Three-Step Strategy to Reverse Mitochondrial Aging

Have you ever wondered how long you’re going to live? The potential answer can be found in the energy-producing cellular powerhouses called mitochondria.

According to a growing number of cell biologists, the number and functionality of the mitochondria specifically determine an individual’s life span.^1-3

When we’re young, we are relatively protected against mitochondrial deterioration. As we age, however, changes within our cells lead to the destruction of mitochondria—paving the way for aging and disease.^4-8

In 2007 scientists made a remarkable age-reversal discovery:

In this article, you’ll learn about a 3-step program aimed at restoring your body’s vital mitochondrial health:

Step 1: Boost your body’s natural mitochondrial DNA defenses with CoQ10.

Step 2: Stimulate the creation of new mitochondria with PQQ.

Step 3: Support your body’s mitochondrial defense system with shilajit.

This strategy to reduce damage to existing mitochondrial DNA and create new mitochondria—is essential to inhibit a destructive cycle believed to be a root cause of aging.

Why We Need Mitochondria

 

Found inside the body’s cells, mitochondria are responsible for producing our primary source of energy, adenosine triphosphate (ATP). ATP provides at least 95% of the cellular energy that powers all living functions.

Unfortunately, a byproduct of this energy generation is the formation of a huge stream of free radicals.^4-7 Free radicals are molecules that possess a free electron—a property that makes them react with other molecules in volatile and highly destructive ways.^10-12

Free radicals attack the structure of our cell membranes, creating metabolic waste products that disturb DNA and RNA production, interfere with the synthesis of protein, and destroy important cellular enzymes. Vital tissues and molecules decay under the assaults of free radicals.^10-14 In addition, free-radical disruption of cell mechanics creates mutant cells, which are linked to cancer and cellular aging.^15,16

Mitochondria are the easiest targets of free-radical injury for two reasons:

1. They are located exactly where these free radicals are produced, and
2. They lack most of the antioxidant defenses found in other parts of the cell.^17,18

Evidence strongly indicates that over time, accumulated damage to the DNA of the mitochondria in particular leads directly to metabolic disorders (such as diabetes) and degenerative disorders (such as Alzheimer’s).^4-8,19-23

Mitochondrial dysfunction is primarily seen in organs and tissues that have a high demand for energy—explaining why cardiovascular tissue and brain neurons are among the most susceptible.²⁴

When we’re young, we are largely protected against mitochondrial deterioration because our bodies produce substances to defend mitochondria from the onslaught of free radicals. However, as we age, that protection wanes, setting us up for a destructive cycle that accelerates aging and disease. As a result of this rapidly accelerating process, mitochondria in the cells of elderly people are mostly dysfunctional, whereas young individuals have virtually no mitochondrial damage.^8,25-27

The Mitochondrial Theory of Aging

 

Over time, there are three devastating changes within our cells that lead to the destruction of mitochondria—paving the way for aging and disease:^4-7

• The rate of cellular production of two free radicals—superoxide anions and hydrogen peroxide —significantly increases, attacking mitochondria the most.
• At the same time, intracellular levels of endogenous antioxidants that help prevent the harmful effects of free radicals decrease. There’s also a reduction in activities of free radical-scavengers that neutralize free radicals before they can attach themselves to other molecules. These decreases diminish the mitochondria’s normal defenses.
• The accumulated oxidative damage to the mitochondrial DNA and other mitochondrial components (as well as the cell as a whole) leads to decay of the mitochondria—and from that decay, the release of even more free radicals!

According to the mitochondrial theory of aging, this ever-increasing spiral is—in itself—an aging process.^{4-8, 25,26} In fact, a growing number of cell biologists have suggested that the number and functionality of the mitochondria can specifically determine an individual’s longevity.^1-3

Based on this body of scientific evidence, scientists determined that a key to slowing—and even reversing—a “natural” aging process would be a substance aimed at revitalizing youthful mitochondrial protection from free radicals.²⁷

They discovered this mitochondrial solution in a substance that may already be in your nutrient regimen…coenzyme Q10.

