Life Extension Magazine 2010
Rejuvenate Your Cells by Growing New Mitochondria
By Kirk Stokel
Mitochondrial dysfunction is a primary cause of age-related decline.1-7 In a revealing study, a team of researchers showed that muscle tissue of a 90-year-old man contained 95% damaged mitochondria compared to almost no damage in that of a 5-year-old.8
When one looks at the boundless energy of a child compared to an elderly person, the devastating impact of mitochondrial degradation become instantly apparent. A myriad of recent scientific reports link defective and deficient mitochondria to virtually all degenerative diseases including Alzheimer’s, type 2 diabetes, heart failure, and cancer.9-13
Up until now, the best we could do was protect and improve the function of existing mitochondria using nutrients like L-carnitine, lipoic acid, and coenzyme Q10.
In an unprecedented breakthrough, a compound has been discovered that promotes the growth of new mitochondria structures within aging cells!14
In this article, you will discover how this novel compound can help reverse cellular aging by activating genes that stimulate mitochondrial biogenesis, which means the generation of new mitochondria.
The more functional mitochondria you have in your cells, the greater your overall health and durability.
Mitochondria are the only cell components (other than the nucleus) to possess their own DNA. This means mitochondria have the ability to replicate and increase their number within a single human cell.
Human cells may house anywhere from 2 to 2,500 mitochondria,15-17 depending on tissue type, antioxidant status, and other factors.
A growing number of biologists espouse the theory that mitochondrial number and function determine human longevity.18-20 To put it simply, the more functional mitochondria you have in your cells, the greater your overall health and durability.
The problem is that as we age, our mitochondria degrade and become dysfunctional. Age-related destruction of the mitochondria occurs more rapidly than in other cell components, meaning that for most people it is loss of functional mitochondria that ultimately leads to personal extinction.
The challenge aging humans face is that methods to increase the generation of new mitochondria are difficult to adhere to. Up until recently, the only natural ways to stimulate mitochondrial biogenesis were calorie restriction or exhaustive physical activity.
A natural agent with the power to safely induce mitochondrial biogenesis would mark an extraordinary advance in the quest to halt and reverse cellular aging. A compound called pyrroloquinoline quinone or PQQ is rapidly emerging as that nutrient.
PQQ: A Quantum Leap That May Reverse Cellular Aging
PQQ (pyrroloquinoline quinone) plays a critical role across a range of basic life functions. As an ultra potent antioxidant, it provides extraordinary defense against mitochondrial decay: PQQ’s chemical structure enables it to withstand exposure to oxidation up to 5,000 times greater than vitamin C.21
When combined with CoQ10, research shows just 20 mg per day of PQQ can significantly preserve and enhance memory, attention, and cognition in aging humans.22
But the most exciting revelation on PQQ emerged early in 2010, when researchers found it not only protected mitochondria from oxidative damage—it also stimulated growth of new mitochondria!14
PQQ Is an Essential Micronutrient
PQQ is ubiquitous in the natural world. It has been found in all plant species tested and is present in human milk. Humans, however, are not capable of synthesizing it.23 This has led researchers to classify PQQ as an essential micronutrient.
PQQ’s potential to stimulate mitochondrial biogenesis was foreshadowed by early findings indicating its central role in growth and development across multiple forms of life.
PQQ has been shown to be a potent growth factor in plants, bacteria, and higher organisms.21,24,25 Pre-clinical studies reveal that when deprived of dietary PQQ, animals exhibit stunted growth, compromised immunity, impaired reproductive capability, and most importantly, fewer mitochondria in their tissue. Rates of conception, the number of offspring, and survival rates in juvenile animals are also significantly reduced in the absence of PQQ.26-28
When PQQ is introduced back into the diet, it reverses these effects, restoring systemic function while simultaneously increasing mitochondrial number and energy efficiency.
These compelling data prompted a team of researchers at the University of California-Davis to specifically analyze PQQ’s influence on cell signaling pathways involved in the formation of new mitochondria.14
Their work, published last year, led to several extraordinary discoveries. They found that PQQ’s critical biological roles stem from its ability to activate genes directly involved in cellular energy metabolism, development, and function.14
Their findings shed light on results from favorable prior studies. For example, PQQ deficiency in juvenile mice results in a 20-30% reduction in the number of mitochondria in the liver, elevated blood glucose, and impairment in oxygen metabolism.26 These are hallmark indicators of mitochondrial dysfunction. Yet when PQQ was put back into the diet, these pathological effects were reversed, along with an increase observed of new mitochondria.
This and additional animal model data28 taken together confirm PQQ’s ability to significantly boost mitochondrial number and function—a key to cellular anti-aging and longevity.
The sidebar on the below reveals the complex mechanisms by which PQQ activates genes that stimulate mitochondrial biogenesis.
