Ubiquinol - the bioactive form of CoQ10 in mitochondrial support and anti-aging

Ubiquinol as a support for declining mitochondrial function

The Decline in the Mitochondrial function is one of the known reasons for our aging. Mitochondria is responsible for multiple interlinked functions within our cells, and hence - bodies. When mitochondrial performance declines or when these organelles start malfunctioning, all of their responsibility areas are affected.

Particularly this decline leads to lower energy levels, slower metabolism, decline in the reproductive function in women (through decline in the mitochondrial function of oocytes), decreased innate immune protection, slower rates of senescent cells removal, compromised mechanisms for the calcium levels regulation etc.
So far, several approaches/remedies have been discovered and studied that may help with the improvement in the mitochondria functioning or to compensate for its decline.

Supplementation with Ubiquinol, a reduced or bio-active form of the co-enzyme CoQ10 is one of them.

CONTENT

References and Literature

CoQ10: Ubiquinone and Ubiquinol

Coenzyme Q10 is a naturally occurring substance that is synthesized in our bodies and stored in mitochondria and in the membranes of other cells. Our bodies would have been unable to function without it.

CoQ10 can exist in two forms: Ubiquinone and Ubiquinol (there is also ubisemiquinone form; it is a highly unstable, pro-oxidant form and is irrelevant for this discussion).
Ubiquinone is the form typically sold as a CoQ10 supplement; it is the fully oxidized form.
Ubiquinol is the fully reduced or bioactive form os CoQ10.

CoQ10 is found at particularly high levels in tissues and organs with the highest energy requirements because it plays an important role in energy production: heart, pancreas, liver, and kidneys. The levels of CoQ10 in humans are the easiest to measure in blood plasma;
CoQ10 levels and the ratio of ubiquinol to ubiquinone are very high in infants, fall during the childhood, and then throughout our lives;
CoQ10 is also present in food sources.

Ubiquinol converts to Ubiquinone and back

Ubiquinol and Ubiquinone are two forms of CoQ10

CoQ10 and Ubiquinol Functions

CoQ10 has three known functions:

One of the most powerful lipid soluble anti-oxidants,
A key role in the electron transport chain for the cellular energy (ATP) production. Presence of both ubiquinone and ubiquinol in our bodies is indispensable to the energy production. They participate in aerobic cellular respiration, generating energy in the form of ATP, and that is 95% of the energy production in our bodies (Kapoor, 2013),
There is also some data that CoQ10 is involved in regulating a large set of genes (Guescini, 2017). The mechanisms behind this role are not yet fully understood.

As you can see on the picture above, Ubiquinol and Ubiquinone (regular CoQ10) are very similar molecules. But a small difference between them is behind their unique roles in the energy production. It also impacts their bioavailability and the anti-oxidant role.

To exert any of its properties, CoQ10 must be in its bioactive form - Ubiquinol. That is, if someone is taking a regular CoQ10 (ubiquinone) supplement, their body first needs to convert it to Ubiquinol, and only then the bioactive form of CoQ10 acts as an anti-oxidant and, in simple words, actively participates in the electron transport chain for the energy production.

CoQ10 - when we are young and in aging

The body of a healthy 20-year-old person -

synthesizes all the ubiquinone it needs, AND
easily converts over 95% of that ubiquinone into the bioactive Ubiquinol.

As we age, both steps are affected:

Endogenous biosynthesis of CoQ10 is a very complex process, and that CoQ10 synthesis within the body seems to decline after about the age of 20. We assume that due to the fact that the functional CoQ10 levels in tissues have been found to decline with age (Ernster, 1995; Kalen, 1989; Miles, 2004, Niklowitz, 2016) and the CoQ10 levels in the body drop by some 65% by the age of 80. An important thing to keep in mind is that to evaluate the functional levels of CoQ10 as tested in blood plasma, the CoQ10 number has to be adjusted for the cholesterol numbers. Otherwise, we could conclude that CoQ10 levels in plasma rise (not fall) from young adulthood until the age of 41 - 60.
Our bodies' ability to convert the oxidized ubiquinone form into the bioactive Ubiquinol form decreases from about the age of 30 and definitely after the age of 40. We know this because the proportion of the bioactive Ubiquinol in the total CoQ10 drops as we age (Miles, 2004);
Also some data suggests that our ability to absorb CoQ10 from the food sources may diminish as we age.