What You Need to Know

Block Mitochondrial Aging

• Daily damage to mitochondrial DNA appears to be a root mechanism of aging.
• If caught before it becomes permanent, early stage mitochondrial dysfunction can be reversed!
• Levels of CoQ10—the body’s natural mitochondrial defense—decline rapidly with age. But breakthrough research has found that supplemental CoQ10 blocks mitochondrial aging.
• Shilajit works synergistically with CoQ10 by replenishing its electron supply and increasing CoQ10 levels.
• PQQ powerfully supports the protection afforded by CoQ10 and shilajit by triggering the creation of new mitochondria.
• Taken together, CoQ10, PQQ, and shilajit offer a potent program to inhibit the intensely destructive cycle believed to be one of the root sources of aging!

Coenzyme Q10 Protects Mitochondria

Scientists have established that coenzyme Q10 (CoQ10) is an essential nutrient for normal mitochondrial function (namely, the production and transfer of energy).^28-30 When CoQ10 levels fall, mitochondrial dysfunction skyrockets.²⁸ Studies have found that boosting CoQ10 levels via supplementation increases mitochondrial electron transport—whether the cells are deficient in CoQ10 or not.^29,30

CoQ10’s ability to protect the vital mitochondria helps put an end to the vicious cycle that underscores a critical aspect of pathological aging. In fact, research with laboratory models has suggested that CoQ10 may be one of our most potent anti-aging nutrients. Studies have found that when cells or organisms are deficient in CoQ10, mitochondrial oxidative stress increases and aging is accelerated.^28,31 However, supplementation triggers a significant slowing down of the aging process and an extended life span.^32,33

One study showed that rats supplemented with CoQ10 experience a 24% increase in maximum life span and an 11.7% increase in average life span.³⁴ In human terms, based on today’s life expectancy of 78.5 years, this mean increase translates to a more than 9-year increase in life span!³⁵

CoQ10 also seems to work via a multi-targeted set of epigenetic mechanisms that not only slow aging—but that also protect against a variety of mitochondria-related diseases.^36-38 Epigenetic mechanisms involve changes in gene function that do not relate to changes in gene structure.³⁹ Studies have shown that CoQ10 protects against neurodegenerative diseases^40-42 and mental health disorders,⁴³ enhances lung function,^44,45 guards against the effects of elevated glucose in diabetes and metabolic syndrome,^46-48 and offers impressive defense against cardiovascular disease, one of the primary diseases of aging.^49-51

Animal studies demonstrate that supplementation with CoQ10 reduces oxidative stress and reduces the buildup of amyloid-beta plaque (associated with Alzheimer’s disease)^40-42,52,53 —resulting in a significant improvement in cognitive performance and memory.⁵³

In human studies, 4 weeks to 6 months of CoQ10 supplementation at 60-300 milligrams a day was shown to improve cardiac systolic function and ejection fraction.^49,50 One study showed that 8 weeks of CoQ10 supplementation at 300 milligrams a day improved heart-muscle systolic function by enhancing both mitochondrial performance and endothelial function.⁵⁰ And in a 5-year, randomized, double-blind, placebo-controlled trial among elderly individuals, CoQ10 combined with selenium slashed the death rate from cardiovascular disease by more than half!⁵⁴ In fact, the authors of one study recognized CoQ10 as a “scientific breakthrough in the management of chronic heart failure.”⁵⁵

CoQ10 offers a powerful way to help slow—or even reverse—a natural aging process by restoring youthful mitochondrial protection from free radicals.^27,56

CoQ10: Potential Therapy for Inherited Mitochondrial Disorder

Newly released research underscores the vital importance of coenzyme Q10 (CoQ10) to mitochondrial health.

A study released ahead of print in April 2013 by the journal Mitochondrion has found that patients with mitochondrial DNA depletion syndrome (MDS) have significantly deficient levels of CoQ10.⁸⁵ MDS is a hereditary condition characterized by grossly reduced cellular levels of mitochrondrial DNA in infancy. MDS involves various progressive disorders that are often fatal in childhood.⁸⁶

Currently, there are no effective therapies available for MDS⁸⁶—but this recent finding indicates that CoQ10 could represent a candidate therapy for this condition.

