Powerful Protection Against Cellular Aging

Reposted from Life Extension
http://www.lef.org/magazine/mag2012/oct2012_Powerful-Protection-Against-Cellular-Aging_01.htm

By Michael Downey

 

Conclusive evidence now indicates that PQQ (pyrroloquinoline quinone) activates cell signaling pathways that have the potential to reverse cellular aging!1
PQQ has previously been shown to promote growth of new mitochondria within aging cells,1-3 up-regulate cellular metabolism,1,2 protect neurons,4-7 and repair DNA!1,8
These and other synergistic signaling effects have the combined ability to promote longevity at the critical subcellular level.
PQQ has been found in all plant species ever tested. Scientists have gone so far as to state that PQQ may be "vital to life."3

An Essential Anti-Aging Nutrient

Scientists have found that PQQ, a critical coenzyme, plays a leading role in boosting critical cell signaling mechanisms.3
These signaling pathways regulate a variety of physiological and molecular processes throughout the body10—processes that have an impact on key biomarkers of aging, such as mitochondrial function11-16 and cellular defense against oxidative stress.10

Through these effects, the cell signaling power of PQQ targets aging at both the cellular and subcellular levels.
New research confirm that humans can obtain these multiple benefits after even just short-term supplementation.17
A wealth of studies now confirm that PQQ's cell-signaling activity translates into substantial protection against degenerative and age-related conditions, such as mitochondrial dysfunction,1 heart degeneration,18-20 brain injury, and cognitive decline.21-40 As one example, research shows that 20 mg of PQQ daily may reverse age-related cognitive decline in aging humans!
Since PQQ cannot be synthesized by your body it is necessary to obtain PQQ from outside sources.24,41-43 Fortunately, compared to other plant compounds, PQQ has greater solubility and bioavailability. PQQ is water-soluble and therefore, more easily absorbed at low supplemental intakes.1,44,45
Let's take a look at the modes of action behind PQQ's multiple effects.

PQQ and Cell Signaling

How can PQQ target multiple aging factors?
The answer lies in the potent and unique capacity of PQQ to activate cell signaling pathways, especially those directly involved in cellular energy metabolism.
Also, similar to the action of CoQ10, PQQ actively participates in the energy transfer within the mitochondria that supplies the body with most of its bioenergy.
PQQ can even trigger spontaneous mitochondrial biogenesis—the creation of fresh, new mitochondria!
Specific cell signaling molecules have been found to be directly activated by PQQ.

Cell Signaling Pathways

Early studies revealed that animals deprived of PQQ exhibit signs of accelerated aging in the form of elevated plasma glucose concentrations, impaired oxygen metabolism, stunted growth, compromised immunity, impaired reproductive capability, reduced numbers and survival rate of offspring, and a decrease in energy-producing mitochondria in their tissue. Reintroducing PQQ to their diet reversed these effects, increasing mitochondrial numbers and restoring systemic function.46-48
PQQ is now linked to favorable effects on cell development, metabolism, and mitochondrial biogenesis. It provides the potential to reverse cellular aging and age-related disease by:

• Stimulating spontaneous growth of new mitochondria within aging cells.1
• Regulating gene expression.3
• Promoting tumor cell death from apoptosis.49
• Supporting mitochondrial protection and repair.1
• Providing powerful antioxidant support to mitochondria and other body molecules—with up to 5,000 times the effect of other antioxidants,4 and protecting the brain's cells and neurotransmitter systems against neurotoxicity5,39,50 and amyloid-beta protein.36

The end result of PQQ's activity is subcellular anti-aging and enhanced longevity.
(For more on these beneficial pathways, see previous box titled, 'PQQ and Cell Signaling.')