To briefly summarize the age related changes: we have less functional CoQ10, we have even less of its bioactive form - Ubiquinol, and we absorb less of it from food.

Measurable results of supplementing with Ubiquinol and CoQ10

Some data from studies -

Ubiquinol supplementation enhances peak power production in trained athletes: a double-blind, placebo controlled study (300 mg/d, 6 weeks) (Alf, 2013);
A mice study showed that supplementing with CoQ10 may restore or improve fertility during reproductive aging (Ben-Meir, 2015). For 15 weeks, the mice were given CoQ10 22 mg/kg of body weight + Alpha Lipoic Acid + Resveratrol. "CoQ10 supplementation not only preserved the ovarian follicle pool [in aged in mice], but also facilitated ovulation of gamets able to support normal development". This publication -> (Anroop B, 2016), provides animal to human dose conversion ratios; and human to mice is 1-to-12 (mice dose [in "per kg of body weight"] divided by 12 should be considered for humans). This would be roughly 110 mg/day for a 60 kg person;
The study named "Ubiquinol-10 Supplementation Activates Mitochondria Functions to Decelerate Senescence in Senescence-Accelerated Mice" showed that Ubiquinol may enhance mitochondrial activity by increasing levels of SIRT1, PGC-1a, and SIRT3 that slow the rate of age-related hearing loss and protect against progression of aging and symptoms of age-related disease (Tian, 2014);
Translation from a Japanese peer-reviewed journal: 6 months supplementation with 100 mg of Ubiquinol/day of 11 elderly women showed "significant increases in the 'vitality' and 'mental health' scores;
Only one patient (an advanced case of familial multiple system atrophy) in this study, but interesting results. Three years of supplementing with 1,200 mg/d. No adverse side effects. Study conclusions: Ubiquinol supplementation may improve mitochondrial oxidative metabolism in the brain (Mitsui, 2017).

Form, Dose, Bioavailability, Interactions

Form: ubiquinol over CoQ10

Several studies showed that ubiquinol has higher bioavailability, at least in the first four hours after the intake, than ubiquinone (conventional CoQ10) has. However, that is not the only difference that makes ubiquinol superior to regular CoQ10;
What justifies taking Ubiquinol instead of regular CoQ10 for people over the age of 30-35 is that no matter how much ubiquinone is taken, our bodies past certain age can convert only so much of it to Ubiquinol. As covered earlier, Ubiquinol is the bioactive form of CoQ10. Studies show that Ubiquinol is not only more effective than ubiquinone in raising blood levels of CoQ10, but it also raises the ratio of Ubiquinol to the total CoQ10 in blood plasma, which regular ubiquinone does not (Langsjoen, 2014).
To be the devil's advocate, one study (Zhang, 2018) showed that supplementing 5 older men with 200 mg/d, all in one dose, of Ubiquinol for 10 weeks raised both Ubiquinone and Ubiquinol levels in plasma, which is already good, but did not affect the ubiquinol to the total CoQ10 ratio.
Ubiquinol is unstable and difficult to manufacturer, and until 2007 the only form available as a supplement was the regular CoQ10 (ubiquinone). Currently, the sole manufacturer of Ubiquinol is Kaneka; it's a patented ingredient.

Interactions

CoQ10 is thought to work most effectively when vitamins K2 and D are present at sufficient levels. Therefore, if you are not consuming a lot of leafy greens (K2) and do not spend enough time in the sun, consider taking vitamin K2 and vitamin D3 supplements as well;
CoQ10 may interact with the blood thinner (anti-coagulants) warfarin and diabetes drug insulin. It may not be compatible with some cancer treatment drugs;
No serious side effects have been reported from taking either CoQ10 or Ubiquinol.