The suggestion that CoQ10 may constitute a therapeutic hope for treating this serious mitochondrial-deficiency disorder demonstrates just how powerfully CoQ10 protects mitochondria.

This also underscores CoQ10’s vital importance in slowing or reversing the “natural” aging process in healthy individuals.

PQQ Creates New Mitochondria

While coenzyme Q10 optimizes mitochondrial function and protects them from free radical damage, scientists have found another coenzyme that triggers the creation of new mitochondria altogether.

A huge research advance in 2012 showed that the coenzyme pyrroloquinoline quinone (or PQQ) activates genes that induce mitochondrial biogenesis—the spontaneous formation of new mitochondria in aging cells!⁵⁷

This represents a major breakthrough in battling the mitochondrial destruction that underlies aging.

PQQ deficiency has a profound effect on your genes—especially those involved in cellular stress, cell signaling, transport of metabolites, and of course, the creation of new mitochondria.⁵⁷ Specifically, PQQ deficiency negatively affects the expression pattern of 438 genes—but research has found that this effect is reversed after supplementation with PQQ.⁵⁷

Prior to this breakthrough, some of the only scientifically validated ways to reliably stimulate the creation of new mitochondria were sustained calorie restriction or strenuous physical activity—both of which are too rigorous and impractical for most aging people.^58,59 PQQ now provides the most practical means of reversing the deadly decline in functional mitochondria that is the underlying cause of premature aging and degenerative disease.

Earlier findings repeatedly indicated PQQ’s central role as a potent growth factor.^60,61 In preclinical trials, when animals were deprived of dietary PQQ, they exhibited stunted growth, impaired conception rates, and most importantly, fewer mitochondria.^62-64 However, re-introducing PQQ into the diet reversed these effects—while simultaneously increasing mitochondrial number and energetic efficiency.^62,63

Like CoQ10, PQQ also actively supports the energy transfer within the mitochondria that supplies the body with most of its bioenergy. Its exceptional stability allows it to carry out thousands of these transfers without undergoing molecular breakdown. PQQ has been proven especially effective in neutralizing two of the most potent free radicals, the superoxide and hydroxyl radicals.⁶⁵

5,000 Times More Effective than Vitamin C!

Research demonstrates that PQQ is 30 to 5,000 times more efficient at reducing oxidation than other common antioxidants such as vitamin C.⁶⁰

In a revealing 2010 study, scientists reported that similar protection of mitochondrial function that is seen with some other compounds (such as quercetin, hydroxytyrosol, and resveratrol) at high dietary concentrations measured in millimoles occurs with PQQ at dietary concentrations measured in nanomoles.⁶⁶ In other words, it takes a million times more of these other compounds to have a mitochondria-protective effect equivalent to PQQ!

The revelation of its ability to favorably affect system-wide cell development, metabolism, and mitochondrial biogenesis helps explain the wealth of data on PQQ’s neuroprotective and cardioprotective benefits.

PQQ has now been shown to block the development of abnormal proteins linked with neurodegenerative diseases. For example, it prevents cellular damage and demise due to accumulation of amyloid beta protein associated with Alzheimer’s disease,^67,68 and of the alpha-synuclein protein that is associated with Parkinson’s disease.^57,69

In humans, supplementation with 20 milligrams a day of PQQ significantly improved cognitive function in middle-aged and elderly people. These results were amplified when the subjects also took 300 milligrams per day of CoQ10.⁷⁰

In animal studies, researchers investigating its impact on cardiovascular disease have demonstrated that PQQ reduces the size of the heart area damaged by acute heart attack and favorably decreases lipid peroxidation.⁷¹ PQQ also helps heart muscle cells resist acute oxidative stress—specifically by preserving and enhancing mitochondrial function.⁷²

Neither humans nor the bacteria that colonize the human digestive tract have demonstrated the ability to synthesize PQQ,⁷³ which has led researchers to classify it as an essential micronutrient. This means that the body can’t make enough of it for good health—and that supplementation is essential.⁷⁴

Shilajit Revitalizes CoQ10

Shilajit

We’ve already learned that CoQ10 protects mitochondria from free radical damage. It does this by “depleting” itself—by donating its own electrons to (and thus neutralizing) the flood of free radicals generated during cellular energy production. Of course, this results in depleted stores of active CoQ10.