Protecting Against Mitochondria-generated Free Radicals
As the primary energy engines of our cells, the mitochondria rank among the structures most vulnerable to destruction from oxidative damage.
The formidable free radical-scavenging capacity of PQQ furnishes the mitochondria considerable antioxidant protection.
At the core of this capacity is an extraordinary molecular stability.35 As a bioactive coenzyme, PQQ actively participates in the energy transfer within the mitochondria that supplies the body with most of its bioenergy (like CoQ10).
Unlike other antioxidant compounds, the stability of PQQ allows it to carry out thousands of electron transfers without undergoing molecular breakdown. It has been proven especially effective in neutralizing the ubiquitous superoxide and hydroxyl radicals.36 According to the most recent research, “PQQ is 30 to 5,000 times more efficient in sustaining redox cycling . . . than other common [antioxidant compounds], e.g. ascorbic acid.”37
Protection Against Brain Aging
PQQ has been shown to optimize function of the entire central nervous system. It reverses cognitive impairment caused by chronic oxidative stress in pre-clinical models, improving performance on memory tests.40 It has also been shown to safeguard a gene involved in the development of Parkinson’s disease (called DJ-1) from self-oxidation—an early step in the onset of Parkinson’s.41
Reactive nitrogen species (RNS), like reactive oxygen species, impose severe stresses on damaged neurons.42 They arise spontaneously following stroke and spinal cord injuries and have been shown to account for a substantial proportion of subsequent long-term neurological damage. PQQ directly suppresses RNS in experimentally induced strokes.43 It also provides additional protection by blocking gene expression of inducible nitric oxide synthase, a major source of RNS, following spinal cord injury.44
PQQ protects brain cells against damage following ischemia-reperfusion injury—the inflammation and oxidative damage that result from the sudden return of blood and nutrients tissues deprived of them by stroke.45 Given immediately before induction of stroke in animal models, PQQ significantly reduces the size of the damaged brain area.46 This finding implies that if a person were to suffer a temporary loss of cerebral blood flow due to cardiac arrest, stroke, or trauma, that having PQQ in their body would afford considerable protection against permanent brain damage.
PQQ also beneficially interacts with brain neurotransmitter systems. In particular, PQQ protects neurons by modifying the important NMDA receptor site.47,48 NMDA is a powerful mediator of “excitotoxicity,” a response to long-term overstimulation of neurons that is associated with many neurodegenerative diseases and seizures.49-51 PQQ protects against neurotoxicity induced by other toxins, including mercury.52,53
A mounting body of evidence points to PQQ as a potent intervention in Alzheimer’s and Parkinson’s disease. Both are triggered by accumulation of abnormal proteins that initiate a cascade of oxidative events resulting in brain cell death.
PQQ prevents development of alpha-synuclein, the protein responsible for Parkinson’s disease.54 It also protects nerve cells from the oxidizing ravages of the Alzheimer’s-causing amyloid-beta protein.55 A 2010 study revealed that PQQ could prevent formation of amyloid-beta molecular structures.56 These effects were traced to three distinct biochemical mechanisms described in the sidebar above.
PQQ has also been shown to protect memory and cognition in aging animals and humans.22,57 It stimulates production and release of nerve growth factor in cells that support neurons in the brain.58 This may partially explain why PQQ supplementation of aging rats resulted in marked retention of their maximum memory function.57
In humans, supplementation with 20 mg per day of PQQ resulted in improvements on tests of higher cognitive function in a group of middle-aged and elderly people.22 These effects were significantly amplified when the subjects also took 300 mg per day of CoQ10. Presumably a lower dose of the more absorbable ubiquinol form of CoQ10 would provide the same benefit as 300 mg of ubiquinone.
PQQ has also been shown to protect memory and cognition in both aging animals and humans.
As with strokes, damage in heart attacks is inflicted via ischemia-reperfusion injury. Ischemia-reperfusion means loss of blood flow (ischemia) to part of the body and the subsequent re-flow (reperfusion) when blood flow is restored. Cells are injured when blood flow is interrupted and often sustain even greater damage when blood flow is suddenly restored.
Supplementation with PQQ reduces the size of ischemia-reperfusion damaged areas in animal models of acute myocardial infarction (heart attack).59 This occurs whether the supplement is given before or after the ischemic event itself.
To further investigate this potential, researchers at the VA Medical Center at UC-San Francisco compared PQQ with metoprolol, a commonly prescribed beta blocker that is standard post-heart attack clinical treatment.60 Given alone, both treatments reduced the damaged areas’ size and protected against heart muscle dysfunction. When they were given together, the left ventricle’s pumping pressure was enhanced. The combination also increased mitochondrial energy-producing functions—but the effect was small compared with the better response seen with PQQ alone!60 And only PQQ favorably reduced lipid peroxidation. The remarkable conclusion: “PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage.”60
Subsequent research from the same team has demonstrated that PQQ helps heart muscle cells resist acute oxidative stress.61 The mechanism? Preserving and enhancing mitochondrial function.