Dose - data from studies

In all studies, CoQ10 levels in plasma continue rising during the first two weeks of supplementation with any dose of ubiquinol (and regular CoQ10 too), then they plateau for the following two weeks. Based on this observation, it is typically recommended to start with a higher dose and switch to the lower maintenance dose after two weeks (Hosoe, 2007);
An increase in the CoQ10 plasma levels is dose dependent. In this study (Mitsui, 2017), CoQ10 plasma levels of a patient with 1,200 mg/d supplementation were higher than with 840 mg/d dose, and with the latter higher than with 600 mg/d dose. The limitation is that there was only one patient with severely compromised health. However, there are multiple studies confirming the dose dependent Co10 levels rise with lower (100 to 300 mg/d) supplementation;
Taking CoQ10 in divided dose (twice daily) leads to a larger increase in serum levels that a single 200 mg dose (Singh, 2005);
In one study of aging mice, lifelong supplementation with reduced CoQ10 decreased senescence experession (better health, more energy) in middle aged mice by 45% (note, it did not prolong lifespan, had no impact on cancer and on the amyloid build up). (Yan J, 2006). The human dose equivalent here would be about 200 - 300 mg/day;
The study mentioned above: A mice study showed that supplementing with CoQ10 may restore or improve fertility during reproductive aging (Ben-Meir, 2015). The human dose equivalent is some 100 - 150 mg/d.

Doses recommended based on what we know

Based on numerous studies published to date about CoQ10, the desirable levels of CoQ10 in blood, unadjusted for cholesterol, should most likely be be 3 mpg/ml of blood or higher. The dose to achieve those levels -

Over the age of 30, the dose should be 100 to 150 mg of Ubiquinol a day, preferably (but not necessarily) in two divided doses, e.g. 100 mg in the morning, 50 mg in the afternoon or evening;
Further, we don't have data so granular as to speak about the precise doses depending on the age, however, given that both CoQ10 levels in total and Ubiquinol to total CoQ10 ratio continue falling as we age, it is reasonable to conclude that it makes sense to increase the dose with each passing decade. For example, for people over 40, 200 mg a day in two doses (100 + 100);
In one study of aging mice, lifelong supplementation with reduced CoQ10 decreased senescence experession (better health, more energy) in middle aged mice by 45% (note, it did not prolong lifespan, had no impact on cancer and on the amyloid build up). (Yan J, 2006). To replicate the results of this anti-aging study, human dose of Ubiquinol should likely be at around 200 - 300 of mg/day, for a healthy person who does not smoke.
Adjust the dose for your weight and calorie intake - a bigger person who eats a lot should consider at least 300 mg a day. A smaller person with a reduced caloric intake lifestyle may derive those remarkable anti-senescence benefits with 200 mg/day.

Based on all of the above, summary on the form and dose -

The ingredient name is Ubiquinol by Kaneka,
around the age of 30, healthy person, 100 - 150 mg/d, in two divided doses;
around the age of 40, healthy person, 200 mg/d, in two divided doses;
start with a dose 50 - 100 mg higher for the first two weeks, decrease to the above after two weeks;
adjust the dose (increase) if smoking, eating a lot, overweight, advanced age, on statin drugs;
consider taking together with vitamins K2 and D3.

Ubiquinol in Treatment of Disease

This web-site focuses on providing information on preventing aging, rather than treating a disease that already occurred.
If you are seeking information on the use and effectiveness of CoQ10 or Ubiquinol in treatment of various disease, Table 1 of this review study, Coenzyme Q10 Therapy, has a list of studies on using CoQ10 for treatment, with clickable links (fibromyalgia, cardiac failure, cancer, diabetes, hypertension etc). There is also a lot information throughout the text of that review. A couple of relevant points from that review paper:

Many disorders and disease are associated with low CoQ10 levels (in many cases we don't know if there is a cause-and-effect and if so, in which direction, or if it is just an association),
CoQ10 is well tolerated in therapeutic doses and no adverse side effects are reported,
If you are trying to find information on treating a particular disease, read the mentioned studies AND take the information to a qualified health care professional.