Studies have detailed how shilajit, a phyto-mineral pitch substance found in the Himalayas,^75-77 stabilizes, revitalizes, and preserves CoQ10 in its active (ubiquinol) form, boosting the levels of CoQ10 available to protect against mitochondrial aging. ^78-81

Cutting-edge scientific evidence has demonstrated that components of shilajit serve as electron reservoirs, replenishing electrons lost by CoQ10 and allowing this vital coenzyme to remain active longer.^78-80

Shilajit’s potent support of CoQ10’s mitochondrial protection against aging was validated when laboratory mice were subjected to strenuous and stressful physical exercise. The combination of shilajit and CoQ10 resulted in 27% greater ATP energy production in muscle cells—and in 40% greater energy production in brain cells—than the energy increase measured in these tissues with CoQ10 alone.⁸⁰

In other research, mice were initially supplemented with oral CoQ10 alone. As expected, CoQ10 levels rose in heart, liver, and kidney tissue. Remarkably, when components from shilajit were added to the supplement, CoQ10 levels rose even further—as much as 29% in liver tissue.⁸¹

Another element of shilajit—fulvic acid—has been shown to further support this process by channeling other electron-rich shilajit components into the mitochondria to support CoQ10 and electron transfer.⁸² Fulvic acid also works independently to stimulate mitochondrial energy metabolism and protect mitochondrial membranes from oxidative damage.^82,83

In an unpublished study, people who took 200 milligrams of shilajit once daily for 15 days registered an increase in ATP levels in the blood after exercise. ⁸⁴

Ultimately, the synergistic effects of shilajit plus CoQ10—combined with the capacity of PQQ to create new mitochondria—offer an unparalleled option to protect mitochondrial DNA and combat aging!

Ubiquinol Provides Superior Bioavailability

Called a “coenzyme” because of its unique ability to participate in chemical reactions but remain at steady-state levels in the cell, coenzyme Q10 plays a central role in energy metabolism.^28-30

CoQ10’s ability to cycle back and forth between ubiquinone and ubiquinol accounts for many of its unique properties. Ubiquinol, with its ability to scavenge free radicals, is an electron donor, while ubiquinone is an electron acceptor. This remarkable ability to cyclically accept and donate electrons, as well as to effect complementary chemical reactions in the mitochondria, accounts for CoQ10’s unparalleled value to almost all life forms.

The chemical difference between ubiquinone and ubiquinol is that the ubiquinol compound contains two hydroxyl groups. These two hydroxyl groups enable ubiquinol to be more easily dissolved into water than ubiquinone, thus making it easier to assimilate, which helps explain why it is so much more bioavailable than ubiquinone.

In a side-by-side single-dose human study, ubiquinol absorption was compared directly to conventional CoQ10 (ubiquinone) using the same delivery system. Subjects were given either 100 mg of ubiquinol or 100 mg of ubiquinone. The findings showed that in aged test subjects, ubiquinol absorption was 60% greater in this single-dose side-by-side comparison.⁸⁷

A review of published studies on human subjects reveals that it requires very high doses of ubiquinone CoQ10 to achieve the same levels attainable with modest amounts of ubiquinol CoQ10.^88-92 Clinical studies using 1,200 and 2,400 mg per day of ubiquinone achieved CoQ10 blood levels similar to 150 and 300 mg per day respectively of ubiquinol.^88-91

Summary

According to the mitochondrial theory of aging, damage to mitochondrial DNA from the massive free-radical assault of cellular energy production is a root mechanism of aging. The body produces CoQ10 to protect mitochondrial DNA, but levels decline rapidly with age.

Scientists have discovered that it can take almost a decade for this aging damage to become permanent. The good news is that early stage mitochondrial dysfunction can be reversed!

Breakthrough research found that two coenzymes (CoQ10 and PQQ) can work together to protect mitochondria against free radical assaults—and to create new mitochondria in the process.

Supplemental coenzyme Q10 blocks mitochondrial aging, while PQQ triggers the creation of new mitochondria. In addition, shilajit works synergistically with CoQ10, replenishing its electrons and prolonging its antioxidative effectiveness.