Heart Benefits

PQQ's cell signaling activities produce measurable health improvements, especially cardio-protective and neuro-protective benefits.
For example, research with animals found that supplementation with PQQ decreased the size of the area of the heart injured by acute coronary artery blockage. This protective effect was found whether PQQ was given before or after the event—suggesting taking PQQ within the first hours following a cardiac event could deliver invaluable benefit to patients.18
Following up on this research, scientists then tested both PQQ and the common post-heart-attack treatment metoprolol (Lopressor®). They found that, while both reduced the size of the damaged area, there was a greater increase in mitochondrial energy-producing functions with PQQ.
And only PQQ lowered lipid peroxidation!
The study team concluded that "PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage."19
These same scientists found in later animal research, that "PQQ reduces oxidative stress, mitochondrial dysfunction, and cell death" in cardiac muscle cells.20

What You Need to Know

PQQ: Powerful Protection Against Cellular Aging

• Pyrroloquinoline quinone (PQQ) activates a number of vital, cell signaling pathways involved in protecting against cellular aging!
• PQQ-powered signaling mechanisms create fresh mitochondria,1-3 upregulate cellular metabolism,1,2 improve cognitive performance and protect neurons,4-7 and repair DNA damage!8
• These synergistic effects deliver substantial, subcellular anti-aging and enhanced longevity.
• Evidenced by studies verifying its wide cardioprotective and neuroprotective effects, PQQ beneficially modulates a host of key biomolecular functions!

Brain Effects

Scientists found in pre-clinical trials that PQQ reversed cognitive impairment caused by oxidative stress and improved performance on memory tests.21 PQQ was shown to protect against a pathologic gene protein associated with Parkinson's disease. 22 Much of the long-term neurological damage that arises after a stroke or spinal cord injury is caused by reactive nitrogen species which impose severe stresses on damaged neurons. However, PQQ was found to suppress reactive nitrogen species in induced strokes.24
PQQ also blocked a source of reactive nitrogen species following spinal cord injury.25 Researchers concluded that PQQ significantly reduces the size of the damaged area of the brain even if administered 3 hours after the stroke!27 Additionally, it provides potent protection against the inflammation and oxidative damage that results from the sudden return of blood and nutrients to tissues deprived of them by stroke.26 It would seem that PQQ should become a standard nutrient in the hospital emergency room setting for rapid administration to stroke victims.

PQQ and Mitochondrial Biogenesis

Greater mitochondrial damage has been found in brain cells of humans over 70 relative to those in their early 40s. Many scientists believe mitochondrial longevity and the number of functioning mitochondria determine overall human longevity.51-53
The coenzyme PQQ, has been shown to induce mitochondrial biogenesis—the growth of new mitochondria in aging cells.
While coenzyme Q10, or CoQ10, optimizes the function of mitochondria, PQQ activates genes that govern mitochondrial reproduction, protection, and repair.
To date, the only ways known to reliably stimulate mitochondrial biogenesis have been sustained calorie restriction or strenuous physical activity—potentially too rigorous for aging individuals.
With its power to safely trigger mitochondrial biogenesis, PQQ represents an extraordinary advance in the quest to reverse cellular aging.

Illustrating its cell signaling mechanism, PQQ protects neurons by modifying a key receptor site within our brain's neurotransmitter system.28,29 This inhibits excitotoxicity, a response to long-term over-stimulation of neurons that is associated with many neurodegenerative diseases and seizures.30-32
PQQ was shown to block neurotoxicity induced by other toxins, including mercury, a factor suspected to play a role in the development of Alzheimer's disease.5,33
Accumulating research indicates that PQQ serves as an intervention in Alzheimer's and Parkinson's disease—blocking development, and oxidative effects, of both the amyloid beta protein associated with Alzheimer's and the alpha-synuclein protein associated with Parkinson's, before they can cause damage.34-37
PQQ has been observed to deliver substantial cognitive benefits, including improved memory and attention.9,38 It activates the manufacture and release of an important, neuro-protective, nerve growth factor.38 Scientists tested PQQ's cognitive effects in a double-blind, placebo-controlled clinical trial conducted on humans. In this study of healthy individuals ranging from 45 to 65 years of age, 20 mg a day of PQQ produced clear improvements on standard tests of greater cognitive function. Also, the PQQ test group scored two-fold higher on memory tests than the control group.9
Scores were dramatically higher for a third group that received 300 mg per day of CoQ10 along with their 20 mg of PQQ. This underscores the powerful cognitive benefits of supplementation with agents shown to be involved in mitochondrial energy production.9

PQQ and Gene Expression

Recent rodent research on gene expression has shown that an induced deficiency of the coenzyme pyrroloquinoline quinone, or PQQ, results in an altering of the expression of a total of 438 genes.54 When the diet is then supplemented with PQQ, the genetic expression pattern reverts to normal. On investigation, the genes most affected by PQQ turned out to be those responsible for:58

• Cell signaling
• Cellular stress
• Growth of new mitochondria
• MAP kinase pathways (cell-surface-to-nucleus signaling proteins)
• Transport of metabolites

These findings shed light on PQQ's genetic involvement with cell signaling, antioxidant activity, and mitochondrial biogenesis.