Cellular aging is intimately associated with the decline in mitochondrial number and functionality. Nutrients that provide protection to existing mitochondria include resveratrol, carnosine, lipoic acid, L-carnitine, and CoQ10.
During the course of normal aging, however, the number of functional mitochondria pathologically diminishes, leading to a host of debilitating disorders followed by death of the organism.
For the first time in scientific history, a natural compound called PQQ is available to increase the functionality of existing mitochondria while promoting the generation of new mitochondria inside aging cells.
If you have questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
1. Bliznakov EG. Aging, mitochondria, and coenzyme Q(10): the neglected relationship. Biochimie. 1999 Dec;81(12):1131-2.
2. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989 Mar 25;1(8639):642-5.
3. Lanza IR, Nair KS. Mitochondrial metabolic function assessed in vivo and in vitro. Curr Opin Clin Nutr Metab Care. 2010 Jul 7.
4. Mota MP, Peixoto FM, Soares JF, et al. Influence of aerobic fitness on age-related lymphocyte DNA damage in humans: relationship with mitochondria respiratory chain and hydrogen peroxide production. Age (Dordr). 2010 Mar 20.
5. Tranah G. Mitochondrial-nuclear epistasis: Implications for human aging and longevity. Ageing Res Rev. 2010 Jun 25.
6. Cho DH, Nakamura T, Lipton SA. Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci. 2010 Jun 25.
7. Wei YH, Ma YS, Lee HC, Lee CF, Lu CY. Mitochondrial theory of aging matures—roles of mtDNA mutation and oxidative stress in human aging. Zhonghua Yi Xue Za Zhi (Taipei). 2001 May;64(5):259-70.
8. 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.
9. Bugger H, Abel ED. Mitochondria in the diabetic heart. Cardiovasc Res. 2010 Jul 16.
10. Conley KE, Amara CE, Jubrias SA, Marcinek DJ. Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo. Exp Physiol. 2007 Mar;92(2):333-9.
11. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL. Mitochondrial dysfunction in cardiac disease: ischemia—reperfusion, aging, and heart failure. J Mol Cell Cardiol. 2001 Jun;33(6):1065-89.
12. Maruszak A, Zekanowski C. Mitochondrial dysfunction and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Jul 15.
13. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann N Y Acad Sci. 2006 May;1067:182-90.
14. Chowanadisai W, Bauerly KA, Tchaparian E, Wong A, Cortopassi GA, Rucker RB. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1 alpha expression. J Biol Chem. 2010 Jan 1;285:142-52.
15. Bruce A, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. New York, NY: Garland Publishing, Inc.;1994.
16. Voet D, Voet JG, Pratt CW. Fundamentals of Biochemistry: Life at the Molecular Level. 2nd ed. New Jersey: John Wiley and Sons, Inc.; 2006:547.
17. Pike RL, Brown M. Nutrition: An Integrated Approach. New York, NY: Prentice-Hall; 1984:450-84.
18. Lanza IR, Nair KS. Mitochondrial function as a determinant of life span. Pflugers Arch. 2010 Jan;459(2):277-89.
19. Robb EL, Page MM, Stuart JA. Mitochondria, cellular stress resistance, somatic cell depletion, and life span. Curr Aging Sci. 2009 Mar;2(1):12-27.
20. Alexeyev MF, LeDoux SP, Wilson GL. Mitochondrial DNA and aging. Clin Sci. 2004;107:355-364.
21. Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009 Sep;14(3):268-77.
22. Nakano M, Ubukata K, Yamamoto T, Yamaguchi H. Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons. FOOD Style. 2009;21:13(7):50-3.
23. Smidt CR, Bean-Knudsen D, Kirsch DG, Rucker RB. Does the intestinal microflora synthesize pyrroloquinoline quinone? Biofactors.1991 Jan;3(1):53-9.
24. Stites TE, Mitchell AE, Rucker RB. Physiological importance of quinoenzymes and the O-quinone family of cofactors. J Nutr. 2000 Apr;130(4):719-27.
25. 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.
26. Stites T, Storms D, Bauerly K, et al. Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. J Nutr. 2006 Feb;136(2):390-6.
27. 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.
28. 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.
29. Entrez Gene: PPARGC1A peroxisome proliferator-activated receptor gamma, coactivator 1 alpha [ Homo sapiens ] GeneID: 10891.
30. Entrez Gene: CREBBP CREB binding protein [ Homo sapiens ] GeneID: 1387.
31. Zhong N, Xu J. Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1alpha: regulation by SUMOylation and oxidation. Hum Mol Genet. 2008 Nov 1;17(21):3357-67.