Natural Ways to Obtain or Increase Ubiquinol Levels: Food and SunLight

CQ10 is present everywhere in the organic world: in the plants, animals, and microorganisms. When talking about food sources, the highest levels of ubiquinol are found in oily fish, organ meats, and whole grains.

However, it is unrealistic to obtain sufficient amount of CoQ10 from food. Statistically, in the western diet, an average person obtains from food 3 - 6 mg of CoQ10 per day, split about equally between Ubiquinone and Ubiquinol (Pravst, 2010). That is some 3% of the recommended daily intake of the lower range of 100 mg/d of Ubiquinol.
For someone over the age of 30, to get the minimum recommended daily ubiquinol dose of 100 mg, a person needs to eat:

15 - 30 oz (~ 1 lb/450 g - 2lb/900 g) of pork heart, or
30 oz (~ 2 lb/900 g) of beef heart, or
20 grass fed 6 oz. steaks (120 oz), or
3.5 pounds (1.5 kg) of peanuts, or
34 chicken breasts (keeping in mind that when cooked ubiquinol in chicken converts to ubiquinone), or
50 cups of spinach, or
60 avocados, or
500 mg of Canola oil or 670 mg of Olive oil, or
33 pounds (15 kg) of sardines.

Taking a supplement may be easier.

There is one interesting study (Qu J, 2013) that showed that diets rich in chlorophyl combined with sunlight exposure may help the body's ability to convert the oxidized ubiquinone into the bioactive ubiquinol. Chlorophyl rich foods are chlorella, spirulina, spinach, collard greens, mustard greens, alfa alfa, parsley, broccoli. It is not clear how much of chlorophyl and sunlight per day is required for those purposes; yet I would count the study findings as another argument for adding to the diet chlorella and spirulina, and eating more leafy greens.

CoQ10 and Ubiquinol Summary

There are two forms of CoQ10: ubiquinone and ubiquinol. Ubiquinone is the oxidized form of CoQ10. Ubiquinol is a "reduced" (not oxidized) and the bioactive form of CoQ10;
Most of the supplements sold as CoQ10 are the oxidized (ubiquinone) form;
Ubiquinol is the form that our body uses as anti-oxidant and to produce energy;
No serious side effects of CoQ10 supplementation have been reported;
With the age, and particularly, after 40, 1) our bodies produce less ubiquinone (the "regular" CoQ10), 2) our bodies convert even less of already diminished ubiquinone into ubiquinol (lower ratio of ubiquinol to the total CoQ10), 3) Ubiquinol and total CoQ10 levels in our bodies decline;
Reduced CoQ10 levels in humans are associated with degenerative disease;
CoQ10 levels in the body may also be reduces by some anti-depressants. beta-blockers, and statins (cholesterol lowering drugs);
CoQ10 can be obtained from the food sources: fish, whole grains, and meat. Sunlight exposure may help too. The dietary intake of CoQ10 is insufficient to compensate for the CoQ10 loss during aging;
Recommended doses of Ubiquinol for healthy adults after the age of 30 are 100 to 300 mg/day depending on several factors, preferably divided into two daily doses;
Ubiquinol may be more effective if taken together with vitamins K2 and D3.

References and Literature

Alf D, Schmidt ME, Siebrecht SC. Ubiquinol supplementation enhances peak power production in trained athletes: a double-blind, placebo controlled study. J Int Soc Sports Nutr. 2013;10:24. Published 2013 Apr 29. doi:10.1186/1550-2783-10-24
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661336/

Ben-Meir A, Burstein E, Borrego-Alvarez A, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015;14(5):887–895. doi:10.1111/acel.12368
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568976/

Ernster L., Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim. Biophys. Acta. 1995;1271:195–204. doi: 10.1016/0925-4439(95)00028-3.
https://www.ncbi.nlm.nih.gov/pubmed/7599208