Summary

Through its broad cell signaling activity, PQQ (pyrroloquinoline quinone) modulates the many pathways of aging!
Scientific findings indicate that PQQ-enhanced signaling stimulates mitochondrial biogenesis,1-3 boosts cellular metabolism,1, improves cognitive performance and protects neurotransmitters, 4-7 and repairs DNA!8
Together, these mechanisms support subcellular anti-aging and promote longevity.
Studies have shown that PQQ beneficially modulates biomolecular functions that result in substantial heart and brain defense. As one example, scientists found that PQQ helped produce remarkable reversal of cognitive decline in aging humans!9
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

Protecting Mitochondrial DNA

Degradation of mitochondrial DNA leads to mitochondria senescence and death—and extinction of the "host" organism.
As the power generators responsible for almost all bioenergetic production, mitochondria are the site of enormous oxidative activity. A nearly incalculable number of electrons are constantly flowing within the mitochondria, throwing off an equally enormous number of free radicals.
As a result, mitochondria are much more vulnerable to biochemical insults than other cellular structures.
And as scientists have discovered over the past several decades, mitochondrial DNA—relative to genetic DNA in the cell's nucleus (nuclear DNA)—possesses few defenses against free radical damage.55,56
Nuclear DNA is protected by numerous guardian proteins—histones and repair enzymes—that blunt the impact of free radicals. Similar repair systems do not exist to protect mitochondrial DNA.55-57
Also, nuclear DNA is housed within a protective double-membrane that separates it from the rest of the cell. This double-membrane is complemented by a dense matrix of filament proteins called the nuclear lamina, a kind of hard shell casing to further buffer DNA from external impacts.
By comparison, mitochondrial DNA is left almost entirely exposed. It is attached directly to the inner membrane where the mitochondria's electrochemical furnace rages continuously, generating an enormous volume of toxic reactive oxygen species.
The mitochondria rank among the physiological structures most vulnerable to destruction from oxidative damage.
And scientific studies link genetic mutation within the mitochondria to human aging.57-59
PQQ's formidable free radical-scavenging capacity furnishes the mitochondria with superior antioxidant protection.
As a bioactive coenzyme, PQQ supports optimal function within the mitochondria which is responsible for supplying the body with most of its bioenergy.60
Unlike other antioxidant compounds, PQQ's ex-ceptional stability allows it to carry out thousands of these electron transfers without undergoing molecular breakdown.
In fact, PQQ is up to 5,000 times more efficient in sustaining antioxidant capacity than other common antioxidant compounds, such as ascorbic acid.4