Taken together, CoQ10 and PQQ and shilajit offer a potent program to inhibit—and reverse—the intensely destructive cycle that is believed to be a root source of aging!

If you have any questions on the scientific content of this article, please call a Life Extension^® Wellness Specialist at 1-866-864-3027.

References

1. Lanza IR, Nair KS. Mitochondrial function as a determinant of life span. Pflugers Arch. 2010 Jan;459(2):277-89.
2. Robb EL, Page MM, Stuart JA. Mitochondria, cellular stress resistance, somatic cell depletion and lifespan. Curr Aging Sci. 2009 Mar;2(1):12-27.
3. Alexeyev MF, LeDoux SP, Wilson GL. Mitochondrial DNA and aging. Clin Sci (Lond). 2004 Oct;107(4):355-64.
4. Wei YH, Lu CY, Lee HC, Pang CY, Ma YS. Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function. Ann NY Acad Sci. 1998 Nov 20;854:155-70.
5. Mandavilli BS, Santos JH, Van Houten B. Mitochondrial DNA repair and aging. Mutat Res. 2002 Nov 30;509(1-2):127-51.
6. Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000 Aug;29(3-4):222-30.
7. Wei YH, Lee HC. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood). 2002 Oct;227(9):671-82.
8. Hamilton ML, Van Remmen H, Drake JA, et al. Does oxidative damage to DNA increase with age? PNAS. 2001;98(18):10469-74.
9. Conley KE, Marcinek DJ, Villarin J. Mitochondrial dysfunction and age. Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):688-92.
10. Barja G. Free radicals and aging. Trends Neurosci. 2004 Oct;27(10):595-600.
11. Hekimi S, Lapointe J, Wen Y. Taking a “good” look at free radicals in the aging process. Trends Cell Biol. 2011 Oct;21(10):569-76.
12. Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med. 2013 Jul;60:1-4.
13. Sinha K, Das J, Pal PB, Sil PC. Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 2013 Mar 30. [Epub ahead of print]
14. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J. 2012 Jan;5(1):9-19.
15. Kumar A, Pant MC, Singh HS, Khandelwal S. Determinants of oxidative stress and DNA damage (8-OhdG) in squamous cell carcinoma of head and neck. Indian J Cancer. 2012 Jul-Sep;49(3):309-15.
16. Berquist BR, Wilson DM 3rd. Pathways for repairing and tolerating the spectrum of oxidative DNA lesions. Cancer Lett. 2012 Dec 31;327(1-2):61-72.
17. Barja G. Updating the Mitochondrial Free Radical Theory of Aging: An integrated view, key aspects, and confounding concepts. Antioxid Redox Signal. 2013 May 5. [Epub ahead of print]
18. Neustadt J, Pieczenik SR. Medication-induced mitochondrial damage and disease. Mol Nutr Food Res. 2008 Jul;52(7):780-8.
19. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989;1(8639):642-5.
20. Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78.
21. Picard M, Turnbull DM. Linking the metabolic state and mitochondrial DNA in chronic disease, health, and aging. Diabetes. 2013 Mar;62(3):672-8.
22. Scheffler K, Krohn M, Dunkelmann T, et al. Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis. Acta Neuropathol. 2012 Aug;124(2):199-208.
23. Maruszak A, Zekanowski C. Mitochondrial dysfunction and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Mar 30;35(2):320-30.
24. De Pauw A, Tejerina S, Raes M, Keijer J, Arnould T. Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. Am J Pathol. 2009 Sep;175(3):927-39.
25. Short KR, Bigelow ML, Kahl J, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA. 2005 Apr 12;102(15):5618-23.
26. Linnane AW, Kovalenko S, Gingold EB. The universality of bioenergetic disease: age-associated cellular bioenergetic degradation and amelioration therapy. Ann N Y Acad Sci. 1998 Nov 20;854:202-13.
27. Karbowski M, Neutzner A. Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathol. 2012 Feb;123(2):157-71.