Garrido-Maraver J, Cordero MD, Oropesa-Ávila M, et al. Coenzyme q10 therapy. Mol Syndromol. 2014;5(3-4):187–197. doi:10.1159/000360101
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112525

Guescini M, Tiano L, Genova ML, et al. The Combination of Physical Exercise with Muscle-Directed Antioxidants to Counteract Sarcopenia: A Biomedical Rationale for Pleiotropic Treatment with Creatine and Coenzyme Q10. Oxid Med Cell Longev. 2017;2017:7083049. doi:10.1155/2017/7083049
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632475

Hernández-Camacho JD, Bernier M, López-Lluch G, Navas P. Coenzyme Q10Supplementation in Aging and Disease. Front Physiol. 2018;9:44. Published 2018 Feb 5. doi:10.3389/fphys.2018.00044
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807419/

James, Andrew M.; Cochemé, Helena M.; Smith, Robin A. J.; Murphy, Michael P. (2005). "Interactions of Mitochondria-targeted and Untargeted Ubiquinones with the Mitochondrial Respiratory Chain and Reactive Oxygen Species: Implications for the use of exogenous ubiquinones as therapies and experimental tools". Journal of Biological Chemistry. 280 (22): 21295–312. doi:10.1074/jbc.M501527200. PMID 15788391.

Kalén A, Appelkvist EL, Dallner G. Age-related changes in the lipid compositions of rat and human tissues. Lipids. 1989; 24:579–84. 10.1007/BF02535072
https://www.ncbi.nlm.nih.gov/pubmed/2779364

Langsjoen PH and Langsjoen AM (2014) Comparison study of plasma coenzyme Q10 levels in healthy subjects supplemented with ubiquinol versus ubiquinone. Clin Pharmacol Drug Dev 3, 13–17.
https://www.ncbi.nlm.nih.gov/pubmed/27128225

Miles M.V., Horn P.S., Tang P.H., Morrison J.A., Miles L., DeGrauw T., Pesce A.J. Age-related changes in plasma coenzyme Q10 concentrations and redox state in apparently healthy children and adults. Clin. Chim. Acta. 2004;347:139–144. doi: 10.1016/j.cccn.2004.04.003.
https://www.ncbi.nlm.nih.gov/pubmed/15313151

Mitsui J, Koguchi K, Momose T, et al. Three-Year Follow-Up of High-Dose Ubiquinol Supplementation in a Case of Familial Multiple System Atrophy with Compound Heterozygous COQ2 Mutations. Cerebellum. 2017;16(3):664–672. doi:10.1007/s12311-017-0846-9
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427137/

Niklowitz P, Onur S, Fischer A, et al. Coenzyme Q10 serum concentration and redox status in European adults: influence of age, sex, and lipoprotein concentration. J Clin Biochem Nutr. 2016;58(3):240–245. doi:10.3164/jcbn.15-73
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865593/

Pravst I, Žmitek K, Žmitek J. Coenzyme Q10 contents in foods and fortification strategies. Crit Rev Food Sci Nutr. (2010) 50:269–80. 10.1080/10408390902773037
https://www.ncbi.nlm.nih.gov/pubmed/20301015

Saini R. Coenzyme Q10: The essential nutrient. J Pharm Bioallied Sci. 2011;3(3):466–467. doi:10.4103/0975-7406.84471
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178961/

Tian G, Sawashita J, Kubo H, et al. Ubiquinol-10 supplementation activates mitochondria functions to decelerate senescence in senescence-accelerated mice. Antioxid Redox Signal. 2014;20(16):2606-20.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025630/

Zhang Y 1, Liu J , Chen XQ , Oliver Chen CY . Ubiquinol is superior to ubiquinone to enhance Coenzyme Q10 status in older men. Food Funct. 2018 Nov 14;9(11):5653-5659. doi: 10.1039/c8fo00971f.
https://www.ncbi.nlm.nih.gov/pubmed/30302465

What is the Difference between Coenzyme Q10 and Ubiquinol
https://ubiquinol.org/blog/what-difference-between-coenzyme-q10-and-ubiquinol
Accessed on July 2, 2019