquinone.
The level of oxidative stress is elevated in heart disease patients. In addition, high levels of systemic inflammation are associated with high levels of oxidative stress [Alehagen & Aaseth 2015].
Thioredoxin Reductase Regenerating Ubiquinol from Ubiquinone
Ubiquinone – the oxidized state of Coenzyme Q10 – is essential to the production of ATPATP (adenosine triphosphate) molecules are the high-energy molecules with easily broken phosphate bonds that release energy to the energy-requiring processes in the cells. Coenzyme Q10 is essential to the process of ATP production.... Read more about this term energy in the mitochondria. In the process of bio-energeticsBio-energetics is both the process and the study of the flow and transformation of energy in living beings. Coenzyme Q10 has both a bio-energetics function and an antioxidant function in the body.... Read more about this term, the ubiquinone is reduced to ubiquinol.
When the ubiquinol molecules donate electrons to protect against oxidative damage, they revert back to their oxidized state – ubiquinone. The question then becomes, how to regenerate the antioxidant state of Coenzyme Q10.
One of the important interrelationships between selenium and Coenzyme Q10 (ubiquinone) is the catalytic role of selenoproteins such as the thioredoxin reductases in the metabolic conversion of ubiquinone to ubiquinol.
Xia et al. [2003] showed that thioredoxin reductase is the most efficient enzyme that reduces ubiquinone to ubiquinol.
Coenzyme Q10 Needed for the Synthesis of the Antioxidant Seleno-Enzymes
Just as we need sufficient quantities of selenoproteins to regenerate ubiquinol, so too do we need adequate quantities of Coenzyme Q10 for the optimal synthesis of the selenocysteine-containing enzymes [Moosmann & Behl 2004].
In our 2015 article, Prof. Alehagen and I explained that there exists a special interrelationship between Coenzyme Q10 and selenium containing selenoproteins as follows:
- A deficiency of selenium could restrict the cells’ ability to obtain optimal concentrations of Coenzyme Q10 in its antioxidant form.
- The cells are dependent on sufficient levels of Coenzyme Q10 for the optimal functioning of selenium
- Coenzyme Q10 plays an important part in the synthesis of selenocysteine, which is required for the synthesis of the antioxidant selenoproteins glutathione peroxidase, thioredoxin reductase, and selenoprotein P.
Importance of the Mevalonate Biological Pathway for Coenzyme Q10 and for Selenoproteins
Moosmann and Behl [2004] have shown that the synthesis of the selenocysteine containing selenoproteins proteins requires a functional mevalonate pathwayThe mevalonate pathway is the biological pathway that produces the building-block molecules that the body needs for its synthesis of cholesterol, Coenzyme Q10, Vitamin K, and all steroid hormones. As such, the mevalonate pathway is the target of the statin medications that inhibit the body’s production of cholesterol and Coenzyme Q10. Mevalonic acid is the precursor to the mevalonate pathway.... Read more about this term.
Note: The mevalonate pathway is the biological pathway in which cholesterolCholesterol is one of the major fat-soluble compounds that is found in animal plasma membranes. It is necessary for life and is found throughout the body. It is carried from the liver to the tissues where it is needed by lipoproteins of which it is a component. Much of the cholesterol is transported in Low density lipoproteins (LDL). High levels... Read more about this term, Coenzyme Q10, and dolichol are produced.
A side road of the mevalonate pathway is the enzymatic isopentenylation of selenocysteine-tRNA, the tRNA to decode the selenocysteine amino acid. The isopentenylation of the selenocysteine-tRNA requires isopentenyl pyrophosphate, which it gets from the mevalonate pathway.
If the mevalonate pathway is not functioning optimally, there will not be enough Coenzyme Q10 synthesized and not enough selenocysteine produced for incorporation into selenoproteins.
Selenium Needed for the Synthesis of Coenzyme Q10
We cannot deprive humans of selenium to see what effect selenium deficiency has on Coenzyme Q10 bio-synthesis.
Vadhanavikit and Ganther [1994] have done animal studies that show that selenium deficiency – animals fed a diet lacking selenium for 18 months – is associated with levels of Coenzyme Q9 and Coenzyme Q10 in the liver that were 40% and 67% of the levels in selenium-adequate animals, respectively. These results are similar to the findings using a shorter feeding period (4.5 months).
Vadhanavikit and Ganther speculated that a decreased ability of the cells to synthesize Coenzyme Q10 because of selenium deficiency is associated with a lack of glutathione peroxidase protection against oxidative stress in the cells.
Conclusion
- The seleno-enzyme thioredoxin reductase has been shown to be the most efficient enzyme for reducing ubiquinone and regenerating the lipid-soluble antioxidant ubiquinol.
- The selenoproteins – the glutathione peroxidases and the thioredoxin reductases – are themselves important antioxidants.
- Elderly people are likely to have reduced Coenzyme Q10 biosynthesis and reduced selenoprotein formation.
- Increased levels of oxidative stress – inadequate availability of antioxidants – are associated with increased risk of ischemic heart disease and heart failure.
References
Alehagen U, Johansson P, Björnstedt M, Rosén A, Dahlström U. Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blindA double-blind study is a study in which neither the investigators nor the study participants know which participants are receiving the active treatment and which participants are receiving the control treatment until the study has been completed and the seal on the code has been broken.... Read more about this term placebo-controlled trial among elderly Swedish citizens. Int J Cardiol. 2013 Sep 1;167(5):1860-6.
Alehagen U, Aaseth J. Selenium and coenzyme Q10 interrelationship in cardiovascular diseases–A clinician’s point of view. J Trace Elem Med Biol. 2015;31:157-62.
Kalén A, Appelkvist EL, Dallner G. Age-related changes in the lipid compositions of rat and human tissues. Lipids. 1989 Jul;24(7):579-84.
Moosmann B, Behl C. Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway. Trends Cardiovasc Med. 2004;14:273–81.
Nordman T, Xia L, Björkhem-Bergman L, Björnstedt M, Olsson J. Regeneration of the antioxidant ubiquinol by lipoamide dehydrogenase, thioredoxin reductase and glutathione reductase. BioFactors. 2003;18(1-4):45-50.
Vadhanavikit S, Ganther HE. Selenium deficiency and decreased coenzyme Q levels. Mol Aspects Med. 1994;15 Suppl:s103-7.
Xia L, Nordman T, Olsson JM, Damdimopoulos A, Björkhem-Bergman L, Nalvarte I, Eriksson LC, Arnér ES, Spyrou G, Björnstedt M. The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. J Biol Chem. 2003 Jan 24;278(4):2141-6.
The information presented in this review article is not intended as medical advice and should not be construed as such.
30 March 2021