28. Duberley KE, Abramov AY, Chalasani A, Heales SJ, Rahman S, Hargreaves IP. Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment. J Inherit Metab Dis. 2013 Jan;36(1):63-73.
29. Fernández-Ayala DJ, López-Lluch G, García-Valdés M, Arroyo A, Navas P. Specificity of coenzyme Q10 for a balanced function of respiratory chain and endogenous ubiquinone biosynthesis in human cells. Biochim Biophys Acta. 2005;1706:174-83.
30. López-Martín JM, Salviati L, Trevisson E, et al. Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis. Hum Mol Genet. 2007;16:1091-7.
31. Cordero MD, Cotán D, del-Pozo-Martín Y, et al. Oral coenzyme Q10 supplementation improves clinical symptoms and recovers pathologic alterations in blood mononuclear cells in a fibromyalgia patient. Nutrition. 2012 Nov-Dec;28(11-12):1200-3.
32. Takahashi M, Ogawara M, Shimizu T, Shirasawa T. Restoration of the behavioral rates and lifespan in clk-1 mutant nematodes in response to exogenous coenzyme Q(10). Exp Gerontol. 2012 Mar;47(3):276-9.
33. Ishii N, Senoo-Matsuda N, Miyake K, et al. Coenzyme Q10 can prolong C. elegans lifespan by lowering oxidative stress. Mech Ageing Dev. 2004 Jan;125(1):41-6.
34. Quiles JL, Ochoa JJ, Huertas JR, Mataix J. Coenzyme Q supplementation protects from age-related DNA double-strand breaks and increases lifespan in rats fed on a PUFA-rich diet. Exp Gerontol. 2004 Feb;39(2):189-94.
35. Available at: http://www.cdc.gov/nchs/fastats/lifexpec.htm. Accessed May 14, 2013.
36. Schmelzer C, Kohl C, Rimbach G, Doring F. The reduced form of coenzyme Q10 decreases the expression of lipopolysaccharide-sensitive genes in human THP-1 cells. J Med Food. 2011 Apr;14(4):391-7.
37. Santos-Gonzalez M, Gomez Diaz C, Navas P, Villalba JM. Modifications of plasma proteome in long-lived rats fed on a coenzyme Q10-supplemented diet. Exp Gerontol. 2007 Aug;42(8):798-806.
38. Lee BJ, Huang YC, Chen SJ, Lin PT. Effects of coenzyme Q10 supplementation on inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, and homocysteine) in patients with coronary artery disease. Nutrition. 2012 Jul;28(7-8):767-72.
39. McGowan PO, Kato T. Epigenetics in mood disorders. Environ Health Prev Med. 2008 Jan;13(1):16-24.
40. Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF. Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer’s disease. J Alzheimers Dis. 2008 Jun;14(2):225-34.
41. Moreira PI, Santos MS, Sena C, Nunes E, Seica R, Oliveira CR. CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol. 2005 Nov;196(1):112-9.
42. Yang X, Yang Y, Li G, Wang J, Yang ES. Coenzyme Q10 attenuates beta-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation. J Mol Neurosci. 2008 Feb;34(2):165-71.
43. Forester BP, Zuo CS, Ravichandran C, et al. Coenzyme Q10 effects on creatine kinase activity and mood in geriatric bipolar depression. J Geriatr Psychiatry Neurol. 2012 Mar;25(1):43-50.
44. Gvozdjáková A, Kucharská J, Bartkovjaková M, Gazdíková K, Gazdík FE. Coenzyme Q10 supplementation reduces corticosteroids dosage in patients with bronchial asthma. Biofactors. 2005;25(1-4):235-40.
45. Fujimoto S, Kurihara N, Hirata K, Takeda T. Effects of coenzyme Q10 administration on pulmonary function and exercise performance in patients with chronic lung diseases. Clin Investig. 1993;71(8 Suppl):S162-6.
46. Mezawa M, Takemoto M, Onishi S, et al. The reduced form of coenzyme Q10 improves glycemic control in patients with type 2 diabetes: an open label pilot study. Biofactors. 2012 Nov-Dec;38(6):416-21.