32. Mitsumoto A, Nakagawa Y. DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin. Free Rad Res. 2001; 35(6):885-93.
33. Nunome K, Miyazaki S, Nakano M, Iguchi-Ariga S, Ariga H. Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1. Biol Pharm Bull. 2008 Jul;31(7):1321-6.
34. Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H. DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. 2004 Feb;5(2):213-8.
35. Paz MA, Martin P, Fluckiger R, Mah J, Gallop PM. The catalysis of redox cycling by pyrroloquinoline quinone (PQQ), PQQ derivatives, and isomers and the specificity of inhibitors. Anal Biochem. 1996;238:145-9.
36. 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.
37. Stites TE, Mitchell AE, Rucker RB. Physiological importance of quinoenzymes and the O-quinone family of cofactors. J Nutr. 2000 Apr;130(4):719-27.
38. Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol. 1995;27:647-53.
39. Miquel J. An update on the mitochondrial-DNA mutation hypothesis of cell aging. Mutat Res. 1992 Sep;275(3-6):209-16.
40. Ohwada K, Takeda H, Yamazaki M, et al. Pyrroloquinoline quinone (PQQ) prevents cognitive deficit caused by oxidative stress in rats. J Clin Biochem Nutr. 2008 Jan;42:29-34.
41. Nunome K, Miyazaki S, Nakano M, Iguchi-Ariga S, Ariga H. Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1. Biol Pharm Bull. 2008 Jul;31(7):1321-6.
42. Ono K, Suzuki H, Sawada M. Delayed neural damage is induced by iNOS-expressing microglia in a brain injury model. Neurosci Lett. 2010 Apr 5;473(2):146-50.
43. 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.
44. Hirakawa A, Shimizu K, Fukumitsu H, Furukawa S. Pyrroloquinoline quinone attenuates iNOS gene expression in the injured spinal cord. Biochem Biophys Res Commun. 2009 Jan 9;378(2):308-12.
45. Jensen FE, Gardner GJ, Williams AP, Gallop PM, Aizenman E, Rosenberg PA. The putative essential nutrient pyrroloquinoline quinone is neuroprotective in a rodent model of hypoxic/ischemic brain injury. Neuroscience. 1994 Sep;62(2):399-406.
46. Zhang Y, Feustel PJ, Kimelberg HK. Neuroprotection by pyrroloquinoline quinone (PQQ) in reversible middle cerebral artery occlusion in the adult rat. Brain Res. 2006 Jun 13;1094(1):200-6.
47. Aizenman E, Hartnett KA, Zhong C, Gallop PM, Rosenberg PA. Interaction of the putative essential nutrient pyrroloquinoline quinone with the N-methyl-D-aspartate receptor redox modulatory site. J Neurosci. 1992 Jun;12(6):2362-9.
48. Aizenman E, Jensen FE, Gallop PM, Rosenberg PA, Tang LH. Further evidence that pyrroloquinoline quinone interacts with the N-methyl-D-aspartate receptor redox site in rat cortical neurons in vitro. Neurosci Lett. 1994 Feb 28;168(1-2):189-92.
49. Hossain MA. Molecular mediators of hypoxic-ischemic injury and implications for epilepsy in the developing brain. Epilepsy Behav. 2005 Sep;7(2):204-13.
50. Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009 Apr;30(4):379-87.
51. Foran E, Trotti D. Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxid Redox Signal. 2009 Jul;11(7):1587-602.
52. Hara H, Hiramatsu H, Adachi T. Pyrroloquinoline quinone is a potent neuroprotective nutrient against 6-hydroxydopamine-induced neurotoxicity. Neurochem Res. 2007 Mar;32(3):489-95.
53. Zhang P, Xu Y, Sun J, Li X, Wang L, Jin L. Protection of pyrroloquinoline quinone against methylmercury-induced neurotoxicity via reducing oxidative stress. Free Radic Res. 2009 Mar;43(3):224-33.
54. 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.
55. 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.
56. Kim J, Kobayashi M, Fukuda M, et al. Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins. Prion. 2010 Jan;4(1):26-31.
57. Takatsu H, Owada K, Abe K, Nakano M, Urano S. Effect of vitamin E on learning and memory deficit in aged rats. J Nutr Sci Vitaminol (Tokyo). 2009;55(5):389-93.
58. Murase K, Hattori A, Kohno M, Hayashi K. Stimulation of nerve growth factor synthesis/secretion in mouse astroglial cells by coenzymes. Biochem Mol Biol Int. 1993 Jul;30(4):615-21.
59. Zhu BQ, Zhou HZ, Teerlink JR, Karliner JS. Pyrroloquinoline quinone (PQQ) decreases myocardial infarct size and improves cardiac function in rat models of ischemia and ischemia/reperfusion. Cardiovasc Drugs Ther. 2004 Nov;18(6):421-31.
60. 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.
61. 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.