References

1. 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-1alpha expression. J Biol Chem. 2010 Jan 1;285(1):142-52.
2. Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ. 2006 Dec;30(4):145-51.
3. Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009;14:268-77.
4. 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.
5. 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 Radical Research. 2009 Mar;43(3):224-33.
6. Hara H, Hiramatsu H, Adachi T. Pyrroloquinoline quinone is a potent neuroprotective nutrient against 6-hydroxydopamine-induced neurotoxicity. Neurochemical Research. 2007 Mar;32(3):489-95.
7. Zhang JJ, Zhang RF, Meng XK. Protective effect of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Neurosc Lett. 2009 Oct 30;464(3):165-9.
8. Available at: http://www.ncbi.nlm.nih.gov/gene/1387. Accessed July 5, 2012.
9. 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.
10. Misra HS, Rajpurohit YS, Khairnar NP. Pyrroloquinoline-quinone and its versatile roles in biological processes. J Biosci. 2012 Jun;37(2):313-25.
11. Cortez E, Neves FA, Bernardo AF, et al. Lymphocytes mitochondrial physiology as biomarker of energy metabolism during fasted and fed conditions. ScientificWorldJournal. 2012;2012:629326. Epub 2012 Mar 12.
12. 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.
13. Lanza IR, Nair KS. Mitochondrial metabolic function assessed in vivo and in vitro. Curr Opin Clin Nutr Metab Care. 2010 Sept;13(5):511.
14. 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 Sept;32(2):337-46.
15. Tranah G. Mitochondrial-nuclear epistasis: Implications for human aging and longevity. Ageing Res Rev. 2010 Jun 25.
16. Cho DH, Nakamura T, Lipton SA. Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci. 2010 Oct;67(20):3435-47.
17. Rucker RB, Harris C, Chowanadisai W, Slupsky C. Pyrroloquinoline quinone (PQQ) and indicators of antioxidant potential, inflammation and metabolism in humans. FASEB J. 2012 April;26[Suppl]:363.1.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. Zhang L, Liu J, Cheng C, et al. The neuroprotective effect of pyrroloquinoline quinone on traumatic brain injury. J Neurotrauma. 2012 Mar 20;29(5):851-64. Epub 2011 Dec 20.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. Hossain MA. Molecular mediators of hypoxic-ischemic injury and implications for epilepsy in the developing brain. Epilepsy Behav. 2005 Sep;7(2):204-13.
31. 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.
32. 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.
33. 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.
34. Kim J, Harada R, Kobayashi M, Kobayashi N, Sode K. The inhibitory effect of pyrroloquinoline quinone on the amyloid formation and cytotoxicity of truncated alpha-synuclein. Mol Neurodegener. 2010 May 20;5:20.
35. 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.
36. 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.
37. Kim J, Kobayashi M, Fukuda M, et al. Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins. Prion. 2010 Jan;4(1):26-31.
38. 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.
39. Scanlon JM, Aizenman E, Reynolds IJ. Effects of pyrroloquinoline quinone on glutamate-induced production of reactive oxygen species in neurons. Eur J Pharmacol. 1997;326(1):67-74.
40. 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.
41. Bishop A, Gallop PM, Karnovsky ML. Pyrroloquinoline quinone: a novel vitamin? Nutr Rev. 1998 Oct;56(10):287-93.
42. Smidt CR, Bean-Knudsen D, Kirsch DG, Rucker RB. Does the intestinal microflora synthesize pyrroloquinoline quinone? Biofactors.1991 Jan;3(1):53-9.
43. Smidt CR, Steinberg FM, Rucker RB. Physiologic importance of pyrroloquinoline quinone. Proc Soc Exp Biol Med. 1991 May;197(1):19-26.
44. Smidt CR, Unkefer CJ, Houck DR, Rucker RB. Intestinal absorption and tissue distribution of [14C] pyrroloquinoline quinone in mice. Proc Soc Exp Biol Med. 1991 May;197(1):27-31.
45. Das S, Lin HS, Ho PC, Ng KY. The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharm Res. 2008 Nov;25(11):2593-600.
46. 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.
47. 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.
48. 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.
49. Shankar B, Pandey R, Amin P, Misra HS, Sainis KB. Role of glutathione in augmenting the anticancer activity of pyrroloquinoline quinone (PQQ). Redox Rep. 2010;15:146-54.
50. 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.
51. Lanza IR, Nair KS. Mitochondrial function as a determinant of life span. Pflugers Arch. 2010 Jan;459(2):277-89.
52. 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.
53. Alexeyev MF, LeDoux SP, Wilson GL. Mitochondrial DNA and aging. Clin Sci (Lond). 2004 Oct;107(4):355-64.
54. Tchaparian E, Marshal L, Cutler G, et al. Identification of transcriptional networks responding to pyrroloquinoline quinine dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways. Biochem J. 429:515-26.
55. Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol. 1995 Jul;27(7):647-53.
56. Miquel J. An update on the mitochondrial-DNA mutation hypothesis of cell aging. Mutat Res.1992 Sep;275(3-6):209-16.
57. 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.
58. Lee HC, Wei YH. Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging. Exp Biol Med (Maywood). 2007 May;232(5):592-606.
59. 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.
60. Bauerly K, Harris C, Chowanadisai W, et al. Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PLoS One. 2011;6(7):e21779. Epub 2011 Jul 21.