47. El-ghoroury EA, Raslan HM, Badawy EA, et al. Malondialdehyde and coenzyme Q10 in platelets and serum in type 2 diabetes mellitus: correlation with glycemic control. Blood Coagul Fibrinolysis. 2009 Jun;20(4):248-51.
48. Hodgson JM, Watts GF, Playford DA, Burke V, Croft KD. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr. 2002 Nov;56(11):1137-42.
49. Sander S, Coleman CI, Patel AA, Kluger J, White CM. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail. 2006 Aug;12(6):464-72.
50. Dai YL, Luk TH, Yiu KH, et al. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial. Atherosclerosis. 2011 Jun;216(2):395-401.
51. Mikhin VP, Kharchenko AV, Rosliakova EA, Cherniatina MA. Application of coenzyme Q(10) in combination therapy of arterial hypertension. Kardiologiia. 2011;51(6):26-31.
52. Yang X, Dai G, Li G, Yang ES. Coenzyme Q10 reduces beta-amyloid plaque in an APP/PS1 transgenic mouse model of Alzheimer’s disease. J Mol Neurosci . 2010 May;41(1):110-3.
53. Dumont M, Kipiani K, Yu F, et al. Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis. 2011;27(1):211-23.
54. Alehagen U, Johansson P, Bjornstedt M, Rosen A, Dahlstrom U. Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: A 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. Int J Cardiol. 2012 May 22.
55. Mortensen SA, et al. Coenzyme Q10: clinical benefits with biochemical correlates suggesting a scientific breakthrough in the management of chronic heart failure. Int J Tissue React. 1990;12(3):155-62.
56. Lenaz G, Bovina C, D’Aurelio M, et al. Role of mitochondria in oxidative stress and aging. Ann N Y Acad Sci. 2002 Apr;959:199-213.
57. Misra HS, Rajpurohit YS, Khairnar NP. Pyrroloquinoline-quinone and its versatile roles in biological processes. J Biosci. 2012 Jun;37(2):313-25.
58. Steiner JL, Murphy EA, McClellan JL, Carmichael MD, Davis JM. Exercise training increases mitochondrial biogenesis in the brain. J Appl Physiol. 2011 Oct;111(4):1066-71.
59. Guarente L. Mitochondria--a nexus for aging, calorie restriction, and sirtuins? Cell. 2008 Jan 25;132(2):171-6.
60. Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009 Sep;14(3):268-77.
61. Choi O, Kim J, Kim JG, et al. Pyrroloquinoline quinone is a plant growth promotion factor produced by Pseudomonas fluorescens B16. Plant Physiol. 2008 Feb;146(2):657-68.
62. Stites T, Storms D, Bauerly K, et al. Tchaparian. Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. J Nutr. 2006 Feb;136(2):390-6.
63. Steinberg F, Stites TE, Anderson P, et al. Pyrroloquinoline quinone improves growth and reproductive performance in mice fed chemically defined diets. Exp Biol Med (Maywood). 2003 Feb;228(2):160-6.
64. Bauerly KA, Storms DH, Harris CB, et al. Pyrroloquinoline quinone nutritional status alters lysine metabolism and modulates mitochondrial DNA content in the mouse and rat. Biochim Biophys Acta. 2006 Nov;1760(11):1741-8.
65. Urakami T, Yoshida C, Akaike T, Maeda H, Nishigori H, Niki E. Synthesis of monoesters of pyrroloquinoline quinone and imidazopyrroloquinoline, and radical scavenging activities using electron spin resonance in vitro and pharmacological activity in vivo. J Nutr Sci Vitaminol (Tokyo). 1997 Feb;43(1):19-33.
66. Tchaparian E, Marshal L, Cutler G, et al. Identification of transcriptional networks responding to pyrroloquinoline quinone dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways. Biochem J. 2010 Aug 1;429(3):515-26.
67. Zhang JJ, Zhang RF, Meng XK. Protective effect of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Neurosci Lett. 2009 Oct 30;464(3):165-9.
68. Kim J, Kobayashi M, Fukuda M, et al. Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins. Prion. 2010 Jan;4(1):26-31.
69. Kobayashi M, Kim J, Kobayashi N, et al. Pyrroloquinoline quinone (PQQ) prevents fibril formation of alpha-synuclein. Biochem Biophys Res Commun. 2006 Oct 27;349(3):1139-44.
70. Nakano M, Ubukata K, Yamamoto T, Yamaguchi H. Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons. FOOD Style 21. 2009;13(7):50-3.
71. Zhu BQ, Simonis U, Cecchini G, et al. Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther. 2006 Jun;11(2):119-28.
72. Tao R, Karliner JS, Simonis U, et al. Pyrroloquinoline quinone preserves mitochondrial function and prevents oxidative injury in adult rat cardiac myocytes. Biochem Biophys Res Commun. 2007 Nov 16;363(2):257-62.
73. Smidt CR, Bean-Knudsen D, Kirsch DG, Rucker RB. Does the intestinal microflora synthesize pyrroloquinoline quinone? Biofactors.1991 Jan;3(1):53-9.
74. Zhang Y, Rosenberg PA. The essential nutrient pyrroloquinoline quinone may act as a neuroprotectant by suppressing peroxynitrite formation. Eur J Neurosci. 2002 Sep;16(6):1015-24.
75. Schepetkin IA, Xie G, Jutila MA, Quinn MT. Complement-fixing activity of fulvic acid from Shilajit and other natural sources. Phytother Res. 2009 Mar;23(3):373-84.
76. Goel RK, Banerjee RS, Acharya SB. Antiulcerogenic and antiinflammatory studies with shilajit. J Ethnopharmacol. 1990 Apr;29(1):95-103.
77. Agarwal SP, Khanna R, Karmarkar R, Anwer MK, Khar RK. Shilajit: a review. Phytother Res. 2007 May;21(5):401-5.
78. Ghosal S. Shilajit in Perspective. Oxford, U.K.: Narosa Publishing House; 2006.
79. Islam A, Ghosh R, Banerjee D, Nath P, Mazumder U, Ghosal S. Biotransformation of 3-hydroxydibenzo-pyrone into 3,8 dihydroxydibenzo-pyrone and aminoacyl conjugates by Aspergillus niger isolated from native “shilajit.” Electro J Biotechno. 2008 Jul 15;11(3):2-10.
80. Bhattacharyya S, Pal D, Gupta AK, Ganguly P, Majumder UK, Ghosal S. Beneficial effect of processed shilajit on swimming exercise induced impaired energy status of mice. Pharmacologyonline. 2009;1:817-25.
81. Bhattacharyya S, Pal D, Banerjee D, et al. Shilajit dibenzo—pyrones: Mitochondria targeted antioxidants. Pharmacologyonline. 2009; 2:690-8.
82. Kang SH, Choi W. Oxidative degradation of organic compounds using zero-valent iron in the presence of natural organic matter serving as an electron shuttle. Environ Sci Technol. 2009 Feb 1;43(3):878-83.
83. Visser SA. Effect of humic substances on mitochondrial respiration and oxidative phosphorylation. Sci Total Environ. 1987 Apr;62:347-54.
84. Pal D, Bhattacharya S. Pilot Study on the Improvement of Human Performance with ReVitalETTM as Energy Booster: Part-IV. 2006. Data on file. Natreon, Inc.
85. Montero R, Grazina M, López-Gallardo E, et al. Coenzyme Q10 deficiency in mitochondrial DNA depletion syndromes. Mitochondrion. 2013 Apr 11.
86. Available at: http://rarediseasesnetwork.epi.usf.edu/namdc/learnmore/diseases.htm. Accessed May 15, 2013.
87. Age difference of bioavailability. Unpublished data, Kaneka Corp.
88. Hosoe K, Kitano M, Kishida H, et al. Study on safety and bioavailability of ubiquinol (Kaneka QH(trade mark)) after single and 4-week multiple oral administration to healthy volunteers. Regul Toxicol Pharmacol. 2006 Aug 17.
89. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50.
90. Shults CW, Flint BM, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol. 2004 Aug;188(2):491-4.
91. Kurowska EM, Dresser G, Deutsch L, Bassoo E, Freeman DJ. Relative bioavailability and antioxidant potential of two coenzyme q10 preparations. Ann Nutr Metab. 2003;47(1):16-21.
92. Shults CW, Haas RH, Beal MF. A possible role of coenzyme Q10 in the etiology and treatment of Parkinson’s disease. Biofactors. 1999;9(2-4):267-72.